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WO2023250431A2 - Multi-cyclic irak and flt3 inhibiting compounds and uses thereof - Google Patents

Multi-cyclic irak and flt3 inhibiting compounds and uses thereof Download PDF

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Publication number
WO2023250431A2
WO2023250431A2 PCT/US2023/068897 US2023068897W WO2023250431A2 WO 2023250431 A2 WO2023250431 A2 WO 2023250431A2 US 2023068897 W US2023068897 W US 2023068897W WO 2023250431 A2 WO2023250431 A2 WO 2023250431A2
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WO
WIPO (PCT)
Prior art keywords
inhibitor
compound
alkyl
halogen
flt3
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PCT/US2023/068897
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French (fr)
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WO2023250431A3 (en
Inventor
Craig Joseph THOMAS
Scott Bryan HOYT
Daniel T. STARCZYNOWSKI
Jan Susan Rosenbaum
Original Assignee
Children's Hospital Medical Center
The United States Of America, As Represented By The Secretary, Department Of Health And Human Servic
Kurome Therapeutics, Inc.
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Application filed by Children's Hospital Medical Center, The United States Of America, As Represented By The Secretary, Department Of Health And Human Servic, Kurome Therapeutics, Inc. filed Critical Children's Hospital Medical Center
Publication of WO2023250431A2 publication Critical patent/WO2023250431A2/en
Publication of WO2023250431A3 publication Critical patent/WO2023250431A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present disclosure generally relates to compounds and compositions which are kinase inhibitors and the use of the same in treating diseases and disorders, including cancers.
  • MDS Myelodysplastic syndromes
  • AML acute myeloid leukemia
  • sAML chemotherapy-resistant secondary acute myeloid leukemia
  • MDS are heterogeneous diseases with few treatment options, as there is a lack of effective medicines capable of providing a durable response.
  • Current treatment options for MDS are limited but include allogeneic HSC transplantation, demethylating agents, and immunomodulatory therapies (Ebert, 2010).
  • HSC hemopoietic stem cell
  • HSC clones can persist in the marrow even after HSC transplantation, and the disease invariably advances (Tehranchi et al., 2010).
  • AML hematopoietic stem/progenitor cell
  • R 14 are each independently selected from 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, wherein 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 is optionally substituted with one or more halogen and/or C 1 -C
  • the compound of Formula (I) is a compound of Formula (IIi): Formula (IIi), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R 20i is selected from C 1 -C 6 alkyl and C 1 - C 6 alkoxy, wherein C 1 -C 6 alkyl and C 1 -C 6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen; R 211 , R 22i , and R 23i are each independently selected from H and halogen; and R 24ia, R 24ib , R 25ia , R 25ib , R 26ia , and R 26ib are each independently selected from H, halogen, -OH, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy, wherein C 1 -C 6 alkyl and C 1 -C 6 alkoxy are
  • the compound is a compound of Formula (IIi), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, with the proviso that when R 20i is R 21i is halogen and R 22i and R 23i are each H; or R 23i is halogen and R 21i and R 22i are each H.
  • R 21i is halogen, R 22i and R 23i are each H; or R 23i is halogen, R 21i and R 22i are each H.
  • one or more of R 24ia , R 24ib , R 25ia , R 25ib , R 26ia , and R 26ib is halogen.
  • At least one of (i)-(iv) applies: (i) R 20i is (ii) R 21i is F, R 22i and R 23i are each H; (iii) R 23i is F, R 21i and R 22i are each H; (iv) R 24ia , R 25ia , R 25ib , R 26ia , R 26ib are each H and R 24ib is F.
  • the compound of Formula (IIi) is selected from:
  • the compound of Formula (I) is a compound of Formula (Ilj):
  • the compound is a compound of Formula (IIj) with the proviso that when R20j is , R j s aogen and R22j and R23j are each H; or R23j is halogen and R21j and R22j are each H.
  • R21j is halogen
  • R22j and R23j are each H; or R 23j is halogen
  • R 21j and R 22j are each H.
  • one or more of R 24ja , R24jb, R25ja, R25jb, R26ja, R26jb, R27ja, R27jb, R28ja, and R28jb is halogen.
  • At least one of (i)-(v) applies: (i) R20j is F, R22j and R23j are each H; (iii) R23j is F, R21j R R and R22j are each H; (iv) R24jb, R25ja, R25jb, R26ja, R26jb , E R27ja, R27jb, R28ja, and R28jb is H; (v) is 4jb, R25ja, R25jb, R26ja, R26jb, R27ja, R28ja, and R28jb is H and R27jb is F.
  • the compound of Formula (IIj) is selected from: .
  • the compound of Formula (IIi), (IIj), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof is an inhibitor of at least one of IRAK1, IRAK4, and FLT3.
  • the compound of Formula (IIi), (IIj), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof is an inhibitor of IRAKI and IRAK4.
  • the compound of Formula (IIi), (Ilj), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof is an inhibitor of IRAKI, IRAK4, and FLT3.
  • the present disclosure provides a composition
  • a composition comprising a compound of any one of Formula (IIi), (Ilj), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, wherein the composition further comprises a formulary ingredient, an adjuvant, or a carrier.
  • the composition is used in combination with one or more of: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, 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, an mAbs/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 glu
  • the composition is used in combination with at least one of a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor.
  • the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof
  • the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof
  • the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone or a pharmaceutically acceptable salt of any one thereof
  • the CDK inhibitor is selected from CDK4/6 inhibitor Palbociclib, CDK7 inhibitor THZ1, and/or CDK9 inhibitors BAY1251152 and Atuveciclib, or a pharmaceutically acceptable salt of any one thereof
  • the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof.
  • the present 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 any one of Formula (IIi), (Ilj), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or a composition comprising a compound of any one of Formula (IIi), (Ilj), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof.
  • the method comprises administering to the subject a composition comprising the therapeutically effective amount of the compound of Formula (I), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and a formulary ingredient, an adjuvant, or a carrier.
  • the disease or disorder is responsive to at least one of interleukin- 1 receptor-associated kinase (IRAK) inhibition and fms-like tyrosine kinase 3 (FLT3) inhibition.
  • IRAK interleukin- 1 receptor-associated kinase
  • FLT3 fms-like tyrosine kinase 3
  • the disease or disorder comprises a hematopoietic cancer.
  • the disease or disorder comprises myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML).
  • the disease or disorder comprises lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL with MYD88 mutation, follicular lymphoma, or marginal zone lymphoma.
  • CLL chronic lymphocytic leukemia
  • CML chronic myeloid leukemia
  • ALL acute lymphoblastic leukemia
  • bone marrow cancer non-Hodgkin lymphoma
  • Waldenstrom’s macroglobulinemia B cell lymphoma
  • DLBCL diffuse large B-cell lymphoma
  • DLBCL with MYD88 mutation follicular lymphoma
  • marginal zone lymphoma or marginal zone lymphoma
  • the disease or disorder comprises at least one cancer selected from glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, Glioma, oral cancer, nasopharyngeal carcinoma, rectal cancer, stomach cancer, and uterine cancer, or combinations thereof.
  • cancer selected from glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma
  • the disease or disorder comprises one or more inflammatory diseases or autoimmune disease 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 mellitus, Crohn’s disease, colitis, or combinations thereof.
  • inflammatory diseases or autoimmune disease 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 mellitus, Crohn’s disease, colitis, or combinations thereof.
  • the method further comprises administering to the subject one or more additional therapies selected from: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, 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, an mAbs/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 steadren
  • the additional therapy is at least one of a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor.
  • the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof
  • the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof
  • the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone, or a pharmaceutically acceptable salt of any one thereof
  • the CDK inhibitor is selected from CDK4/6 inhibitor palbociclib, CDK7 inhibitor THZ1, and/or CDK9 inhibitors BAY1251152 and atuveciclib, or a pharmaceutically acceptable salt of any one thereof
  • the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof.
  • the disease or disorder is BCL2 inhibitor resistant acute myeloid leukemia (AML) and/or FLT3 inhibitor resistant AML.
  • compound of any one of Formula (IIi), (Ilj), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof or the composition comprising a compound of any one of Formula (IIi), (Ilj), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and the one or more additional therapies are administered together in one administration or composition.
  • the compound of any one of Formula (IIi), (Ilj), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof or the composition comprising a compound of any one of Formula (IIi), (Ilj), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and the one or more additional therapies are administered separately in more than one administration or more than one composition.
  • the disease or disorder is alleviated by inhibiting at least one of IRAKI, IRAK4, and FLT3 in the subject.
  • the disease or disorder is alleviated by inhibiting IRAKI and IRAK4 in the subject.
  • the disease or disorder is alleviated by inhibiting IRAKI, IRAK4, and FLT3 in the subject.
  • the present disclosure provides a method of increasing survivability in a subject diagnosed with acute myeloid leukemia (AML) or suspected of having AML, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of Formula (IIi), (Ilj), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or a composition comprising a compound of any one of Formula (IIi), (Ilj), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof.
  • AML acute myeloid leukemia
  • the survivability of the subject is increased compared to a subject treated with a therapeutically effective amount of the standard of care for AML.
  • the standard of care for AML comprises gilteritinib or a pharmaceutically acceptable salt thereof.
  • the subject is a human.
  • the subject is a human and the survivability of the subject is increased by about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, about 11 years, about 12 years, about 13 years, about 14 years, about 15 years, about 16 years, about 17 years, about 18 years, about 19 years, or about 20 years compared to a subject treated with a therapeutically effective amount of the standard of care for AML.
  • the method comprises administering to the subject the therapeutically effective amount of a compound of any one of Formula (IIi), (Ilj), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or a composition comprising a compound of any one of Formula (IIi), (Ilj), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereofabout every 6 hours, every 12 hours, every 18 hours, once a day, every other day, every 3 days, every 4 days, every 5 days, every 6 days, or once a week.
  • the method further comprises administering to the subject one or more additional therapies selected from: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, 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, an mAbs/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 steadren
  • the additional therapy is at least one of a BCL2 inhibitor, a BTK inhibitor, a gluococorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor.
  • the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof
  • the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof
  • the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone, or a pharmaceutically acceptable salt of any one thereof
  • the CDK inhibitor is selected from CDK4/6 inhibitor palbociclib, CDK7 inhibitor THZ1, and/or CDK9 inhibitors BAY1251152 and atuveciclib, or a pharmaceutically acceptable salt of any one thereof
  • the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof.
  • the AML is BCL2 inhibitor resistant and/or FLT3 inhibitor resistant.
  • the compound of any one of Formula (IIi), (Ilj), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof or the composition comprising a compound of any one of Formula (IIi), (Ilj), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and the one or more additional therapies are administered together in one administration or composition.
  • the compound of any one of Formula (IIi), (Ilj), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof or the composition comprising a compound of any one of Formula (IIi), (Ilj), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and the one or more additional therapies are administered separately in more than one administration or more than one composition.
  • the survivability is increased by inhibiting at least one of IRAKI, IRAK4, and FLT3 in the subject. In one embodiment, the survivability is increased by inhibiting IRAKI and IRAK4 in the subject.
  • the survivability is increased by inhibiting IRAKI, IRAK4, and FLT3 in the subject.
  • the compound is a compound of any one of Formula (Ila)-(IIj), Formula (Illa)-(IIIp), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof.
  • FIG. 1 depicts the combination outcomes for representative compounds with Venetoclax in the Cell Titer Gio assay in THP1 cells at 48 hours.
  • Panel A depicts the relative Excess HSA values for Compounds 35 and 82 in comparison to representative FLT3 inhibitors.
  • a negative Excess HSA score illustrates that the drug combination is better than either drug alone, wherein greater synergy is observed at larger negative values of the Excess HSA score.
  • Panel B depicts the relative concentration (nM) of CG-806, Compound 82, Compound 35, Gilteritinib hemifumerate, or emavusertib (CA-4948), respectively, to potentiate ( ⁇ 30%) of the 1250 nM Venetoclax Cell Titer Gio response at 48 hours. A smaller concentration indicates higher potency to synergize with Venetoclax.
  • Panels C and D illustrate the concentration ranges over which the combination of Venetoclax and either Compound 82 (Panel C) or Compound 35 (Panel D) are studied in a 10 x 10 combination matrix.
  • the numbers in each cell represent the % response (left) or the Delta Bliss score (right) at each given concentration combination.
  • the number contained within the circle represents the resultant response at which the indicated concentrations of each agent reduce the activity of 1250 nM of Venetoclax to ⁇ 30%.
  • FIG. 2 depicts the combination outcomes for representative compounds with Venetoclax in the Cell Titer Gio assay in MOLM 14 FLT3 ITD (D835Y) cells at 48 hours.
  • Panel A depicts the relative Excess HSA values for Compounds 35 and 82 in comparison to representative FLT3 inhibitors.
  • a negative Excess HSA score illustrates that the drug combination is better than either drug alone, wherein greater synergy is observed at larger negative values of the Excess HSA score.
  • Panel B depicts the relative concentration (nM) of Compound 82, CG-806, Compound 35, Gilteritinib hemifumerate, or emavusertib (CA-4948), respectively, to potentiate ( ⁇ 10%) of the 125 nM Venetoclax Cell Titer Gio response at 48 hours. A smaller concentration indicates higher potency to synergize with Venetoclax.
  • Panels C and D illustrate the concentration ranges over which the combination of Venetoclax and either Compound 82 (Panel C) or Compound 35 (Panel D) are studied in a 10 x 10 combination matrix.
  • the numbers in each cell represent the % response (left) or the Delta Bliss score (right) at each given concentration combination.
  • the number contained within the circle represents the resultant response at which the indicated concentrations of each agent reduce the activity of 125 nM of Venetoclax to ⁇ 10%.
  • FIG. 3 provides the structures of gilteritinib and emavusertib (CA-4948).
  • FIG. 4 demonstrates that mice treated with Compound 82 have improved survival compared to those treated with either vehicle or emavusertib (CA-4948). Survival data for 80 days of mice engrafted survival of mice intravenously engrafted with M0LM14 FLT3-ITD (D835Y) AML cells and treated orally once/day M-F with Compound 82 (at 10 mg/kg) vs. control vehicle, gilteritinib standard of care (SOC, at 30 mg/kg), and emavusertib (CA-4948) (at 30 mg/kg) are illustrated. At the 10 mg/kg dose, enhanced survival is seen with Compound 82 vs. control vehicle as well as vs. emavusertib (CA-4948) but not vs. Gilteritinib.
  • FIGS. 5A-5B are charts depicting the leukemic grade of mice studied at the time of necropsy. When adjusting for survival, all treated animals show significant improvement compared to controls.
  • FIG. 5A Leukemic grade at the time of necropsy (the statistical analysis used was mean with 95% confidence interval).
  • FIG. 5B Survival-adjusted leukemic grade at the time of necropsy (the statistical analysis used was geometric mean with geometric SD).
  • Gilteritinib and emavusertib (CA-4948) were each administered at 30 mg/kg while Compound 82 was administered at 10 mg/kg.
  • inventive compounds e.g., compounds of Formula (I), Formula (Ila)-(IIj), Formula (IITa)-(IIIp)
  • compositions e.g., pharmaceutical compositions
  • compositions for treating, for example, certain diseases using the inventive compounds include methods of using the inventive compound (e.g., in compositions or in pharmaceutical compositions) for administering and treating. Further embodiments include methods for making the inventive compound. Yet further embodiments include methods for determining whether a particular patient is likely to be responsive to such treatment with the inventive compounds and compositions.
  • substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH 2 O- is equivalent to -OCH 2 -.
  • alkyl means a monovalent, straight or branched hydrocarbon chain, which can be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e., C1-C10 means one to ten carbons).
  • C1-C10 means one to ten carbons.
  • C 1 -C 7 alkyl or C 1 - C4 alkyl refer to straight- or branched-chain saturated hydrocarbon groups having from 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.
  • C 1 -C 7 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.
  • alkenyl means a monovalent, straight or branched hydrocarbon chain that includes one or more (e.g., 1, 2, 3, or 4) double bonds. Double bonds can occur in any stable point along the chain and the carbon-carbon double bonds can have either the cis or trans configuration.
  • this definition shall include 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, l-pentenyl-3-cyclohexenyl, and the like.
  • heteroalkenyl refers to heteroalkyl having one or more double bonds.
  • 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.
  • alkynyl means a monovalent, straight or branched hydrocarbon chain that includes one or more (e.g., 1, 2, 3, or 4) triple bonds and that also may optionally include one or more (e.g. 1, 2, 3, or 4) double bonds in the chain.
  • 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.
  • alkoxy means any of the above alkyl, alkenyl, or alkynyl groups which is attached to the remainder of the molecule by an oxygen atom (alkyl-O-).
  • alkoxy groups include, but are not limited to, methoxy (sometimes shown as MeO-), ethoxy, isopropoxy, propoxy, and butyloxy.
  • alkylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, alkenyl, or alkynyl group, as exemplified, but not limited by, -CH 2 CH 2 CH 2 CH 2 -.
  • an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those 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 eight or fewer carbon atoms.
  • cycloalkyl means a monovalent, monocyclic or bicyclic, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 membered hydrocarbon group.
  • the rings can be saturated or partially unsaturated.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and bicycloalkyls (e.g., bicyclooctanes such as [2.2.2]bicyclooctane or [3.3.0]bicyclooctane, bicyclononanes such as [4.3.0]bicyclononane, and bicyclodecanes such as [4.4.0]bicyclodecane (decalin), or spiro compounds).
  • the ring is not aromatic.
  • bicyclic cycloalkyl if one ring is aromatic, then the other is not aromatic.
  • a bicyclic cycloalkyl one or both rings can be substituted.
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, consisting of at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, and wherein the nitrogen and sulfur atoms can optionally be oxidized, and the nitrogen heteroatom can optionally be quatemized.
  • the heteroatom(s) O, N, P, S, and Si can be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule.
  • -CH CH-N(CH 3 )-CH 3 , -O-CH 3 , -O-CH 2 -CH 3 , and -CN.
  • Up to two heteroatoms can be consecutive, such as, for example, -CH 2 -NH-OCH 3 .
  • heteroalkylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH 2 -CH 2 -S-CH 2 -CH 2 - and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -.
  • heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like).
  • heteroalkyl groups include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', -NR'R", -OR', -SR', and/or -SO 2 R'.
  • heteroalkyl is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R" or the like, it will be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R" or the like.
  • halogen means monovalent Cl, F, Br, or I. Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 ) a lkyl includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3- bromopropyl, and the like.
  • aryl means a monovalent, monocyclic or bicyclic, 5, 6, 7, 8, 9, 10, 11, or 12 member aromatic hydrocarbon group and also means polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently.
  • a fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring.
  • Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tolyl, and xylyl. For an aryl that is bicyclic, one or both rings can be substituted.
  • heteroaryl means a monovalent, monocyclic or bicyclic, 5, 6, 7, 8, 9, 10, 11, or 12 membered, hydrocarbon group, where 1, 2, 3, 4, 5, or 6 carbon atoms are replaced by a hetero atom independently selected from nitrogen, oxygen, or sulfur atom, and the monocyclic or bicyclic ring system is aromatic.
  • Heteroaryl groups (or rings) can contain from one to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quatemized.
  • heteroaryl includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring).
  • 5.6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a
  • 6.6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring.
  • a 6,5- fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring.
  • a heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom.
  • heteroaryl groups include, but are not limited to, thienyl (or thiophenyl), furyl, indolyl, pyrrolyl, pyridinyl, pyrazinyl, oxazolyl, thiaxolyl, quinolinyl, pyrimidinyl, imidazolyl, triazolyl, tetrazolyl, lH-pyrazol-4-yl, l-Me-pyrazol-4-yl, pyridin-3-yl, pyridin-4-yl, 3,5- dimethylisoxazolyl, lH-pyrrol-3-yl, 3,5-di-Me-pyrazolyl, and lH-pyrazol-4-yl.
  • bicyclic heteroaryl if one ring is aryl, then the other is heteroaryl.
  • one or both rings can have one or more hetero atoms.
  • one or both rings can be substituted.
  • arylene and a “heteroarylene,” alone or as part of another substituent mean a divalent radical derived from an aryl and heteroaryl, respectively. Accordingly, the term “aryl” can represent an unsubstituted, mono-, di- or trisubstituted monocyclic, polycyclic, biaryl and heterocyclic aromatic groups covalently attached at any ring position capable of forming a stable covalent bond, certain preferred points of attachment being apparent to those skilled in the art (e. g. 3-indolyl, 4-imidazolyl).
  • the aryl substituents are independently selected from the group consisting of halo, nitro, cyano, trihalomethyl, C 1-16 alkyl, aryl C 1-16 alkyl, C 0-16 alkyloxyC 0-16 alkyl, arylC 0-16 alkyloxyC 0-16 alkyl, C 0- i6alkylthioC 0-16 alkyl, arylC 0-16 alkylthioC 0-16 alkyl, C 0- 16 alky laminoC 0-16 alkyl, arylC 0-16 alkylaminoC 0-16 alkyl, di(arylC 1-16 alkyl) a minoC 0-16 alkyl, C 1 - 16 alky IcarbonylC 0-16 alkyl, aryl C 1-16 alkylcarbonylC 0-16 alkyl, C 1-16 alkylcarboxyC 0-16 alkyl, arylC 1 - 16 alky IcarboxyC
  • aryl when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above.
  • arylalkyl e.g., benzyl, phenethyl, pyridylmethyl, and the like
  • alkyl group e.g., benzyl, phenethyl, pyridylmethyl, and the like
  • alkyl groups e.g., benzyl, phenethyl, pyridylmethyl, and the like
  • an oxygen atom e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(l- naphthyloxy)propyl, and the like
  • sulfur atom e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(l- naphthyloxy)propyl, and the like
  • arylalkyl e.g. (4-hydroxyphenyl)ethyl, (2-aminonaphthyl)hexyl, pyridylcyclopentyl
  • arylalkyl represents an aryl group as defined above attached through an alkyl group as defined above having the indicated number of carbon atoms.
  • Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1 -cyclohexenyl, 3 -cyclohexenyl, cycloheptyl, and the like.
  • heterocycloalkyl or “heterocyclyl” means a monovalent, monocyclic or bicyclic, 5, 6, 7, 8, 9, 10, 11, or 12 membered, hydrocarbon, where 1, 2, 3, 4, 5, or 6 carbon atoms are replaced by a hetero atom independently selected from nitrogen atom, oxygen atom, or sulfur atom, and the monocyclic or bicyclic ring system is not aromatic. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
  • heterocycloalkyl examples include, but are not limited to, l-(l,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, pyrolidinyl (e.g., pyrrolidin-l-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, or pyrrolidin- 4-yl), piperazinyl (e.g., piperazin- 1-yl, piperazin-2-yl, piperazin-3 -yl, or piperazin-4-yl), piperidinyl (e.g.,
  • a bicyclic heterocyclyl if one ring is aromatic (e.g., monocyclic aryl or heteroaryl), then the other ring is not aromatic.
  • one or both rings can have one or more hetero atoms.
  • one or both rings can be substituted and the like.
  • hetero atom means an atom selected from nitrogen atom, oxygen atom, or sulfur atom.
  • hydroxy or “hydroxyl” means a monovalent -OH group.
  • acyl means, unless otherwise stated, -C(O)R where R is a 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.
  • oxo means an oxygen that is double bonded to a carbon atom.
  • alkylsulfonyl means a moiety having the formula -S(O 2 )-R', where R' is an alkyl group as defined above. R' can have a specified number of carbons (e.g., “C1-C4 alkylsulfonyl”).
  • carbonyloxy represents a carbonyl group attached through an oxygen bridge.
  • alkyl and “alkenyl” can be used interchangeably in so far as a stable chemical entity is formed, as would be apparent to those skilled in the art.
  • linker refers to attachment groups interposed between substituents.
  • the linker includes amido (-CONH-R 11 or -NHCO-R n ), thioamido (-CSNH-R” or -NHCS-R”), carboxyl (-CO 2 -R 11 or -OCOR n ), carbonyl (-CO-R n ), urea (-NHCONH-R n ), thiourea (-NHCSNH-R 11 ), sulfonamido (-NHSO 2 -R 11 or -SO 2 NH-R 11 ), ether
  • each of the above terms includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided herein.
  • substituted e.g., as in substituted alkyl
  • substituted alkyl means that one or more hydrogen atoms of a chemical group (with one or more hydrogen atoms) can be replaced by one or more non-hydrogen substituents selected from the specified options. The replacement can occur at one or more positions.
  • optionally substituted means that one or more hydrogen atoms of a chemical group (with one or more hydrogen atoms) can be, but is not required to be substituted.
  • a “substituent group,” as used herein, means a non-hydrogen substituent group that may be, and preferably is, a group selected from the following moieties:
  • AA “ssiizzee--lliimmiitteedd ssuubbssttiittuueenntt”” oorr “ size-limited substituent group,” as used herein, means a group, e.g., selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-20- membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 4 -C 8 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 4-8-membered heterocycloalkyl.
  • a “lower substituent” or “lower substituent group,” as used herein, means a group, e.g., selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-8-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 5 -C 7 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 5-7 -membered heterocycloalkyl.
  • Some compounds of the disclosure can have one or more chiral centers and can exist in and be isolated in optically active and racemic forms, for any of the one or more chiral centers. Some compounds can exhibit polymorphism.
  • the compounds of the present disclosure e.g., Formula I
  • sample encompasses a sample obtained from a subject or patient.
  • the sample can be of any biological tissue or fluid.
  • samples include, but are not limited to, sputum, saliva, buccal sample, oral sample, blood, serum, mucus, plasma, urine, blood cells (e.g., white cells), circulating cells (e.g. stem cells or endothelial cells in the blood), tissue, core or fine needle biopsy samples, cell-containing body fluids, free floating nucleic acids, urine, stool, peritoneal fluid, and pleural fluid, tear fluid, or cells therefrom. Samples can also include sections of tissues such as frozen or fixed sections taken for histological purposes or microdissected cells or extracellular parts thereof.
  • a sample to be analyzed can be tissue material from a tissue biopsy obtained by aspiration or punch, excision or by any other surgical method leading to biopsy or resected cellular material.
  • a sample can comprise cells obtained from a subject or patient.
  • the sample is a body fluid that include, for example, blood fluids, serum, mucus, plasma, lymph, ascitic fluids, gynecological fluids, or urine but not limited to these fluids.
  • the sample can be a non- invasive sample, such as, for example, a saline swish, a buccal scrape, a buccal swab, and the like.
  • blood can include, for example, plasma, serum, whole blood, blood lysates, and the like.
  • assessing includes any form of measurement, and includes determining if 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.
  • monitoring refers to a method or process of determining the severity or degree of the type of cancer or stratifying the type of cancer based on risk and/or probability of mortality. In some embodiments, monitoring relates to a method or process of determining the therapeutic efficacy of a treatment being administered to a patient.
  • outcome can refer to an outcome studied. In some embodiments, “outcome” can refer to survival / mortality over a given time horizon. For example, “outcome” can refer to survival / mortality over 1 month, 3 months, 6 months, 1 year, 5 years, or 10 years or longer. In some embodiments, an increased risk for a poor outcome indicates that a therapy has had a poor efficacy, and a reduced risk for a poor outcome indicates that a therapy has had a good efficacy. [0063] As used herein, the term “high risk clinical trial” refers to one in which the test agent has “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 drug trial.
  • a low risk clinical trial refers to one in which the test agent has “minimal risk” (as defined by the terminology used by IRBs).
  • a low risk clinical trial is one that is not a drug trial.
  • a low risk clinical trial is one that that involves the use of a monitor or clinical practice process.
  • a low risk clinical trial is an observational clinical trial.
  • modulated or modulation can refer to both up regulation (i.e., activation or stimulation, e.g., by agonizing or potentiating) and down regulation (i.e., inhibition or suppression, e.g., by antagonizing, decreasing or inhibiting), unless otherwise specified or clear from the context of a specific usage.
  • up regulation i.e., activation or stimulation, e.g., by agonizing or potentiating
  • down regulation i.e., inhibition or suppression, e.g., by antagonizing, decreasing or inhibiting
  • the term “subject” refers to any suitable (e.g., treatable) member of the animal kingdom.
  • the subject is preferably a mammal.
  • the subject is preferably a human patient.
  • the subject may be a mammalian pediatric patient.
  • the pediatric patient is a mammalian (e.g., preferably human) patient under 18 years of age, while an adult patient is 18 or older.
  • treating is, unless stated otherwise, to be considered in its broadest context and refers to obtaining a desired pharmacologic and/or physiologic effect.
  • the term “treating” may not necessarily imply or require that an animal is treated until total recovery.
  • “treating” includes amelioration of the symptoms, relief from the symptoms or effects associated with a condition, decrease in severity of a condition, or preventing, preventively ameliorating symptoms, or otherwise reducing the risk of developing a particular condition.
  • “treating” may not require or include prevention.
  • reference to “treating” an animal includes but is not limited to prophylactic treatment and therapeutic treatment.
  • Treatment covers any treatment of a disease in a subject, preferably in a mammal (e.g., in a human), and may include one or more of: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., causing regression or elimination of the disease and/or relieving one or more disease symptoms.
  • treatment may be or include reducing such expression or signaling.
  • Treatment can also encompass delivery of an agent or administration of a therapy in order to provide for a pharmacologic 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.
  • “Therapeutically effective amount” means an amount effective to achieve a desired and/or beneficial effect.
  • An effective amount can be administered in one or more administrations.
  • a therapeutically effective amount is an amount appropriate to treat an indication.
  • treating an indication is meant achieving any desirable effect, such as one or more of palliate, ameliorate, stabilize, reverse, slow, or delay disease progression, increase the quality of life, or to prolong life.
  • Such achievement can be measured by any suitable method, such as measurement of tumor size or blood cell count, or any other suitable measurement.
  • the term “marker” or “biomarker” refers to a biological molecule, such as, for example, a nucleic acid, peptide, protein, hormone, and the like, whose presence or concentration can be detected and correlated with a known condition, such as a disease state. It can also be used to refer to a differentially expressed gene whose expression pattern can be utilized as part of a predictive, prognostic or diagnostic process in healthy conditions or a disease state, or which, alternatively, can be used in methods for identifying a useful treatment or prevention therapy.
  • an mRNA “isoform” is an alternative transcript for a specific mRNA or gene. This term includes pre-mRNA, immature mRNA, mature mRNA, cleaved or otherwise truncated, shortened, or aberrant mRNA, modified mRNA (e.g. containing any residue modifications, capping variants, polyadenylation variants, etc.), and the like.
  • Antibody or “antibody peptide(s)” refer to an intact antibody, or a binding fragment thereof that competes with the intact antibody for specific binding; this definition also encompasses monoclonal and polyclonal antibodies. Binding fragments are produced by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact antibodies. Binding fragments include Fab, Fab', F(ab') 2 , Fv, and single-chain antibodies. An antibody other than a “bispecific” or “bifunctional” antibody is understood to have each of its binding sites identical.
  • An antibody for example, substantially inhibits adhesion of a receptor to a counterreceptor when an excess of antibody reduces the quantity of receptor bound to counterreceptor by at least about 20%, 40%, 60% or 80%, and more usually greater than about 85% (as measured in an in vitro competitive binding assay).
  • Embodiments of the disclosure set forth herein include inventive compounds (e.g., compounds of Formula (I), such as compounds of Formula (II) and Formula (III), including Formula (Ila)-(IIj) and Formula (Illa)-(IIIp)).
  • inventive compounds e.g., compounds of Formula (I), such as compounds of Formula (II) and Formula (III), including Formula (Ila)-(IIj) and Formula (Illa)-(IIIp)
  • Other embodiments include compositions (e.g., pharmaceutical compositions) comprising the inventive compound.
  • Still other embodiments of the disclosure include compositions (e.g., pharmaceutical compositions) for treating, for example, certain diseases using the inventive compounds.
  • Some embodiments include methods of using the inventive compound (e.g., in compositions or in pharmaceutical compositions) for administering and treating (e.g., diseases such as cancer or blood disorders).
  • Some embodiments include methods of determining whether a patient is suitable for, or likely to respond favorably to, a particular treatment
  • Some embodiments of the disclosure include compounds having a structure according to Formula (I): or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof.
  • the compound is a pharmaceutically acceptable salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative of a compound of Formula (I).
  • the compound is not an ester, not a solvate, and not a prodrug.
  • 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 (-CO 2 H), C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 heteroalkyl, C 1 -C 7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, which 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 2 -C 6 alkoxy, cycloalkyl,
  • R 2 can be H, halogen, hydroxy, oxo, -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 alkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, aryl, heteroaryl, or fused ring heteroaryl, which amino, amido, -O-aryl, methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, C2- C7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 heteroalkyl, C 1 -C 7 alkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl
  • R 6 can be
  • R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 can be 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, which 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
  • R 2 is H, halogen, hydroxy, O-aryl, amino, C 1 -C 7 alkyl, C 1 -C 7 alkoxy, cycloalkyl, heterocyclyl, aryl, fused ring aryl, heteroaryl, or fused ring heteroaryl which O-aryl, amino, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 2 -C 6 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, C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, C 1
  • R 2 is H, Cl, hydroxy, -NHCH 3 , -N(CH 3 ) 2 , -OCH 3 , -OCF 3 , -OCHF 2 , -OPh, -CF 3 , -CHF 2 , unsubstituted C 1 -C 7 alkyl, substituted amino, substituted C 1 -C 7 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.
  • R 3 is H, halogen, hydroxy, -CN, methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, or C 1 -C 7 alkoxy, which C 1 -C 7 alkyl, or C 2 -C 6 alkoxy, is optionally substituted with one or more of halogen, hydroxy, methanoyl (-COH), carboxy (- CO 2 H), nitro (-NO 2 ), -NH 2 , -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 ,
  • R 4 is H, halogen, hydroxy, -CN, methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, or C 1 -C 7 alkoxy, which C 1 -C 7 alkyl, or C 2 -C 6 alkoxy, is optionally substituted with one or more of halogen, hydroxy, methanoyl (-COH), carboxy (- CO 2 H), nitro (-NO 2 ), -NH 2 , -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 ,
  • R 5 is H, halogen, hydroxy, -CN, methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, or C 1 -C 7 alkoxy, which C 1 -C 7 alkyl, or C 2 -C 6 alkoxy, is optionally substituted with one or more of halogen, hydroxy, methanoyl (-COH), carboxy (- CO 2 H), nitro (-NO 2 ), -NH 2 , -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 ,
  • R 4 is methyl or -CF 3 , and at least one of R 3 and R 5 is H or halogen.
  • the chiral center is an R chiral center, an S chiral center, or a racemate.
  • the chiral center can be represented by the following bonds ""lllllll Where a chiral center is possible at other positions of the compounds according to Formula (I), as would appreciated by one skilled in the art, the straight bond shown can also be can be
  • R 6 is
  • R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 1 1 3 3 , R 14 are independently selected from 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, which methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 2 -C 6 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl
  • R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 is not H.
  • each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 , if present, is H.
  • 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 (-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, which methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 2 -C
  • 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 is not H.
  • each 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 if present, is H.
  • m, n, o, p, q, r, s, t, u, v, w, and x are independently selected from 0, 1, 2, 3, 4, or 5, where q+r+s+t is at least 1, and where u+v+w+x is at least 1.
  • Some embodiments of the disclosure include compounds having a structure according to Formula (I): wherein the wavy bond from Y to R 6 (i.e., ) indicates that, in some instances, there is a chiral center at the R 6 attachment carbon.
  • the wavy bond can indicate an R chiral center, an S chiral center, or a racemate.
  • R 6 is (la), giving a structure of Formula (II), as follows:
  • R 7 , R 8 , R 9 , and R 10 are H, and at least one of R 11 , R 12 , R 13 , and R 14 is halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, C 1 -C 7 alkoxy, cycloalkyl, or spiro-fused cycloalkyl, which methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 2 -C 6 alkoxy, cycloalkyl, or spiro-fused cycloalkyl is optionally substituted with one or more halogen.
  • At least one of R 7 , R 8 , R 9 , and R 10 is halogen, hydroxyl, C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, C 1 -C 7 alkoxy, cycloalkyl, or spiro-fused cycloalkyl.
  • at least one of R 7 , R 8 , R 9 , and R 10 is F, hydroxyl, methyl, methoxy, -CHF 2 , - CF 3 , cyclopropyl, spiro-fused cyclopropyl, spiro-fused cyclobutyl, or spiro-fused cyclopentyl.
  • both of R 7 and R 8 or both of R 9 and R 10 are F, or both of R 7 and R 8 or both of R 9 and R 10 are methyl.
  • at least one of R 11 , R 12 , R 13 , and R 14 is halogen, hydroxyl, C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, C 1 -C 7 alkoxy, cycloalkyl, or spiro-fused cycloalkyl.
  • At least one of R 11 , R 12 , R 13 , and R 14 is F, hydroxyl, methyl, methoxy, - CHF 2 , -CF 3 , cyclopropyl, spiro-fused cyclopropyl, spiro-fused cyclobutyl, or spiro-fused cyclopentyl.
  • both of R 11 and R 12 or both of R 13 and R 14 are F, or wherein both of R 11 and R 12 or both of R 13 and R 14 are methyl
  • the compound can have a structure according to any of (Ila)-(IIe), wherein V, W, X, Y, and Z can independently represent any of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , or R 14 , and wherein at least one of V, W, X, Y, and Z is not H.
  • the compound of Formula (II) is a compound of Formula (Ilf) or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein:
  • R 20f is H. In another embodiment, R 20f is not H. In an embodiment, R 20f is unsubstituted C 1 -C 6 alkyl. In one embodiment, R 20f is t-butyl. In another embodiment, R 20f is C 1 -C 6 alkyl substituted with one or more -OH and/or halogen. In one embodiment, R 20f is C 1 -C 6 alkyl substituted with one or more -OH and/or F. In one embodiment,
  • R 20f is In another embodiment, R 20f is -O-(CH 2 ) a -(C 3 cycloalkyl).
  • R 20f is wherein R 20f is selected from C 1 - C 6 alkyl, C 3 -C 6 cycloalkyl, and C 3 -C 9 heterocyclyl, wherein C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl are each optionally substituted with one or more halogen and/or -OH.
  • R 20f is wherein R 27f is unsubstituted C 1 -C 6 alkyl.
  • R 20f is wherein R 27f is -CH 3 .
  • R 20f is wherein R 27f is C 1 -C 6 alkyl substituted with one or more -OH and/or F.
  • R 29fa and R29fb are each independently selected from H, C 1 -C 6 alkyl, -OH, and halogen, wherein the C 1 -C 6 alkyl is optionally substituted with one or more halogen, and b is 1 or 2.
  • R29fb are each independently selected from H, -CH 3 , -CF 3 , -OH, and F.
  • each of R 21f , R 22f , and R 23f is H.
  • R 21f and R 23f are each independently halogen and R 22f is H.
  • R 21f and R 23f are each F and R 22f is H.
  • R 21f and R 23f are each H and R 22f is halogen.
  • R 21f and R 23f are each H and R 22f is F.
  • each of R 24fa , R 24fb , R 25fa , R 25fb , R 26fa , and R 26fb is H.
  • each of R 25fa , R 25fb , R 26fa , and R 26fb is H and R 24fa and/or R 24fb is halogen.
  • each of R 24fb , R 25fa , R 25fb , R 26fa , and R 26fb is H and R 24fa is F.
  • each of R 25fa , R 25fb , R 26fa , and R 26fb is H and each of R 24fa and R 24fb is F.
  • R 25fa , R 25fb , R 26fa , and R 26fb are each H and R 24fa and/or R 24fb is C 1 -C 6 alkyl. In one embodiment, each of R 25fa , R 25fb , R 26fa , and R 26fb is H and each of R 24fa and R 24fb is -CH 3 . In one embodiment, each of R 24fb , R 25fa , R 25fb , R 26fa , and R 26fb is H and R 24fa is -CH 3 .
  • R 25fa , R 25fb , R 26fa , and R 26fb are each H and R 24fa and/or R 24fb is C 1 -C 6 alkyl substituted with one or more halogen.
  • R 25fa , R 25fb , R 26fa , and R 26fb are each H and R 24fa and/or R 24fb is Ci alkyl substituted with one or more F.
  • R 24fa , R 25fa , R 25fb , R 26fa , and R 26fb are each H andR 24fb is -CF 3 .
  • the compound of Formula (Ilf) has one or more stereocenters.
  • the compound of Formula (Ilf) comprises a stereocenter where the moiety connects to the remaining portion of Formula (Ilf).
  • the compound of Formula (Ilf) comprises a stereocenter at one or more of R 24fa , R 24fb , R 25fa , R 25fb , R 26fa , and/or R 26fb .
  • the compound of Formula (Ilf) comprises a stereocenter on R 20f .
  • the compound of Formula (Ilf) is selected from:
  • the compound of Formula (II) is a compound of Formula (Ilg) or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein:
  • 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 C 1 -C 6 alkyl.
  • 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 C 1 -C 6 alkyl.
  • each of R 24ga , R 24gb , R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , R 27gb , R 28ga , and R 28gb is H.
  • R 20g is H. In another embodiment, R 20g is unsubstituted C 1 -C 6 alkyl. In one embodiment, R 20g is t-butyl. In another embodiment, R 20g is C 1 -C 6 alkyl substituted with one or more F and/or -OH. In one embodiment, R 20g is selected from In another embodiment, R 20g is unsubstituted C 1 -C 6 alkoxy. In one embodiment, R 20g is In another embodiment, R 20g is C 1 -C 6 alkoxy substituted with one F or more F and/or -OH. In one embodiment, R 20g is selected from
  • R 20g is unsubstituted C 3 -C 6 cycloalkyl. In one embodiment, R 20g is unsubstituted C 3 cycloalkyl. In one embodiment, R 20g is C 3 cycloalkyl substituted with C 1 -C 6 alkyl. In one embodiment, R 20g is In one embodiment, R 20g is C 3 cycloalkyl substituted with one or more C 1 -C 6 alkyl and one or more fluorine atoms.
  • R 20g is wherein R 29g is unsubstituted C 1 -C 6 alkyl. In one embodiment, R 20g is wherein R 29g is -CH 3 . In one embodiment, R 20g is wherein R 29g is C 1 -C 6 alkyl substituted with one or more -OH and/or F. In one embodiment, R 20g is wherein R 29g is selected from In one embodiment, R 20g is wherein R 29g is unsubstituted C 3 -C 6 cycloalkyl. In one embodiment, R 20g is wherein R 29g is unsubstituted C 3 cycloalkyl.
  • each of R 21g , R 22g , and R 23g is H.
  • R 21g and R 23g are each independently halogen and R 22g is H.
  • R 21g and R 23g are each F and R 22g is H.
  • R 21g and R 23g are each H and R 22g is halogen,
  • R 21g and R 22g are each H and R 22g is F.
  • R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb is H.
  • each of R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb is H and R 24ga and/or R 24gb is halogen.
  • each of R 24ga , R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb is H and R 24gb is F.
  • each of R 24ga , R 24gb , R 26ga , R 26gb , R 27ga , and R 27gb is H and R 25ga and/or R 25gb is unsubstituted C 1 -C 6 alkyl.
  • each of R 24ga , R 24gb , R 25ga , R 26ga , R 26gb , R 27ga , and R 27gb is H and R 25gb is -CH 3 .
  • each of R 24ga , R 24gb , R 26ga , R 26gb , R 27ga , R 27gb , R 28ga , and R 28gb is H.
  • each of R 24ga , R 24gb , R 26ga , R 26gb , R 28ga , and R 28gb is H and R 27ga and/or R 27gb is halogen.
  • each of R 24ga , R 24gb , R 26ga , R 26gb , R 28ga , and R 28gb is H and each of R 27ga and R 27gb is F.
  • each of R 24ga , R 24gb , R 26ga , R 26gb , R 27ga , R 28ga , and R 28gb is H and R 27gb is F.
  • each of R 24ga , R 24gb , R 26ga , R 26gb , R 28ga , and R 28gb is H and R 27ga and/or R 27gb is unsubstituted C 1 -C 6 alkyl.
  • each of R 24ga , R 24gb , R 26ga , R 26gb , R 28ga , and R 28gb is H and each of R 27ga and R 27gb is -CH 3 .
  • each of R 24ga , R 24gb , R 27ga , R 27gb , R 28ga , and R 28gb is H and R 26ga and/or R 26gb is halogen. In one embodiment, each of R 24ga , R 24gb , R 26ga , R 27ga , R 27gb , R 28ga , and R 28gb is H and R 26gb is F. In an embodiment, each of R 24ga , R 24gb , R 27ga , R 27gb , R 28ga , and R 28gb is H and R 26ga and/or R 26gb is unsubstituted C 1 -C 6 alkyl. In one embodiment, each of R 24ga , R 24gb , R 26ga , R 27ga , R 27gb , R 28ga , and R 28gb is H and R 26gb is -CH 3 .
  • the compound of Formula (Ilg) comprises one or more stereocenters. In one embodiment, the compound of Formula (Ilg) comprises a stereocenter on R 20g . In one embodiment, the compound of Formula (Ilg) comprises a stereocenter where the moiety connects to the remaining portion of Formula (Ilg). In one embodiment, one or more of R 24ga , R 24gb , R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , R 27gb , R 28ga , and/or R 28gb comprises a stereocenter.
  • the compound of Formula (Ilg) is selected from:
  • the compound of Formula (II) is a compound of Formula (Uh): or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein:
  • R2OH is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and C 1 -C 6 cycloalkyl, wherein C 1 -C 6 alkyl and C 1 -C 6 alkoxy are each optionally substituted with one or more substituents selected from halogen and -OH, and C 3 -C 6 cycloalkyl is optionally substituted with one or more substituents selected from C 1 -C 6 alkyl and halogen; and
  • R 21h , R 22h , and R 23h are each independently selected from H and halogen.
  • R 20h is H.
  • R 20h is C 1 -C 6 alkyl substituted with one or more halogen.
  • R 20h is In another embodiment, R 20h is C 1 -C 6 alkoxy substituted with one or more halogen.
  • R 20h is In another embodiment, R 20h is unsubstituted C 3 -C 6 cycloalkyl. In one embodiment, R 20h is unsubstituted C 3 cycloalkyl.
  • R 20h is C 3 -C 6 cycloalkyl substituted with one or more C 1 -C 6 alkyl. In one embodiment, R 20h is in another embodiment, R 20h is C 3 -C 6 cycloalkyl substituted with one or more C 1 -C 6 alkyl and one or more fluorine atoms. In one embodiment, R 20h is
  • R 21h , R 22h , and R 23h are each H. In an embodiment, R 21h and R 23h are each independently halogen and R 22h is H. In one embodiment, R 21h and R 23h are each F and R 22h is H. In an embodiment, R 21h and R 23h are each H and R 22h is halogen, In one embodiment, R 21h and R 23h are each H and R 22h is F.
  • the compound of Formula (Ilh) comprises one or more stereocenters. In one embodiment, the compound of Formula (Ilh) comprises a stereocenter on R 20h . In one embodiment, the compound of Formula (Ilh) comprises a stereocenter where the moiety connects to the remaining portion of Formula (Ilh).
  • the compound of Formula (Ilh) is selected from:
  • the compound of Formula (I) is a compound of Formula (IIi): or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein:
  • R 20i is selected from C 1 -C 6 alkyl and C 1 -C 6 alkoxy, wherein C 1 -C 6 alkyl and C 1 -C 6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen;
  • R 21 i , R 22i , and R 23i are each independently selected from H and halogen; and R 24ia , R 24ib , R 25ia , R 25ib , R 26ia , and R 26ib are each independently selected from H, halogen, - OH, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy, wherein C 1 -C 6 alkyl and C 1 -C 6 alkoxy are each optionally substituted with one or more halogen atoms.
  • R 20i when R 20i is R 21i is halogen and R 21i and R 23i are each H; or R 23i is halogen and R 21i and R 22i are each H. In one embodiment, when R 20i is R 21i is F and R 22i and R 23i are each H; or R 23i is F and R 21i and R 22i are each H.
  • the compound of Formula (IIi) is not one of the following compounds: ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof
  • R 20i is C 1 -C 6 alkyl optionally substituted with one or more -
  • R 20i is C 1 -C 6 alkyl substituted with one -OH. In one embodiment, R 20i is C 3 alkyl optionally substituted with one -OH. In one embodiment, R 20i is
  • R 21i is halogen, R 22i and R 23i are each H; or R 23i is halogen, R 21i and R 22i are each H.
  • R 21i is F, R 22i and R 23i are each H; or R 23i is F, R 21i and R 22i are each H.
  • one or more of R 24ia , R 24ib , R 25ia , R 25ib , R 26ia , and R 26ib is halogen. In one embodiment, one or more of R 24ia , R 24ib , R 25ia , R 25ib , R 26ia , and R 26ib is F. In one embodiment, R 24ia , R 25ia , R 25ib , R 26ia , R 26ib are each H and R 24ib is F.
  • the compound of Formula (IIi) is selected from:
  • the compound of Formula (IIi) has one or more stereocenters.
  • the compound of Formula (IIi) comprises a stereocenter where the moiety connects to the remaining portion of Formula (IIi). In one embodiment, the compound of Formula (IIi) comprises a stereocenter at one or more of R 24ia , R 24ib , R 25ia , R 25ib , R 26ia , and/or R 26ib . In one embodiment, the compound of Formula (IIi) comprises a stereocenter on R 20i
  • the compound of Formula (I) is a compound of Formula (Ilj): or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R 20j is selected from C 1 -C 6 alkyl and C 1 -C 6 alkoxy, wherein C 1 -C 6 alkyl and C 1 -C 6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen;
  • R 21j , R 22j , and R 23j are each independently selected from H and halogen;
  • R 24ja , R 24jb , R 25ja , R 25jb , R 26ja , R 26jb , R 27ja , R 27jb , R 28ja , and R 28jb are each independently selected from H, halogen, -OH, and C 1 -C 6 alkyl.
  • R 20j when R 20j is halogen and R 22j and R 23j are each H; or R 23j is halogen and R 21j and R 22j are each H. In one embodiment, when R 20j is s F and R 22j and R 23j are each H; or R 23j is F and R 21j and R 22j are each H.
  • the compound of Formula (Ilj) is not one of the following: or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof.
  • R 20j is C 1 -C 6 alkyl optionally substituted with one or more - OH. In one embodiment, R 20j is C 1 -C 6 alkyl substituted with one -OH. In one embodiment, R 20j is C 3 alkyl optionally substituted with one -OH. In one embodiment, R 20j is
  • R 21j and R 22j are each H.
  • R 21j is F, R 22j and R 23j are each H; or R 23j is F, R 21j and R 22j are each H.
  • R 28ja , and R 28jb is halogen. In one embodiment, one or more of Rz4ja, R 24jb , R 25ja , R 25jb , R 26ja ,
  • R 26jb , R 27ja , R 27jb , R 28ja , and R 28jb is F. In one embodiment, wherein each of R 24ja , R 24jb , R 25ja , R 25jb , R 26ja , R 26jb , R 27ja , R 27jb , R 28ja , and R 28jb is H. In one embodiment, wherein each of R 24ja , R 24jb , R 25ja , R 25jb , R 26ja , R 26jb , R 27ja , R 28ja , and
  • R 28jb is H and R 27jb is halogen.
  • R 24ja , R 24jb , R 25ja , R 25jb , R 26ja , R 26jb , R 27ja , R 28ja , and R 28jb is H and R 27jb is F.
  • the compound of Formula (Ilj) comprises a stereocenter where the moiety connects to the remaining portion of Formula (Ilj).
  • one or more of R 24ja , R 24jb , R 25ja , R 25jb , R 26ja , R 26jb , R 27ja , R 27jb , R 28ja , and/or R 28jb comprises a stereocenter.
  • the compound of Formula (Ilj) is selected from:
  • q, r, s, t, u, v, w, and x are independently 0, 1, or 2.
  • 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
  • x is 0 or 1.
  • 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 H.
  • all 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 H.
  • the compounds of Formula (I), such as compounds of Formula (II) or Formula (III), including Formulas (Ila)-(IIj) and Formulas (Illa)-(IIIp), can be in the form of salts, optical and geometric isomers, and salts of isomers.
  • 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 hydrochloride, hydrobromide, sulphate, phosphate, nitrate, borate, acetate, maleate, tartrate, and salicylate.
  • salts can include metals, amines, or organic cations (e.g. quaternary ammonium).
  • organic cations e.g. quaternary ammonium
  • simple derivatives of the compounds e.g., ethers, esters, or amides which have desirable retention and release characteristics but which are easily hydrolyzed by body pH, enzymes, or other suitable means, can be employed.
  • optically active forms can be accomplished by any suitable method, including but not limited to, resolution of the racemic form by recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase.
  • the compounds disclosed herein can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds can be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds disclosed herein, whether radioactive or not, are encompassed within the contemplated scope.
  • metabolites of the compounds disclosed herein are useful for the methods disclosed herein.
  • prodrug refers to a compound that can be converted into a compound (e.g., a biologically active compound) described herein in vivo.
  • Prodrugs can be useful for a variety of reason known in the art, including e.g., ease of administration due e.g., to enhanced bioavailability in oral administration, and the like.
  • the prodrug can also have improved solubility in pharmaceutical compositions over the biologically active compounds.
  • prodrug is a compound which is administered as an ester (i.e., the "prodrug") to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water solubility is beneficial.
  • ester i.e., the "prodrug”
  • 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 hereby incorporated herein by reference for the limited purpose describing procedures and preparation of suitable prodrug derivatives.
  • Certain compounds disclosed herein can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of contemplated compounds. Certain compounds of the present disclosure can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the compounds and methods contemplated herein and are intended to be within the scope disclosed herein.
  • one or more compounds of the disclosure can be part of a composition and can be in an amount (by weight of the total composition) 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 75%, at least about 90%, at least about 95%, at least about 99%, at least about 99.99%, no more than about 75%, no more than about 90%, no more than about 95%, no more than about 99%, or no more than about 99.99%, from about 0.0001% to about 99%, from about 0.0001% to about 50%, from about 0.01% to about 95%, from about
  • one or more compounds of the disclosure can be purified or isolated in an amount (by weight of the total composition) 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 75%, at least about 90%, at least about 95%, at least about 99%, at least about 99.99%, no more than about 75%, no more than about 90%, no more than about 95%, no more than about 99%, no more than about 99.99%, from about 0.0001% to about 99%, from about 0.0001% to about 50%, from about 0.01% to about 95%, from about 1%
  • Some embodiments of the present disclosure include methods for the preparation of compounds of Formula (I).
  • a compound of Formula (I) such as a compound of any one of Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp) can be prepared comprising one or more of the steps set forth in Example 2 herein.
  • the synthetic routes shown and described in Example 2 can, for example, be used to prepare Compounds 1-138, as set forth in Tables 1-2, and structurally related compounds.
  • compositions comprising one or more compounds of the disclosure (e.g., Formula (I), a compound of any one of Formula (Ila)-(IIj) or Formula (Illa)-(IIIp)).
  • the composition comprising a compound of the disclosure further comprises one or more therapeutic agents described elsewhere herein.
  • the present disclosure includes a separate composition comprising one or more of the therapeutic agents described elsewhere herein.
  • the composition is a pharmaceutical composition, such as compositions that are suitable for administration to animals (e.g., mammals, primates, monkeys, humans, canine, feline, porcine, mice, rabbits, rats, etc.).
  • a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient.
  • the compound can be a compound of any of Formulae (I)-(III) as disclosed herein, a compound as set forth in Tables 1-2, or a pharmaceutically acceptable salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof.
  • the compound is set forth in any of Tables 1-2 herein.
  • the present disclosure further relates to a composition comprising a compound of Formula (I), such as a compound of any one of Formula (Ila)-(IIj) or Formula (Illa)-(IIIp), and a composition comprising a therapeutic agent.
  • a compound of Formula (I) such as a compound of any one of Formula (Ila)-(IIj) or Formula (Illa)-(IIIp)
  • a composition comprising a therapeutic agent.
  • exemplary therapeutic agents are described elsewhere herein.
  • the compound of Formula (I) and the therapeutic agent are co-formulated into a single composition.
  • the compound of Formula (I), such as a compound of any one of Formula (Ila)-(IIj) or Formula (Illa)-(IIIp) are administered together in one administration or composition.
  • the compound of Formula (I), such as a compound of any one of Formula (Ila)-(IIj) or Formula (Illa)-(IIIp), and the therapeutic agent are administered separately in more than one administration or more than one composition.
  • the composition comprising the compound of Formula (I), such as a compound of any one of Formula (Ila)-(IIj) or Formula (Illa)-(IIIp), and the composition comprising the therapeutic agent are administered to a subject at the same time.
  • the composition comprising the compound of Formula (I), such as a compound of any one of Formula (Ila)-(IIj) or Formula (Illa)-(IIIp) and the composition comprising the therapeutic agent are administered to a subject sequentially.
  • composition comprising the compound of Formula (I), such as a compound of any one of Formula (Ila)-(IIj) or Formula (Illa)-(IIIp), and the composition comprising the therapeutic agent are co-administered (or administered within a defined time period) such that the subject is exposed to both inhibitors over a period of time in which they can act synergistically.
  • salts are meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like.
  • inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic,
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galacturonic acids and the like (see, for example, Berge et al, “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19).
  • Certain specific compounds disclosed herein contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • Compounds disclosed herein can exist as salts, such as with pharmaceutically acceptable acids. Accordingly, the compounds contemplated herein include such salts. Examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates, (-) -tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid. These salts can be prepared by methods known to those skilled in the art.
  • 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.
  • salts of the compounds above, where a basic or acidic group is present in the structure are also included within the scope of compounds contemplated herein.
  • an acidic substituent such as -NHSO3H, -COOH and -P(O)(OH) 2
  • ammonium, sodium, potassium, calcium salt, and the like for use as the dosage form.
  • Basic groups such as amino or basic heteroaryl radicals, or pyridyl and acidic salts, such as hydrochloride, hydrobromide, acetate, maleate, palmoate, methanesulfonate, p-toluenesulfonate, and the like, can be used as the dosage form.
  • esters can be employed, e. g. , methyl, ethyl, tert-butyl, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
  • the pharmaceutical composition is non-toxic, does not cause side effects, or both. In some embodiments, there may be inherent side effects (e.g., it may harm the patient or may be toxic or harmful to some degree in some patients).
  • one or more compounds of the disclosure can be part of a pharmaceutical composition and can be 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 75%, at least about 90%, at least about 95%, at least about 99%, at least about 99.99%, no more than about 75%, no more than about 90%, no more than about 95%, no more than about 99%, no more than about 99.99%, from about 0.001% to about 99%, from about 0.001% to about 50%, from about 0.1% to about 99%, from about 1% to about 95%, from about 10% to
  • the pharmaceutical composition can be presented in a dosage form which is suitable for the topical, subcutaneous, intrathecal, intraperitoneal, oral, parenteral, rectal, cutaneous, nasal, vaginal, or ocular administration route.
  • the pharmaceutical composition can be presented in a dosage form which is suitable for parenteral administration, aa mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration.
  • the pharmaceutical composition can be in the form of, for example, tablets, capsules, pills, powders granulates, suspensions, emulsions, solutions, gels (including hydrogels), pastes, ointments, creams, plasters, drenches, delivery devices, suppositories, enemas, injectables, implants, sprays, aerosols or other suitable forms.
  • the compounds disclosed herein can be administered orally as tablets, aqueous or oily suspensions, lozenges, troches, powders, granules, emulsions, capsules, syrups or elixirs.
  • the composition for oral use can contain one or more agents selected from the group of sweetening agents, flavoring agents, coloring agents and preserving agents in order to produce pharmaceutically elegant and palatable preparations. Accordingly, there are also provided pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and one or more compounds disclosed herein.
  • tablets contain the acting ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets.
  • 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 com starch or alginic acid; (3) binding agents, such as starch, gelatin or acacia; and (4) lubricating agents, such as magnesium stearate, stearic acid or talc.
  • These tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
  • pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substance that can also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • a compound disclosed herein in the form of a free compound or a pharmaceutically-acceptable pro-drug, metabolite, analogue, derivative, solvate or salt, can be administered, for in vivo application, parenterally by injection or by gradual perfusion over time. Administration can be intravenously, intraperitoneally, intramuscularly, subcutaneously, intracavity, or transdermally. For in vitro studies the compounds can be added or dissolved in an appropriate biologically acceptable buffer and added to a cell or tissue.
  • the carrier is a finely divided solid in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from 5% to 70% of the active compound.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term “preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions.
  • liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
  • injectable, sterile solutions preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants, including suppositories.
  • This suspension can be formulated according to known methods using those suitable dispersing or wetting agents and suspending agents that have been mentioned above.
  • the sterile injectable preparation can also a sterile injectable solution or suspension in a non-toxic parenterally- acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles, carriers, and solvents that can be employed are water, Ringer’s solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono-or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • carriers for parenteral administration include aqueous solutions of dextrose, saline, pure water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene-block polymers, and the like. Ampoules are convenient unit dosages.
  • the compounds disclosed herein can also be incorporated into liposomes or administered via transdermal pumps or patches.
  • compositions and methods suitable for use in the pharmaceuticals compositions and methods disclosed herein include those described, for example, in PHARMACEUTICAL SCIENCES (17th Ed., Mack Pub. Co., Easton, PA) and WO 96/05309, the teachings of both of which are hereby incorporated by reference.
  • preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • 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 (such as those based on Ringer’s dextrose), and the like.
  • Preservatives and other additives can also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, growth factors and inert gases and the like.
  • Preservatives include antimicrobial, anti-oxidants, chelating agents and inert gases.
  • Other pharmaceutically acceptable carriers include aqueous solutions, non-toxic excipients, including salts, preservatives, buffers and the like, as described, for instance, in Remington’s Pharmaceutical Sciences, 15th ed. Easton: Mack Publishing Co. , 1405-1412, 1461- 1487 (1975) and The National Formulary XIV., 14th ed. Washington: American Pharmaceutical Association (1975), the contents of which are hereby incorporated by reference.
  • the pH and exact concentration of the various components of the pharmaceutical composition are adjusted according to routine skills in the art. See e.g., Goodman and Gilman (eds.), 1990, THE PHARMACOLOGICAL BASIS FOR THERAPEUTICS (7th ed.).
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, me thylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
  • Aqueous suspensions normally contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspension.
  • excipients can be (1) suspending agent such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; (2) dispersing or wetting agents which can be (a) naturally occurring phosphatide such as lecithin; (b) a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate ; (c) a condensation product of ethylene oxide with aa long chain aliphatic alcohol, for example, heptadecaethylenoxycetanol; (d) a condensation product of ethylene oxide with a partial ester derived from a fatty acid and hexitol such as polyoxyethylene sorbitol monooleate, or (e) a condensation product of ethylene oxide with a partial ester derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monoo
  • solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • These preparations can contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the pharmaceutical preparation is preferably in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the pharmaceutical composition can include one or more formulary ingredients.
  • a “formulary ingredient” can be any suitable ingredient (e.g., suitable for the drug(s), for the dosage of the drug(s), for the timing of release of the drugs(s), for the disease, for the disease state, or for the delivery route) including, but not limited to, water (e.g., boiled water, distilled water, filtered water, pyrogen-free water, or water with chloroform), sugar (e.g., sucrose, glucose, mannitol, sorbitol, xylitol, or syrups made therefrom), ethanol, glycerol, glycols (e.g., propylene glycol), acetone, ethers, DMSO, surfactants (e.g., anionic surfactants, cationic surfactants, zwitterionic surfactants, or nonionic surfactants (e.g., polysorbates)), oils (e.g., animal oils, plant oils, and solubility,
  • compositions can be formulated to release the active ingredient (e.g., one or more compounds of the disclosure such as Formula (I), a compound of any one of Formula (Ila)-(IIj) or Formula (Illa)-(IIIp)) substantially immediately upon the administration or any substantially predetermined time or time after administration.
  • active ingredient e.g., one or more compounds of the disclosure such as Formula (I), a compound of any one of Formula (Ila)-(IIj) or Formula (Illa)-(IIIp)
  • Such formulations can include, for example, controlled release formulations such as various controlled release compositions and coatings.
  • formulations can, in certain embodiments, include those incorporating the drug (or control release formulation) into food, food stuffs, feed, or drink.
  • Some compounds can have limited solubility in water and therefore can require a surfactant or other appropriate co-solvent in the composition.
  • co-solvents include: Polysorbate 20, 60, and 80; Pluronic F-68, F-84, and P-103; cyclodextrin; and polyoxyl 35 castor oil.
  • Such co-solvents are typically employed at a level between about 0.01 % and about 2% by weight.
  • Viscosity greater than that of simple aqueous solutions can be desirable to decrease variability in dispensing the formulations, to decrease physical separation of components of a suspension or emulsion of formulation, and/or otherwise to improve the formulation.
  • Such viscosity building agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose, chondroitin sulfate and salts thereof, hyaluronic acid and salts thereof, and combinations of the foregoing.
  • Such agents are typically employed at a level between about 0.01% and about 2% by weight.
  • compositions disclosed herein can additionally include components to provide sustained release and/or comfort.
  • Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides, and finely-divided drug carrier substrates. These components are discussed in greater detail in U.S. Pat. Nos. 4,911,920; 5,403,841; 5,212,162; and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes.
  • compositions useful for ameliorating certain diseases and disorders are prepared by formulating a compound disclosed herein in the form of a free compound or a pharmaceutically-acceptable pro-drug, metabolite, analogue, derivative, solvate or salt, either alone or together with other pharmaceutical agents, suitable for administration to a subject using carriers, excipients and additives or auxiliaries.
  • Frequently used carriers or auxiliaries include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycols and solvents, such as sterile water, alcohols, glycerol and polyhydric alcohols.
  • Intravenous vehicles include fluid and nutrient replenishers.
  • compositions useful for ameliorating certain diseases and disorders are prepared by formulating a compound disclosed herein in the form of a free compound or a pharmaceutically-acceptable pro-drug, metabolite, analogue, derivative, solvate or salt, either alone or together with other pharmaceutical agents, suitable for administration to a subject using carriers, excipients and additives or auxiliaries.
  • Frequently used carriers or auxiliaries include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycols and solvents, such as sterile water, alcohols, glycerol and polyhydric alcohols.
  • Intravenous vehicles include fluid and nutrient replenishers.
  • IRAK inhibitors In addition to their ability to inhibit IRAK, IRAK inhibitors have been demonstrated to have selectivity for multiple kinases.
  • IRAK interleukin- 1 receptor-associated kinase
  • FLT3 FMS-like tyrosine kinase 3
  • the inhibitory action against one or more kinase can allow for treatment and/or prevention of diseases in an animal (e.g., mammals, porcine, canine, avian (e.g., chicken), bovine, feline, primates, rodents, monkeys, rabbits, mice, rats, and humans) using a compound of the disclosure (e.g., Formula (I), a compound of any one of Formula (Ila)-(IIj) or Formula (Illa)-(IIIp)) including, but not limited to hematopoietic cancers (e.g., disorders of hematopoietic stem cells in the bone marrow or disorders related to myeloid lineage), MDS, AML, myeloproliferative disease, and diseases (e.g., hematopoietic cancers) related to mutations in IRAKI, IRAK4, and/or FLT3 (e.g., mutations in the juxtamembrane region
  • an animal e.g.
  • the compounds of the disclosure can inhibit the activity of one or more of FLT3, mutations of FLT3 (e.g., mutations in the juxtamembrane region of FLT3, mutations in the kinase domain of FLT3, FLT3 point mutations, FLT3 internal tandem duplication mutations, the FLT3-ITD mutation, the D835Y FLT3 mutation, the D835V FLT3 mutation, the F691L FLT3 mutation, or the R834Q FLT3 mutation), IRAK4 (interleukin- 1 receptor associated kinase 4), isoforms of IRAK4, mutations of IRAK4, IRAKI (interleukin- 1 receptor associated kinase 1), isoforms of IRAKI, and/or mutations of IRAKI.
  • FLT3, mutations of FLT3 e.g., mutations in the juxtamembrane region of FLT3, mutations in the kinase domain of FLT3, FLT3
  • the compounds of the disclosure can inhibit the activity of one or both of FLT3 and mutations of FLT3 (e.g., mutations in the juxtamembrane region of FLT3, mutations in the kinase domain of FLT3, FLT3 point mutations, FLT3 internal tandem duplication mutations, the FLT3-ITD mutation, the D835Y FLT3 mutation, the D835V FLT3 mutation, the F691L FLT3 mutation, or the R834Q FLT3 mutation) and optionally inhibits one or more of IRAK4, isoforms of IRAK4, mutations of IRAK4, IRAKI, isoforms of IRAKI, or mutations of IRAKI.
  • FLT3 and mutations of FLT3 e.g., mutations in the juxtamembrane region of FLT3, mutations in the kinase domain of FLT3, FLT3 point mutations, FLT3 internal tandem duplication mutations, the FLT3-ITD mutation
  • the compounds of the disclosure can inhibit the activity of one or both of FLT3 and mutations of FLT3 (e.g., mutations in the juxtamembrane region of FLT3, mutations in the kinase domain of FLT3, FLT3 point mutations, FLT3 internal tandem duplication mutations, the FLT3-ITD mutation, the D835Y FLT3 mutation, the D835V FLT3 mutation, the F691L FLT3 mutation, or the R834Q FLT3 mutation) and optionally inhibits one or both of IRAK4 and IRAKI, or an isoform or mutation thereof.
  • the compounds of the disclosure can inhibit FLT3 in combination with IRAK4, IRAKI, or with IRAK4 and IRAKI.
  • compounds exhibit inhibitory activity against IRAK and/or FLT-3 with activities > 1 ⁇ M, e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000 nM, or even greater.
  • the compounds exhibit inhibitory activity against IRAK and/or FLT-3 with activities 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.
  • compounds described herein exhibit inhibitory activity against IRAK and/or FLT-3 with activities > 0.1 ⁇ M, e.g., about 1, 2, 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, or 100 nM.
  • Ranges of values using a combination of any 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.
  • 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 ⁇ M, 1-10 ⁇ M, 10-100 ⁇ M, 100-200 ⁇ M, 200-500 ⁇ M, or even 500-1000 ⁇ M.
  • IC 50 in the customary sense (i.e., concentration to achieve half-maximal inhibition.
  • hematopoietic cancers that can be treated in an animal (e.g., mammals, porcine, canine, avian (e.g., chicken), bovine, feline, primates, rodents, monkeys, rabbits, mice, rats, and humans) using a compound of the disclosure (e.g., Formula (I), Formulas (Ila)-(IIj), or Formulas (Illa)-(IIIp)) include, but are not limited to hematopoietic cancers and cancers of the myeloid line of blood cells, cancers with an increased risk of occurrence due to other blood disorders, cancers with an increased risk of occurrence due to chemical exposure (e.g., anti-cancer therapies or occupational chemical exposure), cancers with an increased risk of occurrence due to ionizing radiation (e.g., anti-cancer therapies), cancers evolving from myelodysplastic syndromes, cancers evolving from myeloproliferative disease, and cancers of the B cells.
  • an animal e.g.
  • hematopoietic cancers that can be treated include, but are not limited to, MDS, AML, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non- Hodgkin lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL) (e.g. ABC DLBCL with MYD88 mutation (e.g., L265P)), follicular lymphoma, or marginal zone lymphoma, or combinations thereof.
  • MDS MDS
  • AML lymphoma
  • leukemia chronic lymphocytic leukemia
  • CML chronic myeloid leukemia
  • ALL acute lymphoblastic leukemia
  • bone marrow cancer non- Hodgkin lymphoma
  • Waldenstrom’s macroglobulinemia B cell lymphoma,
  • cancers characterized by dysregulated IRAK expression can be treated, and include, but are not limited to, glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, Glioma, oral cancer, nasopharyngeal carcinoma, rectal cancer, stomach cancer, and uterine cancer, and the like, and combinations thereof.
  • compounds of the present disclosure can be used to inhibit targets in the context of additional conditions characterized by overactive IRAKI and/or IRAK4.
  • compounds of the present disclosure can be used to inhibit overactive IRAKI and/or IRAK4 in conditions such as inflammatory diseases and autoimmune disease, wherein said inflammatory diseaess and autoimmune diseases are characterized by overactive IRAKI and/or IRAK4.
  • inflammatory and autoimmune diseases characterized by dysregulated (e.g., hyperactive) IRAK expression (IRAKI and/or IRAK4) and/or IRAK-meidated intracellular signaling can be treated, and include, but are not limited to, chronic inflammation (i.e., associated with viral and bacterial infection), sepsis, rheumatoid arthritis, hidradenitis suppurativa, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjogren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, and the like, and combinations thereof.
  • chronic inflammation i.e., associated with viral and bacterial infection
  • sepsis rheumatoid arthritis
  • hidradenitis suppurativa systemic lupus erythematosus
  • inflammatory bowel disease multiple sclerosis
  • MDS that can be treated in a subject e.g., mammals, porcine, canine, avian (e.g., chicken), bovine, feline, primates, rodents, monkeys, rabbits, mice, rats, and humans
  • a compound of the disclosure e.g., Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp)
  • MDS with a splicing factor mutation include but are not limited to MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, MDS with a mutation in isocitrate dehydrogenase 2, refractory cytopenia with unilineage dysplasia (e.g., refractory anemia, refractory neutropenia, and refractory thrombocytopenia), refractory anemia with ring sideroblasts, refractory cytopenia with multilineage dysplasia (
  • MDS that can be treated include, but are not limited to, MDS that is inherited, MDS with an increased risk of occurrence due to an inherited predisposition, MDS with an increased risk of occurrence due to other blood disorders, MDS with an increased risk of occurrence due to chemical exposure, MDS with an increased risk of occurrence due to ionizing radiation, MDS with an increased risk of occurrence due to cancer treatment (e.g., a combination of radiation and the radiomimetic alkylating agents such as busulfan, nitrosourea, or procarbazine (with a latent period of 5 to 7 years) or DNA topoisomerase inhibitors), MDS evolving from acquired aplastic anemia following immunosuppressive treatment and Fanconi's anemia, MDS with an increased risk due to an mutation in splicing factors, MDS with an increased risk due to a mutation in isocitrate dehydrogenase 1 , and MDS with an increased risk due to a mutation in isocitrate de
  • Animals that can be treated include but are not limited to mammals, rodents, primates, monkeys (e.g., macaque, rhesus macaque, pig tail macaque), humans, canine, feline, porcine, avian (e.g., chicken), bovine, mice, rabbits, and rats.
  • the term “subject” may refer to both human and non-human subjects.
  • the subject is in need of the treatment (e.g., by showing signs of disease, e.g. MDS, AML, cancer, autoimmune disease, inflammatory condition, etc., or by having a low blood cell count).
  • MDS that can be treated in a subject e.g., mammals, porcine, canine, avian (e.g., chicken), bovine, feline, primates, rodents, monkeys, rabbits, mice, rats, and humans
  • a compound of the disclosure e.g., Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp)
  • FLT3 e.g., using FLT3 inhibitor
  • MDS that can be treated include, but are not limited to MDS that can be treated by inhibiting IRAK4 (or its mutations), MDS that can be treated by inhibiting and IRAKI (or its mutations), or MDS that can be treated by inhibiting IRAK4 (or its mutations) and IRAKI (or its mutations).
  • MDS that can be treated include, but are not limited to MDS that can be treated by inhibiting FLT3 in combination with IRAK4, IRAKI, or both IRAK4 and IRAKI.
  • inhibiting FLT3 in combination with IRAK4, IRAKI, or both IRAK4 and IRAKI provides for treating tumors with FLT3 mutations, which can be or become resistant to FLT3 inhibitors due to adaptive resistance mechanism(s), e.g., driven by IRAK.
  • MDS that can be treated is characterized by MDS having enhanced IRAK4-Long expression and/or activity relative to IRAK4-Short, and/or wherein the MDS is not driven by FLT3 mutations but expresses IRAK4- Long, based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S (e.g. as described in U.S. Patent Application No.
  • AML that can be treated in a subject e.g., mammals, porcine, canine, avian (e.g., chicken), bovine, feline, primates, rodents, monkeys, rabbits, mice, rats, and humans
  • a compound of the disclosure e.g., Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp)
  • AML that is inherited AML with an increased risk of occurrence due to an inherited predisposition
  • AML with one or more recurrent genetic abnormality e.g., with inversions or translocations, such as MLLT3/MLL which is a translocation between chromosome 9 and 11 (“MLL”)
  • M3 translocation between chromosomes
  • AML that can be treated include AML that by inhibiting one or more of FLT3 (e.g., using FLT3 inhibitors), mutations of FLT3 (e.g., using inhibitors of FLT3 mutants), IRAK4 (e.g., using IRAK4 inhibitors), mutations of IRAK4 (e.g., using inhibitors of IRAK4 mutants), IRAKI (e.g., using IRAK 1 inhibitors), and/or mutations of IRAKI (e.g., using inhibitors of IRAKI mutant).
  • FLT3 e.g., using FLT3 inhibitors
  • mutations of FLT3 e.g., using inhibitors of FLT3 mutants
  • IRAK4 e.g., using IRAK4 inhibitors
  • mutations of IRAK4 e.g., using inhibitors of IRAK4 mutants
  • IRAKI e.g., using IRAK 1 inhibitors
  • IRAKI e.g., using inhibitors
  • AML that can be treated include, but are not limited to AML that can be treated by inhibiting IRAK4 (or its mutations), MDS that can be treated by inhibiting and IRAKI (or its mutations), or AML that can be treated by inhibiting IRAK4 (or its mutations) and IRAKI (or its mutations).
  • AML that can be treated include, but are not limited to AML that can be treated by inhibiting FLT3 in combination with IRAK4, IRAKI, or both IRAK4 and IRAKI .
  • inhibiting FLT3 in combination with IRAK4, IRAKI, or both IRAK4 and IRAKI provides for treating tumors with FLT3 mutations which can be or become resistant to FLT3 inhibitors due to adaptive resistance mechanism(s), e.g. driven by IRAK.
  • AML that can be treated is characterized by AML having enhanced IRAK4-Long expression and/or activity relative to IRAK4-Short, and/or wherein the AML is not driven by FLT3 mutations but expresses IRAK4-Long, based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S (e.g. as described in U.S. Patent Application No.
  • hematopoietic cancers that can be treated in a subject (e.g., mammals, porcine, canine, avian (e.g., chicken), bovine, feline, primates, rodents, monkeys, rabbits, mice, rats, and humans) using a compound of the disclosure (e.g., Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp),) include, but are not limited to hematopoietic cancers (e.g.
  • FLT3 e.g., using FLT3 inhibitors
  • mutations of FLT3 e.g., using inhibitors of FLT3 mutants
  • IRAK4 e.g., using IRAK4 inhibitors
  • isoforms of IRAK4 e.g
  • hematopoietic cancers that can be treated include, but are not limited to cancers that can be treated by inhibiting (e.g., reducing the activity or expression of) FLT3 (or its mutations) and IRAK4 (or its mutations), hematopoietic cancers that can be treated by inhibiting (e.g., reducing the activity or expression of) FLT3 (or its mutations) and IRAKI (or its mutations), or hematopoietic cancers that can be treated by inhibiting (e.g., reducing the activity or expression of) FLT3 (or its mutations), IRAK4 (or its isoforms or mutations), and IRAKI (or its isoforms mutations).
  • hematopoietic cancer that can be treated include, but are not limited to hematopoietic cancer that can be treated by inhibiting FLT3 in combination with IRAK4, IRAKI, or both IRAK4 and IRAKI.
  • inhibiting FLT3 in combination with IRAK4, IRAKI, or both IRAK4 and IRAKI provides for treating tumors with FLT3 mutations which can be or become resistant to FLT3 inhibitors due to adaptive resistance mechanism(s), e.g. driven by IRAK.
  • hematopoietic cancer that can be treated is characterized by hematopoietic cancer having enhanced IRAK4-Long expression and/or activity relative to IRAK4-Short, and/or wherein the hematopoietic cancer is not driven by FLT3 mutations but expresses IRAK4-Long, based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S (e.g. as described in U.S. Patent Application No. 16/339,692; and Smith, M. A., et al. (2019).
  • cancers that can be treated include, but are not limited to, glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, Glioma, oral cancer, nasopharyngeal carcinoma, rectal cancer, stomach cancer, and uterine cancer, and the like, and combinations thereof, that can be treated by inhibiting FLT3 in combination with IRAK4, IRAKI, or both IRAK4 and IRAKI.
  • inhibiting FLT3 in combination with IRAK4, IRAKI, or both IRAK4 and IRAKI provides for treating tumors with FLT3 mutations which can be or become resistant to FLT3 inhibitors due to adaptive resistance mechanism(s), e.g., driven by IRAK.
  • cancer that can be treated is characterized by cancer having enhanced IRAK4-Long expression and/or activity relative to IRAK4-Short, and/or wherein the cancer is not driven by FLT3 mutations but expresses IRAK4- Long, based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S (e.g. as described in U.S. Patent Application No.
  • inflammatory and autoimmune diseases characterized by dysregulated (e.g., hyperactive) IRAK expression (IRAKI and/or IRAK4) and/or IRAK- meidated intracellular signaling that can be treated include, but are not limited to, chronic inflammation (i.e., associated with viral and bacterial infection), sepsis, rheumatoid arthritis, hidradenitis suppurativa, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjogren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, and the like, and combinations thereof, that can be treated by inhibiting FLT3 in combination with IRAK4, IRAKI, or both IRAK4 and IRAKI.
  • chronic inflammation i.e., associated with viral and bacterial infection
  • sepsis rheumatoid arthritis
  • hidradenitis suppurativa
  • inhibiting FLT3 in combination with IRAK4, IRAKI, or both IRAK4 and IRAKI provides for treating inflammatory and autoimmune diseases with FLT3 mutations which can be or become resistant to FLT3 inhibitors due to adaptive resistance mechanism(s), e.g., driven by IRAK.
  • inflammatory and autoimmune disease that can be treated is characterized by inflammatory and autoimmune disease having enhanced IRAK4-Long expression and/or activity relative to IRAK4-Short, and/or wherein the inflammatory and autoimmune disease is not driven by FLT3 mutations but expresses IRAK4-Long, based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S (e.g.
  • treating can include but is not limited to prophylactic treatment and therapeutic treatment.
  • treatment can include, but is not limited to: preventing 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); reducing the risk 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); ameliorating or relieving symptoms 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); eliciting a bodily response against MDS (e.g., MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 2
  • hematopoietic cancer e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, or 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, and the like), treating can include but is not limited to prophylactic treatment and therapeutic treatment.
  • CLL chronic lymphocytic leukemia
  • CML chronic myeloid leukemia
  • ALL acute lymphoblastic leukemia
  • bone marrow cancer non-Hodgkin lymphoma
  • non-Hodgkin lymphoma or Waldenstrom
  • treatment can include, but is not limited to: preventing cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, or Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof, and the like); 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 lymphoma, or Waldenstrom’s macroglobulinemia, B cell lymphoma
  • treating does not include prophylactic treatment of cancer (e.g., preventing or ameliorating future cancer).
  • Treatment of a subject can occur using any suitable administration method (such as those disclosed herein) and using any suitable amount of a compound of the disclosure (e.g., Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp)).
  • methods of treatment comprise 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).
  • methods of treatment comprise treating an animal or human for a hematopoietic cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone mmaarrrrooww cancer, non-Hodgkin lymphoma, Waldenstrom’s macroglobulinemia Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof, and the like).
  • a hematopoietic cancer e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone mmaarr
  • Other embodiments include treatment after one or more of having a blood disorder, having myelodysplastic syndrome, having myeloproliferative disease, an occurrence of chemical exposure, an exposure to ionizing radiation, or a treatment for a hematopoietic cancer (e.g., with chemotherapy, ionizing radiation, or both).
  • a blood disorder having myelodysplastic syndrome, having myeloproliferative disease
  • an occurrence of chemical exposure an exposure to ionizing radiation
  • a treatment for a hematopoietic cancer e.g., with chemotherapy, ionizing radiation, or both.
  • Some embodiments of the disclosure include a method for treating a subject (e.g., an animal such as a human or primate) with a composition comprising a compound of the disclosure (e.g., Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp)) (e.g., a pharmaceutical composition) which comprises one or more administrations of one or more such compositions; the compositions may be the same or different if there is more than one administration.
  • a subject e.g., an animal such as a human or primate
  • a composition comprising a compound of the disclosure (e.g., Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp)) (e.g., a pharmaceutical composition) which comprises one or more administrations of one or more such compositions; the compositions may be the same or different if there is more than one administration.
  • the method of treatment includes administering to a subject an effective amount of a composition comprising a compound of the disclosure (e.g., Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp)).
  • a composition comprising a compound of the disclosure (e.g., Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp)).
  • the term “effective amount” refers to a dosage or a series of dosages sufficient to affect treatment (e.g., to treat MDS such as but not limited to 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); 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), bone marrow cancer, non-Hodgkin lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations
  • MDS
  • an effective amount can encompass a therapeutically effective amount, as disclosed herein.
  • an effective amount can vary depending on the subject and the particular treatment being affected. The exact amount that is required can, for example, vary from subject to subject, depending on the age and general condition of the subject, the particular adjuvant being used (if applicable), administration protocol, and the like. As such, the effective amount can, for example, vary based on the particular circumstances, and an appropriate effective amount can be determined in a particular case.
  • An effective amount can, for example, include any dosage or composition amount disclosed herein.
  • an effective amount of at least one compound of the disclosure (e.g., Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp), such as but not limited to Compounds 1-138, as listed in Tables 1-2) (which can be administered to a subject such as mammals, primates, monkeys or humans) can be an amount of about 0.005 to about 50 mg/kg body weight, about 0.01 to about 15 mg/kg body weight, about 0.1 to about 10 mg/kg body weight, about 0.5 to about 7 mg/kg body weight, about 0.005 mg/kg, about 0.01 mg/kg, about 0.05 mg/kg, about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 3 mg/kg, about 5 mg/kg, about 5.5 mg/kg, about 6 mg/kg, about 6.5 mg/kg, about 7 mg/kg, about 7.5 mg/kg, about 8 mg/kg, about 10 mg/kg, about 12 mg/kg, or about 15 mg
  • the dosage can be about 0.5 mg/kg body weight or about 6.5 mg/kg body weight.
  • an effective amount of at least one compound of the disclosure e.g., Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp) such as but not limited to Compounds 1-138, as listed in Tables 1-2
  • an effective amount of at least one compound of the disclosure can be an amount of about 0.005 to about 50 mg/kg body weight, about 0.01 to about 15 mg/kg body weight, about 0.1 to about 10 mg/kg body weight, about 0.5 to about 7 mg/kg body weight, about 0.005 mg/kg, about 0.01 mg/kg, about 0.05 mg/kg, about 0.1 mg/kg, about 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
  • an effective amount of at least one compound of the disclosure (e.g., Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp), such as but not limited to Compounds 1-138, as listed in Tables 1-2) (which can be administered to an animal such as mammals, primates, monkeys or humans) can be an amount of about 1 to about 1000 mg/kg body weight, about 5 to about 500 mg/kg body weight, about 10 to about 200 mg/kg body weight, about 25 to about 100 mg/kg body weight, about 1 mg/kg, about 2 mg/kg, about 5 mg/kg, about 10 mg/kg, about 25 mg/kg, about 50 mg/kg, about 100 mg/kg, about 150 mg/kg, about 200 mg/kg, about 300 mg/kg, about 400 mg/kg, about 500 mg/kg, about 600 mg/kg, about 700 mg/kg, about 800 mg/kg, about 900 mg/kg, or about 1000 mg/kg.
  • the dosage can be about 20 mg/kg human body weight or about 100 mg/kg human body weight.
  • an effective amount of at least one compound of the disclosure e.g., Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp), such as but not limited to Compounds 1-138, as listed in Tables 1-2
  • an effective amount of at least one compound of the disclosure can be an amount of about 1 to about 1000 mg/kg body weight, about 5 to about 500 mg/kg body weight, about 10 to about 200 mg/kg body weight, about 25 to about 100 mg/kg body weight, about 1 mg/kg, about 2 mg/kg, about 5 mg/kg, about 10 mg/kg, about 25 mg/kg, about 50 mg/kg, about 100 mg/kg, about 150 mg/kg, about 200 mg/kg, about 300 mg/kg, about 400 mg/kg, about 500 mg/kg, about 600 mg/kg
  • the treatments can also include one or more of surgical intervention, chemotherapy, radiation therapy, hormone therapies, immunotherapy, and adjuvant systematic therapies.
  • Adjuvants may include but are not limited to chemotherapy (e.g., temozolomide), radiation therapy, antiangiogenic therapy (e.g., bevacizumab), and hormone therapies, such as administration of LHRH agonists; anti-estrogens, such as tamoxifen; high-dose progestogens; aromatase inhibitors; and/or adrenalectomy.
  • chemotherapy e.g., temozolomide
  • radiation therapy e.g., antiangiogenic therapy (e.g., bevacizumab)
  • hormone therapies such as administration of LHRH agonists
  • anti-estrogens such as tamoxifen
  • high-dose progestogens aromatase inhibitors
  • aromatase inhibitors and/or adrenalectomy.
  • Chemotherapy can be used as a single-agent or as
  • the administration to a subject of at least one compound of the disclosure is an adjuvant cancer therapy or part of an adjuvant cancer therapy.
  • Adjuvant treatments include treatments by the mechanisms disclosed herein and of cancers as disclosed herein, including, but not limited to tumors.
  • Corresponding primary therapies can include, but are not limited to, surgery, chemotherapy, or radiation therapy.
  • the adjuvant treatment can be a combination of chemokine receptor antagonists with traditional chemotoxic agents or with immunotherapy that increases the specificity of treatment to the cancer and potentially limits additional systemic side effects.
  • a compound of the disclosure e.g., Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp)
  • a compound of the disclosure e.g., Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp)
  • the use of a compound of the disclosure may, in some instances, reduce the duration of the dose of both drugs and drug combinations reducing the side effects.
  • the administration to a subject may decrease the incidence of one or more symptoms associated with MDS / AML / a type of hematopoietic cancer.
  • the administration may decrease marrow failure, immune dysfunction, transformation to overt leukemia, or combinations thereof in said subject, as compared to a subject not receiving said composition.
  • the method may decrease a marker of viability of MDS cells AML cells, or cancer cells in a subject.
  • the method may decrease a marker of viability of MDS, AML, and/or cancer cells.
  • the marker may be selected from survival over time, proliferation, growth, migration, formation of colonies, chromatic assembly, DNA binding, RNA metabolism, cell migration, cell adhesion, inflammation, or a combination thereof.
  • Formula (II) or Formula (III), including Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp), are administered with one or more therapeutic agents.
  • exemplary therapeutic agents include, but are not limited to, a CDK inhibitor, a BCL2 inhibitor, a PTEFb inhibitor, a DNA polymerase inhibitor, a cytidine deaminase inhibitor, a DNA methyltransferase (DNMT) inhibitor, an immunomodulatory imide, a cereblon modulator, a purine nucleoside antimetabolite, a Type II topoisomerase inhibitor, a DNA intercalator, a hedgehog antagonist, an IDH2 inhibitor, an IDH1 inhibitor, a ribonucleotide reductase inhibitor, an adenosine deaminase inhibitor, a Mek 1/2 inhibitor, an ERK 1/2 inhibitor, an AKT inhibitor, a PTPN11 inhibitor, an SHP2 inhibitor, a glucocor
  • the treatments disclosed herein can include use of other drugs (e.g., antibiotics) or therapies for treating disease, e.g. MDS / AML / a type of hematopoietic cancer.
  • antibiotics can be used to treat infections and can be combined with a compound of the disclosure to treat disease (e.g., infections).
  • IVIG intravenous immunoglobulin
  • treatment regimens for various types of cancers can involve one or more elements selected from chemotherapy, targeted therapy, alternative therapy, immunotherapy, and the like.
  • the compounds and/or compositions described herein can be used in one or more administrations to a subject, in combination with one or more BCL2 inhibitor, BTK inhibitor, chemotherapy, targeted therapy, alternative therapy, immunotherapy, DNA methyltransferase inhibitor/hypomethylating agent, anthracycline, histone deacetylase (HD AC) inhibitor, purine nucleoside analogue (antimetabolite), isocitrate dehydrogenase 1 oorr 2 (IDH1 and/or IDH2) inhibitor, antibody-drug conjugate, mAbs/immunotherapy, CAR-T cell therapy, Plk inhibitor, MEK inhibitor, CDK9 inhibitor, CDK8 inhibitor, retinoic acid receptor agonist, TP53 activator, smoothened receptor antagonist, ERK inhibitor, PI3K inhibitor, mTOR inhibitor, glucocorticoid receptor modulator, or EZH2 inhibitor, and the like, or one or more combinations thereof, where the compositions
  • the therapeutic agent comprises a BCL2 inhibitor.
  • the BCL2 inhibitor is venetoclax or a salt thereof.
  • the therapeutic agent comprises a DNA polymerase inhibitor.
  • the DNA polymerase inhibitor is cytidine.
  • the therapeutic agent comprises a cytidine deaminase inhibitor.
  • the cytidine deaminase inhibitor is zebularine.
  • the therapeutic agent comprises a DNMT inhibitor.
  • the DNMT inhibitor is zebularine, decitabine, or azacitidine.
  • the therapeutic agent comprises an immunomodulatory imide (cereblon modulator).
  • the immunomodulatory imide is lenalidomide.
  • the therapeutic agent comprises a purine nucleoside antimetabolite.
  • the purine nucleoside antimetabolite is clofarabine.
  • the therapeutic agent comprises a Type II topoisomerase inhibitor/ DNA intercalator.
  • the Type II topoisomerase inhibitor/ DNA intercalator is vosaroxin.
  • the therapeutic agent comprises a hedgehog antagonist.
  • the hedgehog antagonist is glasdegib.
  • the therapeutic agent comprises an IDH1 inhibitor.
  • the IDH1 inhibitor is ivosidenib.
  • the therapeutic agent comprises an IDH2 inhibitor.
  • the IDH2 inhibitor is enasidenib.
  • the therapeutic agent comprises a ribonucleotide reductase inhibitor. In one embodiment, the ribonucleotide reductase inhibitor is gemcitabine. In one embodiment, the therapeutic agent comprises an adenosine deaminase inhibitor. In one embodiment, the adenosine deaminase inhibitor is cladribine. In one embodiment, the therapeutic agent comprises a Mek 1/2 inhibitor. In one embodiment, the Mek 1/2 inhibitor is trametinib. In one embodiment, the therapeutic agent comprises an ERK 1/2 inhibitor. In one embodiment, the ERK 1/2 inhibitor is ulixertinib.
  • the therapeutic agent comprises an AKT inhibitor.
  • the AKT inhibitor is capivasertib (AZD5363).
  • the therapeutic agent comprises a PTPN11/SHP2 inhibitor.
  • the PTPN11/SHP2 inhibitor is TNO-155.
  • the therapeutic agent comprises a glucocorticoid steroid.
  • the glucocorticoid steroid is selected from dexamethasone, methylprednisolone, prednisolone, cortisol, prednisone, betamethasone, triamcinolone, deflazacort, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone, and beclometasone.
  • the glucocorticoid steroid is selected from dexamethasone, methylprednisolone, and prednisolone.
  • the therapeutic agent comprises a menin inhibitor.
  • the menin inhibitor is SNDX-5613.
  • the therapeutic agent comprises an MDM2 inhibitor.
  • the MDM2 inhibitor is navtemadlin (AMG 232, KRT-232).
  • the therapeutic agent comprises a BTK inhibitor.
  • the BTK inhibitor is selected from ibrutinib, acalabrutinib, and zanubrutinib.
  • the therapeutic agent comprises a mutant/ inactivated p53 reactivator.
  • the mutant/inactivated p53 reactivator is Eprenetapopt (APR- 246).
  • the therapeutic agent comprises a CDK inhibitor.
  • the CDK inhibitor can be any CDK inhibitor known to a person of ordinary skill in the art.
  • the CDK inhibitor is a CKD1, CKD2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12, or CDK13 inhibitor or a combination thereof.
  • the CDK inhibitor comprises an inhibitor described in one of the following patents or patent applications: US 20210332071, US 20210330653, WO 2021214253, WO 2021178595, WO 2021207632, US 8685660, US 20200361906, US 10695346, US 11142507, WO 2021198439, WO 2021201170, US 8153632, US 11013743, US 11135198, US 20210299111, WO 2021190637, WO 2021188855, WO 2021188849, US 20210292299, US 11124836, US 10961527, US 20210284629, US 20210283265, WO 2021183994, WO 2021181233, US 11116755, WO 2021176045, WO 2021177816, WO 2021176049, WO 2021176349, US 20210275522, US 20210275491, US 20210277037, US 11111250
  • 20190369104 WO 2019230654, US 8329683, US RE47739, WO 2019222521, US
  • 20190275049 WO 2019168446, US 20190270967, US 20190248774, WO 2019159126, WO 2019150181, US 20180098963, US 20190224189, US 20160024084, WO 2019143719, WO
  • 20190105340 US 20190105309, WO 2019057141, US 9878994, WO 2019054865, US
  • 2012101064 WO 2012101062, US 7976517, US 8222256, US 8216571, US 20110130380, US
  • 20070179161 US 7250515, WO 2007081060, US 20070167466, US 20070155816, US
  • the CDK inhibitor comprises an inhibitor described in: Alsfouk, A., Journal of Enzyme Inhibition and Medicinal Chemistry, 2021, 36(l):693-706; Goel, B. et al., Curr. Top. Med. Chem., 2020, 20(17): 1535-1563; Heptinstall, A. B. et al., Future Med. Chem., 2018, 10(11):1369-1388; Sanchez-Martinez, C.
  • the CDK inhibitor is a CDK9 inhibitor.
  • the CDK9 inhibitor is Atuveciclib (BAY-1143572) or BAY-1251152 (VIP152).
  • BAY- 1251152 (VIP 152) is a selective CDK9 inhibitor while Atuveciclib (BAY- 1143572) is a CDK9/PTEFb inhibitor.
  • the CDK inhibitor is a CDK4/6 inhibitor.
  • the CDK4/6 inhibitor is Palbociclib.
  • the CDK inhibitor is a CDK7 inhibitor. In one embodiment, the CDK7 inhibitor is THZ1.
  • CDK inhibitors include, but are not limited to: Compound 21 (PMID 27326333) CYC065; YKL-1-116; i-CDK9; JH-VII-49; JH-XI-10-02; SEL120-34A; MM-D37K; PF-06873600; BEY-1007; BEY-1107; birociclib (XZP-3297); FCN-437; TP-1287; BEBT-209; TQB-3616; AMG-925 (FLX-925); CS3002; HS-10342; terameprocol (EM-1421); NU-6102; CGP-60474; BMS-265246; NU-6027; Purvalanol A; Purvalanol B; RGB-286147; Indirubin; 7- Hydroxystaurosporine; BS-194; PHA-690509; Cdk4/6 Inhibitor IV; FCN437c;
  • X is NH or O
  • R is tetrahydro-pyran-4-yl and R’ is H, R is -CH 2 CH 3 and R’ is -OCH 3 , R is isopropyl and R’ is H, or R is - CH 2 CH 3 and R’ is F;
  • R is t-butyl carboxyl and n is 1 or R is H and n is 2; wherein X is NH or O; wherein R is H and R’ is F, R is F and R’ is F, or R is
  • R’ is H; wherein R is -OCH 3 and R’ is F, R is F and R’ is SF 5 , or
  • R is -OCH 3 and R’ is -SF 5 ; wherein R is F and R’ is -CH 3 or R is -SF 5 and R’ is H; wherein R is -CF 3 and R’ is -CH 3 or R is H and R’ is cyclopropyl; wherein R is 3-fluoroailin-lyl and R’ is F or R is phenyl and
  • the therapeutic agent comprises a BCL2 inhibitor and a DNMT inhibitor.
  • the therapeutic agent comprises venetoclax, or a salt thereof, and azacitidine, or a salt thereof.
  • the one or more therapeutic agents can be in the form of salts, optical and geometric isomers, and salts of isomers.
  • the therapeutic agent can be in various forms, such as uncharged molecules, components of molecular complexes, or non-irritating pharmacologically acceptable salts, including but not limited to hydrochloride, hydrobromide, sulphate, phosphate, nitrate, borate, acetate, maleate, tartrate, and salicylate.
  • salts can include metals, amines, or organic cations (e.g. quaternary ammonium).
  • simple derivatives of the therapeutic agents e.g., ethers, esters, or amides
  • which have desirable retention and release characteristics but which are easily hydrolyzed by body pH, enzymes, or other suitable means can be employed.
  • the therapeutic agent has a chiral center and can exist in and be isolated in optically active and racemic forms. In other embodiments, the therapeutic agent may exhibit polymorphism.
  • Some embodiments of the present disclosure encompass any racemic, optically active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound described herein, including isotopically-labeled and radio-labeled compounds. See e.g., Goding, 1986, Monoclonal Antibodies Principles and Practice; Academic Press, p. 104.
  • Such isomers can be isolated by standard resolution techniques, including e.g., fractional crystallization, chiral chromatography, and the like. See e.g., Eliel, E. L.
  • optically active forms can be accomplished by any suitable method, including but not limited to, resolution of the racemic form by recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase.
  • the therapeutic agent has asymmetric centers and can occur as racemates, racemic mixtures, and as individual enantiomers or diastereoisomers, with all isomeric forms as well as mixtures thereof being contemplated for use in the compounds and methods described herein.
  • the compounds contemplated for use in the compounds and methods described herein do not include those that are known in the art to be too unstable to synthesize and/or isolate.
  • the therapeutic agents disclosed herein can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds can be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds disclosed herein, whether radioactive or not, are encompassed within the contemplated scope.
  • metabolites of the therapeutic agents disclosed herein are useful for the methods disclosed herein.
  • the therapeutic agents contemplated herein may be provided in the form of a prodrug.
  • prodrug refers to a compound that can be converted into a compound (e.g., a biologically active compound) described herein in vivo.
  • Prodrugs can be useful for a variety of reason known in the art, including e.g., ease of administration due e.g., to enhanced bioavailability in oral administration, and the like.
  • the prodrug can also have improved solubility in pharmaceutical compositions over the biologically active compounds.
  • prodrug is a compound which is administered as an ester (i.e., the "prodrug") to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water solubility is beneficial.
  • ester i.e., the "prodrug”
  • 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 hereby incorporated herein by reference for the limited purpose describing procedures and preparation of suitable prodrug derivatives.
  • Certain the therapeutic agent disclosed herein can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of contemplated compounds. Certain the therapeutic agents of the present disclosure can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the compounds and methods contemplated herein and are intended to be within the scope disclosed herein.
  • IRAK inhibitors have been demonstrated to have synergistic effects when administered in combination with an apoptosis modulator/inhibitor, such as a BCL2 inhibitor.
  • an exemplary apoptosis/BCL2 inhibitor has been shown to have a synergistic effect when used in combination with an exemplary IRAK inhibitor in multiple AML cell lines. Venetoclax was used as a representative apoptosis/BCL2 inhibitor.
  • the present disclosure encompasses methods for treating a disease or disorder which is responsive to inhibition of IRAK, comprising administration to a subject of a composition comprising an IRAK inhibiting compound, wherein some embodiments of the method can further involve administration of an apoptotic modulator.
  • the apoptotic modulator may comprise a BTK and/or a BCL2 inhibitor.
  • BTK and BCL2 inhibitors may be, for example, those known in the art.
  • the method may comprise the step of administering to the subject an apoptotic modulator.
  • the apoptotic modulator may comprise a BCL2 inhibitor selected from ABT-263 (Navitoclax), ABT-737, ABT-199 (venetoclax), GDC -0199, GX15-070 (Obatoclax) (all available from Abbott Laboratories), HA14-1, SI, 2-methoxy antimycin A3, gossypol, AT-101, apogossypol, WEHI- 539, A-l 155463, BXI-61, BXL72, TW37, MIMI, UML77, and the like, and combinations thereof.
  • the BCL2 inhibitor comprises venetoclax.
  • the administration step comprises administration to a subject of a composition comprising an IRAK inhibiting compound and a BCL2 inhibitor. In some embodiments, the administration step comprises administration of a composition comprising an IRAK inhibiting compound in combination with a composition comprising a BCL2 inhibitor.
  • the IRAK inhibiting compound is selected from Compounds 1-138, or a salt, isomer, derivative or analog thereof, and the BCL2 inhibitor is venetoclax, or a salt, isomer, derivative or analog thereof.
  • the method can further involve administration to a subject of an immune modulator.
  • the immune modulator can include, for example, Lenalidomide (Revlamid; Celgene Corporation).
  • the method can involve administration of an epigenetic modulator.
  • the epigenetic modulator can include, for example, a hypomethylating agent such as azacitidine, decitabine, or a combination thereof.
  • the compounds and/or compositions described herein can be used in one or more administrations to a subject, together with or in combination with one or more BTK inhibitor, such as, for example, ibrutinib, or a salt, isomer, derivative or analog thereof.
  • BTK inhibitor such as, for example, ibrutinib, or a salt, isomer, derivative or analog thereof.
  • the compounds and/or compositions described herein can be used in one or more administrations, together with or in combination with a DNA methyltransferase inhibitor/hypomethylating agent, such as, for example, azacitidine, decitabine, cytarabine, and/or guadecitabine; an anthracycline, such as, for example, daunorubicin, idarubicin, doxorubicin, mitoxantrone, epirubicin, and/or CPX-351 (a combination cytarabine and daunorubicin in a fixed 5:1 molar ratio), and the like; a histone deacetylase (HD AC) inhibitor, such as, for example, vorinostat, panobinostat, valproic acid, and/or pracinostat, and the like; a purine nucleoside analogue (antimetabolite), such as, for example, fludarabine, cladribine,
  • Anti-CD70 e.g. ARGX-110, cusatuzumab
  • a bispecific antibody e.g. floteuzumab (CD 123 x CD 3 )
  • Anti-CTLA4 e.g. ipilimumab
  • Anti-PDl/PDLl e.g.
  • nivolumab nivolumab, pembrolizumab, atezolizumab, avelumab, PDR001, MBG453), and/or Anti-CD47 (e.g. 5F9 (Magrolimab)), and the like; a Plk inhibitor, such as, for example, volasertib and/or rigosertib, and the like; a MEK inhibitor, such as, for example, trametinib, cobimetinib, selumetinib, pimasertib, and/or refametinib, and the like; a CDK9 inhibitor, such as, for example, alvocidib and/or voruciclib, and the like; a CDK8 inhibitor, such as, for example, SEL120, and the like; a retinoic acid receptor agonist, such as, for example, ATRA (all-trans retinoic acid) and/or SY- 1425 (a selective
  • Cancers are commonly treated with chemotherapy and/or targeted therapy and/or alternative therapy.
  • Chemotherapies act by indiscriminately targeting rapidly dividing cells, including healthy cells as well as tumor cells, whereas targeted cancer therapies rather act by interfering with specific molecules, or molecular targets, which are involved in cancer growth and progression.
  • Targeted therapy generally targets cancer cells exclusively, having minimal damage to normal cells.
  • Chemotherapies and targeted therapies which are approved and/or in the clinical trial stage are known to those skilled in the art. Any such compound can be utilized in the practice of the present disclosure.
  • approved chemotherapies include abitrexate (Methotrexate Injection), abraxane (Paclitaxel Injection), adcetris (Brentuximab Vedotin Injection), adriamycin (Doxorubicin), adrucil Injection (5-FU (fluorouracil)), afmitor (Everolimus), Armitor Disperz (Everolimus), alimta (PEMETREXED), alkeran Injection (Melphalan Injection), alkeran Tablets (Melphalan), aredia (Pamidronate), arimidex (Anastrozole), aromasin (Exemestane), arranon (Nelarabine), arzerra (Ofatumumab Injection), avastin (Bevacizumab), beleodaq (Belinostat Injection), bexxar (Tositumomab),
  • approved targeted therapies include ado-trastuzumab emtansine (Kadcyla), afatinib (Gilotrif), aldesleukin (Proleukin), alectinib (Alecensa), alemtuzumab (Campath), axitinib (Inlyta), belimumab (Benlysta), belinostat (Beleodaq), bevacizumab (Avastin), bortezomib (Velcade), bosutinib (Bosulif), brentuximab vedotin (Adcetris), cabozantinib (Cabometyx, Cometriq), canakinumab (Haris), carfilzomib (Kyprolis), ceritinib (Zykadia), cetuximab (Erbitux), cobimetinib (Cotellic), crizot
  • Those skilled in the art can determine appropriate chemotherapy and/or targeted therapy and/or alternative therapy options, including treatments that have been approved and those that in clinical trials or otherwise under development. Some targeted therapies are also immunotherapies. Any relevant chemotherapy, target therapy, and alternative therapy treatment strategies can be utilized, alone or in combination with one or more additional cancer therapy, in the practice of the present disclosure.
  • immunotherapies include cell-based immunotherapies, such as those involving cells which effect an immune response (such as, for example, lymphocytes, macrophages, natural killer (NK) cells, dendritic cells, cytotoxic T lymphocytes (CTL), antibodies and antibody derivatives (such as, for example, monoclonal antibodies, conjugated monoclonal antibodies, polyclonal antibodies, antibody fragments, radiolabeled antibodies, chemolabeled antibodies, etc.), immune checkpoint inhibitors, vaccines (such as, for example, cancer vaccines (e.g. tumor cell vaccines, antigen vaccines, dendritic cell vaccines, vector-based vaccines, etc.), e.g.
  • an immune response such as, for example, lymphocytes, macrophages, natural killer (NK) cells, dendritic cells, cytotoxic T lymphocytes (CTL), antibodies and antibody derivatives (such as, for example, monoclonal antibodies, conjugated monoclonal antibodies, polyclonal antibodies, antibody fragments, radiolabeled
  • Immune checkpoint inhibitor immunotherapies are those that 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 immunotherpaies include cytokines, interleukins, interferons, and the like.
  • an immunotherapy assigned or administered to a subject can include an interleukin, and/or interferon (IFN), and/or one or more suitable antibody-based reagent, such as denileukin diftitox and/or administration of an antibody-based reagent selected from the group consisting of ado-trastuzumab emtansine, alemtuzumab, atezolizumab, bevacizumab, blinatumomab, brentuximab vedotin, cetuximab, catumaxomab, gemtuzumab, ibritumomab tiuxetan, ilipimumab, natalizumab, nimotuzumab, nivolumab, ofatumumab, panitumumab, pembrolizumab, rituximab, tositumomab, trastuzumab
  • IFN
  • an immunotherapy assigned or administered to a subject can include an indoleamine 2,3-dioxygenase (IDO) inhibitor, adoptive T-cell therapy, virotherapy (T-VEC), and/or any other immunotherapy whose efficacy extensively depends on anti-tumor immunity.
  • IDO indoleamine 2,3-dioxygenase
  • T-VEC virotherapy
  • cancer can additionally be treated by other strategies. These include surgery, radiation therapy, hormone therapy, stem cell transplant, precision medicine, and the like; such treatments and the compounds and compositions utilized therein are known to those skilled in the art. Any such treatment strategies can be utilized in the practice of the present disclosure.
  • inventions of the disclosure can include methods of administering or treating an animal/human, which can involve treatment with an amount of at least one compound of the disclosure (e.g., Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp)) that is effective to treat the disease, condition, or disorder that the organism has, or is suspected of having, or is susceptible to, or to bring about a desired physiological effect.
  • an amount of at least one compound of the disclosure e.g., Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp)
  • the composition or pharmaceutical composition comprises at least one compound of the disclosure (e.g., Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp)) which can be administered to an animal (e.g., mammals, primates, monkeys, or humans) 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.
  • an animal e.g., mammals, primates, monkey
  • the dosage can be about 0.5 mg/kg human body weight or about 6.5 mg/kg human body weight.
  • some subjects e.g., mammals, mice, rabbits, feline, porcine, or canine
  • a dose or a therapeutically effective dose of a compound disclosed herein will be that which is sufficient to achieve a plasma concentration of the compound or its active metabolite(s) within a range 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.
  • 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 ⁇ M, 1-10 ⁇ M, 10-100 ⁇ M, 100-200 ⁇ M, 200-500 ⁇ M, or even 500-1000 ⁇ M, preferably about 1-10 nM, 10-100 nM, or 0.1- 1 ⁇ M.
  • hematopoietic cancers such as, for example, MDS and/or AML and/or DLBCL, etc., other types of cancers, inflammatory conditions, and/or autoimmune diseases, as described herein.
  • the compounds and/or pharmaceutical compounds of the disclosure can be administered in combination with one or more other therapeutic agents for a given disease, condition, or disorder.
  • the compounds and pharmaceutical compositions are preferably prepared and administered in dose units.
  • Solid dose units are tablets, capsules and suppositories.
  • different daily doses can be used for treatment of a subject, depending on activity of the compound, manner of administration, nature and severity of the disease or disorder, age and body weight of the subject.
  • the administration of the daily dose can be carried out both by single administration in the form of an individual dose unit or else several smaller dose units and also by multiple administrations of subdivided doses at specific intervals.
  • the compounds and pharmaceutical compositions contemplated herein can be administered locally or systemically in a therapeutically effective dose. Amounts effective for this use will, of course, depend on the severity of the disease or disorder and the weight and general state of the subject. Typically, dosages used in vitro can provide useful guidance in the amounts useful for in situ administration of the pharmaceutical composition, and animal models can be used to determine effective dosages for treatment of particular disorders.
  • the compounds and/or pharmaceutical compositions can include a unit dose of one or more compounds of the disclosure (e.g., compounds of Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp), and pharmaceutical compositions including the same) in combination with a pharmaceutically acceptable carrier and, in addition, can include other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, and excipients.
  • the carrier, vehicle or excipient can facilitate administration, delivery and/or improve preservation of the composition.
  • the one or more carriers include but are not limited to, saline solutions such as normal saline, Ringer's solution, PBS (phosphate-buffered saline), and generally mixtures of various salts including potassium and phosphate salts with or without sugar additives such as glucose.
  • Carriers can include aqueous and non-aqueous sterile injection solutions that can contain antioxidants, buffers, bacteriostats, bactericidal antibiotics, and solutes that render the formulation isotonic with the bodily fluids of the intended recipient; and aqueous and non-aqueous sterile suspensions, which can include suspending agents and thickening agents.
  • the one or more excipients can include, but are not limited to water, saline, dextrose, glycerol, ethanol, or the like, and combinations thereof.
  • Nontoxic auxiliary substances such as wetting agents, buffers, or emulsifiers may also be added to the composition.
  • Oral formulations can include such normally employed excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, and magnesium carbonate.
  • the quantity of active component in a unit dose preparation can be varied or adjusted from 0.1 mg to 10000 mg, more typically 1.0 mg to 1000 mg, most typically 10 mg to 500 mg, according to the particular application and the potency of the active component.
  • the composition can, if desired, also contain other compatible therapeutic agents.
  • the compounds of the disclosure can be administered to subjects by any number of suitable administration routes or formulations.
  • the compounds of the disclosure e.g., Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp)
  • the compounds of the disclosure can also be used to treat subjects for a variety of diseases.
  • Subjects include but are not limited to mammals, primates, monkeys (e.g., macaque, rhesus macaque, or pig tail macaque), humans, canine, feline, bovine, porcine, avian (e.g., chicken), mice, rabbits, and rats.
  • the route of administration of the compounds of the disclosure can be of any suitable route.
  • Administration routes can be, but are not limited to the oral route, the parenteral route, the cutaneous route, the nasal route, the rectal route, the vaginal route, and the ocular route.
  • administration routes can be parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration.
  • administration route can depend on the compound identity (e.g., the physical and chemical properties of the compound) as well as the age and weight of the animal/human, the particular disease (e.g., cancer or MDS), and the severity of the disease (e.g., stage or severity of cancer or MDS). Of course, combinations of administration routes can be administered, as desired.
  • Some embodiments of the disclosure include a method for providing a subject with a composition comprising one or more compounds of the disclosure (e.g., Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp)) described herein (e.g., a pharmaceutical composition) which comprises one or more administrations of one or more such compositions; the compositions may be the same or different if there is more than one administration.
  • a composition comprising one or more compounds of the disclosure (e.g., Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp) described herein (e.g., a pharmaceutical composition) which comprises one or more administrations of one or more such compositions; the compositions may be the same or different if there is more than one administration.
  • the present disclosure provide a method of increasing survivability in a subject diagnosed with acute myeloid leukemia (AML) or suspected of having AML, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of Formulas (I), (Ila)-(IIj), Formulas (Illa)-(IIIp), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or a composition comprising a compound of any one of Formulas (I), (Ila)-(IIj), Formulas (Illa)-(IIIp), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof.
  • AML acute myeloid leukemia
  • the survivability of the subject is increased compared to a subject treated with a therapeutically effective amount of the standard of care for AML.
  • the standard of care for AML comprises gilteritinib or a pharmaceutically acceptable salt thereof.
  • the survivability is increased by inhibiting at least one of IRAKI, IRAK4, and FLT3 in the subject.
  • the survivability is increased by inhibiting IRAKI and IRAK4 in the subject.
  • the survivability is increased by inhibiting IRAKI, IRAK4, and FLT3 in the subject.
  • the AML is BCL2 inhibitor resistant and/or FLT3 inhibitor resistant.
  • the method comprises administering to the subject the therapeutically effective amount of a compound of any one of Formulas (I), (Ila)-(IIj), Formulas (Illa)-(IIIp), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or the composition comprising a compound of any one of Formulas (I), (Ila)-(IIj), Formulas (Illa)-(IIIp), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof about every 6 hours, every 12 hours, every 18 hours, once a day, every other day, every 3 days, every 4 days, every 5 days, every 6 days, or once a week.
  • the method further comprise administering to the subject one or more additional therapies selected from: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, 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, an mAbs/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
  • the additional therapy is at least one of a BCL2 inhibitor, a BTK inhibitor, a gluococorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor.
  • the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof
  • the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof
  • the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone, or a pharmaceutically acceptable salt of any one thereof
  • the CDK inhibitor is selected from CDK4/6 inhibitor palbociclib, CDK7 inhibitor THZ1, and/or CDK9 inhibitors BAY 1251152 and atuveciclib, or a pharmaceutically acceptable salt of any one thereof
  • the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof.
  • the compound of any one of Formulas (I), (Ila)-(IIj), Formulas (Illa)-(IIIp), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or the composition comprising a compound of any one of Formulas (I), (Ila)- (Ilj), Formulas (Illa)-(IIIp), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof and the one or more additional therapies are administered separately in more than one administration or more than one composition.
  • the subject is a human.
  • the subject is a human and the survivability of the subject is increased by about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, about 11 years, about 12 years, about 13 years, about 14 years, about 15 years, about 16 years, about 17 years, about 18 years, about 19 years, or about 20 years compared to a subject treated with a therapeutically effective amount of the standard of care for AML.
  • the subject is a non-human mammal engrafted with AML cells.
  • the subject is a mouse engrafted with AML cells.
  • the AML cells are MOLM14-FLT3-ITD(D835Y) cells.
  • the subject is a mouse engrafted with AML cells wherein the survivability of the subject is increased by about 1 day, about 2 days, about 5 days, about 10 days, about 15 days, about 20 days, about 25 days, about 30 days, about 35 days, about 40 days, about 45 days, about 50 days, about 55 days, about 60 days, about 65 days, about 70 days, about 75 days, about 80 days, about 85 days, or about 90 days compared to a subject treated with a therapeutically effective amount of the standard of care for AML.
  • the ratio between toxicity and therapeutic effect for a particular compound is its therapeutic index and can be expressed as the ratio between LD50 (the amount of compound lethal in 50% of the population) and EDso (the amount of compound effective in 50% of the population).
  • LD50 the amount of compound lethal in 50% of the population
  • EDso the amount of compound effective in 50% of the population.
  • Compounds that exhibit high therapeutic indices are preferred.
  • Therapeutic index data obtained from in vitro assays, cell culture assays and/or animal studies can be used in formulating a range of dosages for use in humans.
  • the dosage of such compounds preferably lies within a range of plasma concentrations that include the ED50 with little or no toxicity.
  • the dosage can vary within this range depending upon the dosage form employed and the route of administration utilized.
  • R 2 is H, halogen, hydroxy, oxo, -CN, amino, -O-aryl, methanoyl (-COH), carboxy (-CO 2 H), C 1 - C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 alkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, aryl, heteroaryl, or fused ring heteroaryl, which amino, -O-aryl, methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 heteroalkyl, C 1 -C 7 alkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl
  • R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 are independently selected from 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, which 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
  • 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 (-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, which 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, cyclo
  • Clause 66. The compound of any of clauses 1-5, wherein R 3 is H, halogen, hydroxy, -CN, methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, or C 1 -C 7 alkoxy, which C 1 -C 7 alkyl, or C 2 -C 6 alkoxy, is optionally substituted with one or more of halogen, hydroxy, methanoyl (-COH), carboxy (-CO 2 H), nitro (-NO2), -NH2, -N(CH 3 ) 2 , cyano (-CN), ethynyl (- CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH 3 , -CON
  • Clause 77 The compound of any of clauses 1-6, wherein R 3 is H, halogen, hydroxy, -CN, methyl, -CF 3 , or methoxy.
  • Clause 13 The compound of any of clauses 1-12, wherein R 6 is [00264] Clause 14. The compound of any of clauses 1-13, wherein m is 0 or 1, wherein n is 0 or 1 , wherein o is 0 or 1 , and wherein p is 0 or 1.
  • Clause 15 The compound of any of clauses 1-14, wherein R 7 , R 8 , R 9 , and R 10 are H, and wherein at least one of R 11 , R 12 , R 13 , and R 14 is not H.
  • Clause 16 The compound of any of clauses 1-15, wherein R 11 , R 12 , R 13 , and R 14 are H, and wherein at least one of R 7 , R 8 , R 9 , and R 10 is not H.
  • R n , R 12 : , R 13 , and R 14 are H.
  • Clause 20 The compound of clause 18, wherein R 11 , R 12 , R 13 , and R 14 are H, and wherein at least one of R 7 , R 8 , R 9 , and R 10 is halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, C 1 -C 7 alkoxy, cycloalkyl, or spiro-fused cycloalkyl, which methanoyl (- COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 2 -C 6 alkoxy, cycloalkyl, or spiro-fused cycloalkyl is optionally substituted with one or more halogen.
  • Clause 21 The compound of any of clauses 1-20, wherein at least one of R 7 , R 8 ,
  • R 9 , and R 10 is halogen, hydroxyl, C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, C 1 -C 7 alkoxy, cycloalkyl, or spiro-fused cycloalkyl.
  • R10 is F, hydroxyl, methyl, methoxy, -CHF 2 , -CF 3 , spiro-fused cyclopropyl, spiro-fused cyclobutyl, or spiro-fused cyclopentyl.
  • Clause 23 The compound of clause 22, wherein both of R 7 and R 8 or both of R 9 and R 10 are F, or wherein both of R 7 and R 8 or both of R 9 and R 10 are methyl.
  • Clause 24 The compound of any of clauses 1-23, wherein at least one of R 11 , R 12 , R 13 , and R 14 is halogen, hydroxyl, C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, C 1 -C 7 alkoxy, cycloalkyl, or spiro-fused cycloalkyl.
  • Clause 25 The compound of clause 24, wherein at least one of R 11 , R 12 , R 13 , and
  • R 14 is F, hydroxyl, methyl, methoxy, -CHF 2 , -CF 3 , spiro-fused cyclopropyl, spiro-fused cyclobutyl, or spiro-fused cyclopentyl.
  • Clause 29 The compound of clause 27 or clause 28, wherein q is 0 or 1, wherein r is 0 or 1, wherein s is 0 or 1, wherein t is 0 or 1, wherein u is 0 or 1, wherein v is 0 or 1, wherein w is 0 or 1, and wherein x is 0 or 1 .
  • Clause 30 The compound of any of clauses 27-29, wherein 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 (-CO 2 H), C 1 -C 7 alkyl, C 1 -C 7 alkoxy, or spiro-fused cycloalkyl, which methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 2 -C 6 alkoxy, or spiro-fused cycloalkyl is optionally substituted with one or more halogen.
  • Clause 31 The compound of any of clauses 27-30, wherein one or more of R 15 , R 16 , R 17 ,, RR 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 H, or wherein all 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 H.
  • Clause 34 The compound of any of clauses 1-33, wherein the compound is selected from Compounds 1-64, as listed in Example 1 and Tables 1.
  • Clause 35 The compound of any of clauses 1-34, 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.
  • Clause 36 The compound of any of clauses 1-35, 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.
  • Clause 37 A composition comprising a compound of any of clauses 1-36.
  • Clause 38 The composition of clause 37, wherein the amount of the compound is from about 0.0001% (by weight total composition) to about 99%.
  • Clause 39 The composition of clause 37 or clause 38, further comprising a formulary ingredient, an adjuvant, or a carrier.
  • Clause 40 The composition of any of clauses 37-39, wherein the composition further comprises a BCL2 inhibitor.
  • Clause 41 The composition of any of clauses 37-40, wherein the composition is used in combination with a second composition comprising a BCL2 inhibitor.
  • Clause 42 The composition of any of clauses 37-41, wherein the BCL2 comprises venetoclax, or a salt, isomer, derivative or analog thereof.
  • Clause 43 The composition of any of clauses 37-42, wherein the composition is used in combination with oonnee oorr mmoorree chemotherapy, DNA methyltransferase inhibitor/hypomethylating agent, anthracycline, histone deacetylase (HDAC) inhibitor, purine nucleoside analogue (antimetabolite), isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor, antibody-drug conjugate, mAbs/immunotherapy, CAR-T cell therapy, Plk inhibitor, MEK inhibitor, CDK9 inhibitor, CDK8 inhibitor, retinoic acid receptor agonist, TP53 activator, smoothened receptor antagonist, ERK inhibitor, PI3K inhibitor, mTOR inhibitor, glucocorticoid receptor modulator, or EZH2 inhibitor, or one or more combinations thereof.
  • HDAC histone deacetylase
  • IDH1 and/or IDH2 isocitrate dehydrogenase 1
  • the DNA methyltransferase inhibitor/hypomethylating agent comprises azacitidine, decitabine, cytarabine, and/or guadecitabine; wherein the anthracycline comprises daunorubicin, idarubicin, doxorubicin, mitoxantrone, epirubicin, and/or CPX-351 (a combination cytarabine and daunorubicin in a fixed 5:1 molar ratio); wherein the histone deacetylase (HDAC) inhibitor comprises vorinostat, panobinostat, valproic acid, and/or pracinostat; wherein the purine nucleoside analogue (antimetabolite) comprises fludarabine, cladribine, and/or clofarabine; wherein the isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor comprises ivosideni
  • the mAbs/immunotherapy comprises Anti-CD70 (e.g. ARGX-110, cusatuzumab), a bispecific antibody (e.g. floteuzumab (CD 123 x CD 3 )), Anti-CTLA4 (e.g. ipilimumab), Anti-PDl/PDLl (e.g.
  • Anti-CD70 e.g. ARGX-110, cusatuzumab
  • a bispecific antibody e.g. floteuzumab (CD 123 x CD 3 )
  • Anti-CTLA4 e.g. ipilimumab
  • Anti-PDl/PDLl e.g.
  • the Plk inhibitor comprises volasertib and/or rigosertib; wherein the MEK inhibitor comprises trametinib, cobimetinib, selumetinib, pimasertib, and/or refametinib; wherein the CDK9 inhibitor comprises alvocidib and/or voruciclib; wherein the CDK8 inhibitor comprises SEL120; wherein the retinoic acid receptor agonist comprises ATRA (all-trans retinoic acid) and/or SY- 1425 (a selective RARa agonist); wherein the TP53 activator comprises APR-246 (Eprenetapopt); wherein the smoothened receptor antagonist comprises glasdegib; wherein the ERK inhibitor comprises an ERK
  • Clause 45 A method for providing a subject with a compound comprising one or more administrations of one or more compositions comprising the compound of any of clauses 1- 36, wherein the compositions may be the same or different if there is more than one administration.
  • Clause 46 The method of clause 45, wherein at least one of the one or more compositions further comprises a formulary ingredient.
  • Clause 47 The method of clause 45 or clause 46, wherein at least one of the one or more compositions comprises the composition of any of clauses 37-44.
  • Clause 48 The method of any of clauses 45-47, wherein at least one of the one or more administrations comprises parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration.
  • Clause 49 The method of any of clauses 45-48, wherein if there is more than one administration at least one composition used for at least one administration is different from the composition of at least one other administration.
  • Clause 50 The method of any of clauses 45-49, wherein the compound of at least one of the one or more compositions is administered to the subject in an amount of from about 0.005 mg/kg subject body weight to about 50 mg /kg subject body weight.
  • Clause 51 The method of any of clauses 45-50, wherein the subject is a mammal, preferably wherein the subject is a human, a rodent, or a primate.
  • Clause 52 A method for treating a disease or disorder, comprising one or more administrations to a subject of one or more compositions comprising the compound of any of clauses 1-36, wherein the compositions may be the same or different if there is more than one administration.
  • Clause 53 The method of clause 52, wherein the disease or disorder is responsive to at least one of interleukin- 1 receptor-associated kinase (IRAK) inhibition or fms-like tyrosine kinase 3 (FLT3) inhibition.
  • IRAK interleukin- 1 receptor-associated kinase
  • FLT3 fms-like tyrosine kinase 3
  • Clause 54 The method of clause 52 or clause 53, wherein at least one of the one or more compositions further comprises a formulary ingredient.
  • Clause 55 The method of clause 53 or clause54, wherein at least one of the one or more compositions comprises the composition of any of clauses 37-44.
  • Clause 56 The method of any of clauses 52-55, wherein at least one of the one or more administrations comprises parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, transdermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration.
  • Clause 57 The method of any of clauses 52-56, wherein at least one of the one or more administrations comprises an oral administration.
  • Clause 58 The method of any of clauses 52-57, wherein if there is more than one administration at least one composition used for at least one administration is different from the composition of at least one other administration.
  • Clause 59 The method of any of clauses 52-58, wherein the compound of at least one of the one or more compositions is administered to the subject in an amount of from about 0.005 mg/kg subject body weight to about 50 mg /kg subject body weight.
  • Clause 60 The method of any of clauses 52-59, wherein the subject is a mammal, preferably wherein the subject is a human, a rodent, or a primate.
  • Clause 61 The method of any of clauses 52-60, wherein the subject is in need of the treatment.
  • Clause 62 The method of any of clauses 52-61, wherein the method is for treating a hematopoietic cancer.
  • Clause 63 The method of any of clauses 52-62, wherein the method is for treating a myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML).
  • MDS myelodysplastic syndrome
  • AML acute myeloid leukemia
  • Clause 64 The method of any of clauses 52-62, 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 lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL with MYD88 mutation, follicular lymphoma, or marginal zone lymphoma.
  • CLL chronic lymphocytic leukemia
  • CML chronic myeloid leukemia
  • ALL acute lymphoblastic leukemia
  • bone marrow cancer non- Hodgkin lymphoma
  • Waldenstrom’s macroglobulinemia B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL with MYD88 mutation, follicular lymphoma, or marginal zone lympho
  • Clause 6655 The method of any of clauses 52-61, wherein the method is for treating at least one cancer selected from glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, Glioma, oral cancer, nasopharyngeal carcinoma, rectal cancer, stomach cancer, and uterine cancer, or one or more inflammatory diseases or autoimmune disease characterized by overactive IRAKI and/or IRAK4, or combinations thereof.
  • glioblastoma multiforme endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma,
  • Clause 66 The method of clause 65, wherein the method is for treating one or more inflammatory diseases or autoimmune disease selected from chronic inflammation (i.e., associated with viral and bacterial infection), sepsis, rheumatoid arthritis, hidradenitis suppurativa, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjogren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, or combinations thereof.
  • chronic inflammation i.e., associated with viral and bacterial infection
  • sepsis rheumatoid arthritis
  • hidradenitis suppurativa systemic lupus erythematosus
  • inflammatory bowel disease i.e., multiple sclerosis
  • psoriasis psoriasis
  • Sjogren’s syndrome Ankylosing spondylitis
  • Clause 67 The method of any of clauses 52-63, wherein the method is for treating MDS, MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, MDS with a mutation in isocitrate dehydrogenase 2, or wherein the method is for treating AML having enhanced IRAK4-Long expression and/or activity relative to IRAK4- Short, and/or wherein the AML is not driven by FLT3 mutations but expresses IRAK4-Long.
  • Clause 68 The method of clause 64, wherein the method is for treating DLBCL, and wherein the DLBCL comprises a L265P MYD88 mutant (ABC) subtype of DLBCL.
  • Clause 69 The method of clause 68, wherein the method further comprises administration of a composition comprising a BTK inhibitor.
  • Clause 70 The method of clause 69, wherein the BTK inhibitor comprises ibrutinib.
  • Clause 71 The method of any of clauses 52-70, wherein the subject is susceptible to AML and/or MDS, and/or wherein the method prevents or ameliorates future AML and/or MDS.
  • Clause 72 The method of any of clauses 52-71, wherein the method occurs after one or more of having MDS, having myeloproliferative disease, an occurrence of chemical exposure, an exposure to ionizing radiation, or a treatment for cancer.
  • Clause 73 The method of any of clauses 52-71, wherein the method further comprises administration of a composition comprising a BCL2 inhibitor, or wherein the at least one or more compositions comprises the compound of any of clauses 1-36 and further comprises a BCL2 inhibitor.
  • Clause 74 The method of clause 73 wherein the compound of any of clauses 1- 36 and the BCL2 inhibitor may be administered together or separately, in one or more administrations of one or more compositions.
  • Clause 76 The method of any of clauses 52-75, wherein the method further comprises administration of one or more additional therapy selected from one or more chemotherapy, DNA methyltransferase inhibitor/hypomethylating agent, anthracycline, histone deacetylase (HD AC) inhibitor, purine nucleoside analogue (antimetabolite), isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor, antibody-drug conjugate, mAbs/immunotherapy, CAR-T cell therapy, Plk inhibitor, MEK inhibitor, CDK9 inhibitor, CDK8 inhibitor, retinoic acid receptor agonist, TP53 activator, smoothened receptor antagonist, ERK inhibitor, PI3K inhibitor, mTOR inhibitor, glucocorticoid receptor modulator, or EZH2 inhibitor, or one or more combinations thereof.
  • additional therapy selected from one or more chemotherapy, DNA methyltransferase inhibitor/hypomethylating agent, anthracycline, histone de
  • the DNA methyltransferase inhibitor/hypomethylating agent comprises azacitidine, decitabine, cytarabine, and/or guadecitabine; wherein the anthracycline comprises daunorubicin, idarubicin, doxorubicin, mitoxantrone, epirubicin, and/or CPX-351 (a combination cytarabine and daunorubicin in a fixed 5:1 molar ratio); wherein the histone deacetylase (HD AC) inhibitor comprises vorinostat, panobinostat, valproic acid, and/or pracinostat; wherein the purine nucleoside analogue (antimetabolite) comprises fludarabine, cladribine, and/or clofarabine; wherein the isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor comprises ivo
  • the mAbs/Immunotherapy comprises Anti-CD70 (e.g. ARGX-110, cusatuzumab), a bispecific antibody (e.g. floteuzumab (CD 123 x CD 3 )), Anti-CTLA4 (e.g. ipilimumab), Anti-PDl/PDLl (e.g.
  • Anti-CD70 e.g. ARGX-110, cusatuzumab
  • a bispecific antibody e.g. floteuzumab (CD 123 x CD 3 )
  • Anti-CTLA4 e.g. ipilimumab
  • Anti-PDl/PDLl e.g.
  • the Plk inhibitor comprises volasertib and/or rigosertib; wherein the MEK inhibitor comprises trametinib, cobimetinib, selumetinib, pimasertib, and/or refametinib; wherein the CDK9 inhibitor comprises alvocidib and/or voruciclib; wherein the CDK8 inhibitor comprises SEL120; wherein the retinoic acid receptor agonist comprises ATRA (all-trans retinoic acid) and/or SY- 1425 (a selective RARa agonist); wherein the TP53 activator comprises APR-246 (Eprenetapopt); wherein the smoothened receptor antagonist comprises glasdegib; wherein the ERK inhibitor comprises an ERK
  • Clause 78 A compound according to any one of clauses 1-36, 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, wherein the compositions may be the same or different if there is more than one administration.
  • Clause 79 The compound for use of clause 78, wherein the disease or disorder is responsive to at least one of interleukin- 1 receptor-associated kinase (IRAK) inhibition or fms- like tyrosine kinase 3 (FLT3) inhibition.
  • IRAK interleukin- 1 receptor-associated kinase
  • FLT3 tyrosine kinase 3
  • Clause 80 The compound for use of clause 78 or clause 79, wherein at least one of the one or more compositions further comprises a formulary ingredient.
  • Clause 81 The compound for use of any one of clauses 78-80, wherein at least one of the one or more compositions comprises the composition of any of clauses 37-44.
  • Clause 82 The compound for use of any one of clauses 78-81, wherein at least one of the one or more administrations comprises parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, transdermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration.
  • Clause 83 The compound for use of any one of clauses 78-82, wherein at least one of the one or more administrations comprises an oral administration.
  • Clause 84 The compound for use of any one of clauses 78-83, wherein if there is more than one administration at least one composition used for at least one administration is different from the composition of at least one other administration.
  • Clause 85 The compound for use of any one of clauses 78-84, wherein the compound is administered to the subject in an amount of from about 0.005 mg/kg subject body weight to about 50 mg /kg subject body weight.
  • Clause 86 The compound for use of any one of clauses 78-85, wherein the subject is a mammal, preferably wherein the subject is a human, a rodent, or a primate.
  • Clause 8877 The compound for use of any one of clauses 78-86, wherein the subject is in need of the treatment.
  • Clause 88 The compound for use of any one of clauses 78-87, wherein the method is for treating a hematopoietic cancer.
  • Clause 89 The compound for use of any one of clauses 78-88, wherein the method is for treating MDS and/or AML.
  • Clause 90 The compound for use of any one of clauses 78-88, 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 lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B- cell lymphoma (DLBCL), DLBCL with MYD88 mutation, follicular lymphoma, or marginal zone lymphoma.
  • CLL chronic lymphocytic leukemia
  • CML chronic myeloid leukemia
  • ALL acute lymphoblastic leukemia
  • bone marrow cancer non-Hodgkin lymphoma
  • Waldenstrom’s macroglobulinemia B cell lymphoma, diffuse large B- cell lymphoma (DLBCL), DLBCL with MYD88 mutation, follicular lymphoma, or
  • Clause 91 The compound for use of any one of clauses 78-87, wherein the method is for treating at least one cancer selected from glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular ccaarrcciinnoommaa,, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, Glioma, oral cancer, nasopharyngeal carcinoma, rectal cancer, stomach cancer, and uterine cancer, or one or more inflammatory diseases or autoimmune disease characterized by overactive IRAKI and/or IRAK45 or combinations thereof.
  • cancer selected from glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder
  • Clause 92 The compound for use of clause 91, wherein the method is for treating one or more inflammatory diseases or autoimmune disease selected from chronic inflammation (i.e., associated with viral and bacterial infection), sepsis, rheumatoid arthritis, hidradenitis suppurativa, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjogren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, or combinations thereof.
  • chronic inflammation i.e., associated with viral and bacterial infection
  • sepsis rheumatoid arthritis
  • hidradenitis suppurativa systemic lupus erythematosus
  • inflammatory bowel disease i.e., multiple sclerosis
  • psoriasis psoriasis
  • Sjogren’s syndrome Ankylosing spondylitis
  • Clause 93 The compound for use of any one of clauses 78-89, wherein the method is for treating MDS, MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, MDS with a mutation in isocitrate dehydrogenase 2, or wherein the method is for treating AML having enhanced IRAK4-Long expression and/or activity relative to IRAK4-Short, and/or wherein the AML is not driven by FLT3 mutations but expresses IRAK4- Long.
  • Clause 94 The compound for use of clause 90, wherein the method is for treating DLBCL, and wherein the DLBCL comprises a L265P MYD88 mutant (ABC) subtype of DLBCL.
  • Clause 9955 The compound for use of clause 94, wherein the method further comprises administration of a composition comprising a BTK inhibitor.
  • Clause 96 The compound for use of clause 95, wherein the BTK inhibitor comprises ibrutinib.
  • Clause 97. The compound for use of any one of clauses 78-96, wherein the subject is susceptible to AML and/or MDS, and/or wherein the method prevents or ameliorates future AML and/or MDS.
  • Clause 98 The compound for use of any one of clauses 78-97, wherein the method occurs after one or more of having MDS, having myeloproliferative disease, an occurrence of chemical exposure, an exposure to ionizing radiation, or a treatment for cancer.
  • Clause 99 The compound for use of any one of clauses 78-98, wherein the method further comprises administration of a composition comprising a BCL2 inhibitor, or wherein the at least one or more compositions comprises the compound of any of clauses 1-36 and further comprises a BCL2 inhibitor.
  • Clause 100 The compound for use of clause 99, wherein the compound of any of clauses 1-36 and the BCL2 inhibitor may be administered together or separately, in one or more administrations of the one or more compositions.
  • Clause 101 The compound for use of clause 99 or clause 100, wherein the BCL2 inhibitor comprises venetoclax, or a salt, isomer, derivative or analog thereof.
  • Clause 102 The compound for use of any one of clauses 78-101, wherein the method further comprises administration of one or more additional therapy selected from one or more chemotherapy, DNA methyltransferase inhibitor/hypomethylating agent, anthracycline, histone deacetylase (HDAC) inhibitor, purine nucleoside analogue (antimetabolite), isocitrate dehydrogenase 1 oorr 2 (IDH1 and/or IDH2) inhibitor, antibody-drug conjugate, mAbs/immunotherapy, CAR-T cell therapy, Plk inhibitor, MEK inhibitor, CDK9 inhibitor, CDK8 inhibitor, retinoic acid receptor agonist, TP53 activator, smoothened receptor antagonist, ERK inhibitor, PI3K inhibitor, mTOR inhibitor, glucocorticoid receptor modulator, or EZH2 inhibitor, or one or more combinations thereof.
  • additional therapy selected from one or more chemotherapy, DNA methyltransferase inhibitor/hypomethylating agent, anthr
  • Clause 103 The compound for use of any one of clauses 78-102, wherein the DNA methyltransferase inhibitor/hypomethylating agent comprises azacitidine, decitabine, cytarabine, and/or guadecitabine; wherein the anthracycline comprises daunorubicin, idarubicin, doxorubicin, mitoxantrone, epirubicin, and/or CPX-351 (a combination cytarabine and daunorubicin in a fixed 5:1 molar ratio); wherein the histone deacetylase (HDAC) inhibitor comprises vorinostat, panobinostat, valproic acid, and/or pracinostat; wherein the purine nucleoside analogue (antimetabolite) comprises fludarabine, cladribine, and/or clofarabine; wherein the isocitrate dehydrogenase 1 or 2 (IDH1 and/or I
  • the mAbs/Immunotherapy comprises Anti-CD70 (e.g. ARGX-110, cusatuzumab), a bispecific antibody (e.g. floteuzumab (CD123 x CD 3 )), Anti-CTLA4 (e.g. ipilimumab), Anti-PDl/PDLl (e.g.
  • Anti-CD70 e.g. ARGX-110, cusatuzumab
  • a bispecific antibody e.g. floteuzumab (CD123 x CD 3 )
  • Anti-CTLA4 e.g. ipilimumab
  • Anti-PDl/PDLl e.g.
  • the Plk inhibitor comprises volasertib and/or rigosertib; wherein the MEK inhibitor comprises trametinib, cobimetinib, selumetinib, pimasertib, and/or refametinib; wherein the CDK9 inhibitor comprises alvocidib and/or voruciclib; wherein the CDK8 inhibitor comprises SEL120; wherein the retinoic acid receptor agonist comprises ATRA (all-trans retinoic acid) and/or SY- 1425 (a selective RARa agonist); wherein the TP53 activator comprises APR-246 (Eprenetapopt); wherein the smoothened receptor antagonist comprises glasdegib; wherein the ERK inhibitor comprises an ERK
  • a compound of Formula (I): or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof, wherein: 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 (-CO 2 H), C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 heteroalkyl, C 1 -C 7 alkoxy, cycloalkyl, spiro-fiised cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, wherein amino, amido, -O-aryl, methanoyl (-COH), carboxy (-
  • R 6 is 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 (-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-fiised cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, wherein methanoyl (-C0H), 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-fiised cycloalkyl, heterocyclyl, aryl,
  • 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 (- 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-fiised cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, wherein methanoyl (-C0H), carboxy (-CO 2 H), C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 alkoxy
  • (I) is a compound of Formula (Ilf): or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein:
  • 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, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy, wherein C 1 -C 6 alkyl and C 1 -C 6 alkoxy are each optionally substituted with one or more halogen atoms; and a is selected from 0, 1, 2, 3, 4, 5, and 6.
  • Clause 204 The compound of clause 202 or 203, wherein R 20f is H.
  • R 20f is selected from t-butyl, unsubstituted C 3 cycloalkyl, pyrrolidinyl, -OCH 3 , -OCH 2 CH 3 ,
  • R 20f is wherein R 27f is selected from -CH 3 ,
  • R 220fb bond or fuse to form oxetanyl
  • R 21f , R 22f , and R 23f are each H;
  • R 21f and R 23f are each F and R 22f is H;
  • R 21f and R 23f are each H and R 22f is F;
  • R 24fa , R 24fb , R 25fa , R 25fb , R 26fa , and R 26fb are each H;
  • R 25fa , R 25fb , R 26fa , and R 26fb are each H and R 24fa and/or R 24fb are selected from F, -CH 3 , and -CF 3 .
  • Clause 220066 The compound of any one of clauses 202-205, wherein the compound is selected from:
  • (I) is a compound of Formula (Ilg): or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein:
  • Clause 208 The compound of clause 207, wherein one or more of 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, - OH, and C 1 -C 6 alkyl.
  • Clause 210 The compound of any one of clauses 207-209, wherein at least one of (i)-(xi) applies:
  • R 20g is selected from t-butyl, unsubstituted C 3 cycloalkyl, wherein c is 1 or 2;
  • R 20g is 29g wherein R 29g is selected from unsubstituted C 3 cycloalkyl, -CH 3 ,
  • R 21g , R 22g , and R 23g are each H;
  • R 21g and R 23g are each F and R 22g is H;
  • R 21g and R 23g are each H and R 22g is F;
  • R 27gb is H
  • (I) is a compound of Formula (Uh): or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R 20h is selected from 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 alkoxy are each optionally substituted with one or more substituents selected from halogen and -OH, and wherein C 3 -C 6 cycloalkyl is optionally substituted with one or more substituents selected from C 1 -C 6 alkyl and halogen; and
  • R 21h , R 22h , and R. 23H are each independently selected from H and halogen.
  • R 21h , R 22h , and R 23h are each H;
  • R 21h and R 23h are each F and R 22h is H;
  • R 21h and R 23h are each H and R 22h is F;
  • Clause 221155. The compound of any one of clauses 212-214, wherein the compound is selected from:
  • Clause 221166 The compound of any one of clauses 201-215, wherein the compound is an inhibitor of at least one of IRAKI, IRAK4, and FLT3.
  • Clause 217 The compound of any one of clauses 201-216, wherein the compound is an inhibitor of at least two of IRAKI, IRAK4, and FLT3.
  • Clause 218 The compound of any one of clauses 201-217, wherein the compound is an inhibitor of IRAKI and IRAK4.
  • Clause 219. The compound of any one of clauses 201-217, wherein the compound is an inhibitor of IRAKI, IRAK4, and FLT3.
  • Clause 220 The compound of any one of clauses 216, 217, or 219, wherein FLT3 is selected from WT FLT3, activated FLT3, and mutated FLT3.
  • Clause 221. The compound of clause 220, wherein the mutated FLT3 is D835Y mutated FLT3 or F691L mutated FLT3.
  • Clause 222. A composition comprising a compound of any one of clauses 201- 221, wherein the composition further comprises a formulary ingredient, an adjuvant, or a carrier.
  • Clause 223. The composition of clause 222, wherein the composition is used in combination with one or more of: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, 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, an mAbs/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 ERK inhibitor
  • ABL1/2/SRC/EPHA2/LCK/YES1/KIT/PDGFRB/FYN inhibitor a famesyltransferase inhibitor, a BRAF/MAP2K1/MAP2K2 inhibitor, a Menin-KMT2A/MLL inhibitor, and a multikinase inhibitor.
  • Clause 222244. The composition of clause 223, wherein the composition is used in combination with a BCL2 inhibitor.
  • Clause 226 A method of treating a disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of clauses 201-221 or a composition of any one of clauses 222-225.
  • 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 201 and a formulary ingredient, an adjuvant, or a carrier.
  • Clause 228. The method of clause 226 or 227, wherein the disease or disorder is responsive to at least one of interleukin- 1 receptor-associated kinase (IRAK) inhibition and fins-like tyrosine kinase 3 (FLT3) inhibition.
  • IRAK interleukin- 1 receptor-associated kinase
  • FLT3 fins-like tyrosine kinase 3
  • Clause 229. The method of any one of clauses 226-228, wherein the administration comprises parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration.
  • Clause 230 The method of any one of clauses 226-229, wherein the compound is administered to the subject in an amount of from about 0.005 mg/kg subject body weight to about 1,000 mg /kg subject body weight.
  • Clause 23 The method of any one of clauses 226-230, wherein the disease or disorder comprises a hematopoietic cancer.
  • Clause 232 The method of any one of clauses 226-230, wherein the disease or disorder comprises myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML).
  • MDS myelodysplastic syndrome
  • AML acute myeloid leukemia
  • Clause 233 The method of any one of clauses 226-230, wherein the disease or disorder comprises lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL with MYD88 mutation, follicular lymphoma, or marginal zone lymphoma.
  • CLL chronic lymphocytic leukemia
  • CML chronic myeloid leukemia
  • ALL acute lymphoblastic leukemia
  • bone marrow cancer non-Hodgkin lymphoma
  • Waldenstrom’s macroglobulinemia B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL with MYD88 mutation, follicular lymphoma, or marginal zone lymphoma
  • Clause 223344 The method of any one of clauses 226-230, wherein the disease or disorder comprises at least one cancer selected from glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, Glioma, oral cancer, nasopharyngeal carcinoma, rectal cancer, stomach cancer, and uterine cancer, or one or more inflammatory diseases or autoimmune disease characterized by overactive IRAKI and/or IRAK4, or combinations thereof.
  • the disease or disorder comprises at least one cancer selected from glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell
  • Clause 223355 The method of any one of clauses 226-230, wherein the disease or disorder comprises one or more inflammatory diseases or autoimmune disease 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 mellitus, or combinations thereof.
  • inflammatory diseases or autoimmune disease 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 mellitus, or combinations thereof.
  • Clause 236 The method of any one of clauses 226-230, wherein the disease or disorder comprises:
  • MDS, MDS with a splicing factor mutation MDS with a mutation in isocitrate dehydrogenase 1, MDS with a mutation in isocitrate dehydrogenase 2;
  • AML with a splicing factor mutation AML having enhanced IRAK4-Long expression and/or activity relative to IRAK4-Short, and/or wherein the AML is not driven by FLT3 mutations but expresses IRAK4-Long.
  • Clause 238 The method of any one of clauses 226-230, wherein the disease or disorder comprises DLBCL, and wherein the DLBCL comprises a L265P MYD88 mutant (ABC) subtype of DLBCL or a S219C MYD88 mutant (GCB) subtype of DLBCL.
  • the disease or disorder comprises DLBCL
  • the DLBCL comprises a L265P MYD88 mutant (ABC) subtype of DLBCL or a S219C MYD88 mutant (GCB) subtype of DLBCL.
  • Clause 240 The method of clause 239, wherein the additional therapy is a BCL2 inhibitor.
  • Clause 242 The method of any one of clauses 226-241, wherein the disease or disorder is a BCL2 inhibitor resistant disease or disorder.
  • Clause 243 The method of any one of clauses 226-241, wherein the disease or disorder is a venetoclax resistant disease or disorder.
  • Clause 224444 The method of any one of clauses 226-241, wherein the disease or disorder is a FLT3 inhibitor resistant disease or disorder.
  • Clause 245. The method of any one of clauses 226-241, wherein the disease or disorder is BCL2 inhibitor resistant acute myeloid leukemia (AML).
  • AML BCL2 inhibitor resistant acute myeloid leukemia
  • Clause 246 The method of any one of clauses 226-241, wherein the disease or disorder is venetoclax resistant acute myeloid leukemia (AML).
  • AML venetoclax resistant acute myeloid leukemia
  • Clause 247 The method of any one of clauses 226-241, wherein the disease or disorder is FLT3 inhibitor resistant acute myeloid leukemia (AML).
  • AML FLT3 inhibitor resistant acute myeloid leukemia
  • Clause 248 The method of any one of clauses 226-241, wherein the disease or disorder is BCL2 inhibitor resistant refractory acute myeloid leukemia (AML).
  • AML BCL2 inhibitor resistant refractory acute myeloid leukemia
  • Clause 250 The method of any one of clauses 226-241, wherein the disease or disorder is FLT3 inhibitor resistant refractory acute myeloid leukemia (AML).
  • AML FLT3 inhibitor resistant refractory acute myeloid leukemia
  • Clause 25 The method of any one of clauses 226-241, wherein the disease or disorder is BCL2 inhibitor resistant relapsed acute myeloid leukemia (AML).
  • AML BCL2 inhibitor resistant relapsed acute myeloid leukemia
  • Clause 252 The method of any one of clauses 226-241, wherein the disease or disorder is venetoclax resistant relapsed acute myeloid leukemia (AML).
  • AML venetoclax resistant relapsed acute myeloid leukemia
  • Clause 253 The method of any one of clauses 226-241, wherein the disease or disorder is FLT3 inhibitor resistant relapsed acute myeloid leukemia (AML).
  • AML FLT3 inhibitor resistant relapsed acute myeloid leukemia
  • Clause 255 The method of clause 239, wherein the compound of any one of clauses 201-221 or the composition of any one of clauses 222-225 and the one or more additional therapies are administered separately in more than one administration or more than one composition.
  • Clause 256 The method of any one of clauses 226-255, wherein the disease or disorder is alleviated by inhibiting at least one of IRAKI, IRAK4, and FLT3 in the subject.
  • Clause 257 The method of any one of clauses 226-256, wherein the disease or disorder is alleviated by inhibiting at least two of IRAKI, IRAK4, and FLT3 in the subject.
  • Clause 258 The method of any one of clauses 226-255, wherein the disease or disorder is alleviated by inhibiting IRAKI and IRAK4 in the subject.
  • Clause 260 The method of any one of clauses 256, 257, or 259, wherein FLT3 is selected from WT FLT3, activated FLT3, and mutated FLT3.
  • R 6 is 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 (-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, wherein 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
  • 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 (- 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, wherein 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,
  • (I) is a compound of Formula (Ilf): or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein:
  • R 21f , R 22f , and R 23f are each independently selected from H and halogen;
  • R24f a , R 24fb , R 25fa , R 25fb , R 26fa , and R 26fb are each independently selected from H, halogen, -OH, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy, wherein C 1 -C 6 alkyl and C 1 -C 6 alkoxy are each optionally substituted with one or more halogen atoms; and a is selected from 0, 1, 2, 3, 4, 5, and 6.
  • R 25fa , R 25fb , R 26fa , and R 26fb is independently selected from halogen, -OH, optionally substituted C 1 -C 6 alkyl, and optionally substituted C 1 -C 6 alkoxy.
  • R 20f is selected from t-butyl, unsubstituted C 3 cycloalkyl, pyrrolidinyl, -OCH 3 , -
  • R 20f is wherein R 27f is selected from -CH 3 ,
  • R 220fa and R 220fb bond or fuse to form oxetanyl
  • R 21f , R 22f , and R 23f are each H;
  • R 21f and R 23f are each F and R 22f is H;
  • R 21f and R 23f are each H and R 22f is F;
  • R 22f and R 23f are each H and R 21f is F;
  • R 21f and R 22f are each H and R 23f is F;
  • R 24fa , R 24fb , R 25fa , R 25fb , R 26fa , and R 26fb are each H;
  • R 25fa , R 25fb , R 26fa , and R 26fb are each H andR 24fa and/or R 24fb are selected from F, -CH 3 , and -CF 3 .
  • Clause 330066 The compound of any one of clauses 302-305, wherein the compound is selected from:
  • (I) is a compound of Formula (Ilg): or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein:
  • R 21g , R 22g , and R23g are each independently selected from H and halogen; and 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 C 1 -C 6 alkyl.
  • Clause 310 The compound of any one of clauses 307-309, wherein at least one of (i)-(xiii) applies:
  • R 20g is selected from t-butyl, unsubstituted C 3 cycloalkyl, wherein c is 1 or 2; wherein R 29g is selected from unsubstituted C 3 cycloalkyl, -
  • R 21g , R 22g , and R 22g are each H;
  • R 21g and R 23g are each F and R 22g is H;
  • R 21g and R 23g are each H and R 22g is F;
  • R 22g and R 23g are each H and R 21g is F;
  • R 21g and R 22g are each H and R 23g is F;
  • R 28gb isH andR 26gb isF or-CH 3 .
  • (I) is a compound of Formula (Ilh): Formula (Ilh), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: is selected from
  • R 20h is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and C 1 -C 6 cycloalkyl, wherein C 1 -C 6 alkyl and C 1 -C 6 alkoxy are each optionally substituted with one or more substituents selected from halogen and -OH, and wherein C 3 -C 6 cycloalkyl is optionally substituted with one or more substituents selected from C 1 -C 6 alkyl and halogen; and R 21h , R 22h , and R 23h are each independently selected from H and halogen.
  • R 20h is selected from
  • R 21h , R 22h , and R 23h are each H;
  • R 21h and R 23h are each F and R 22h is H;
  • R2111 and R 23h are each H and R 22h is F;
  • Clause 315 The compound of any one of clauses 312-314, wherein the compound is selected from:
  • Clause 331166 The compound of any one of clauses 301-315, wherein the compound is an inhibitor of at least one of IRAKI, IRAK4, and FLT3.
  • Clause 317 The compound of any one of clauses 301-316, wherein the compound is an inhibitor of at least two of IRAKI, IRAK4, and FLT3.
  • Clause 318 The compound of any one of clauses 301-317, wherein the compound is an inhibitor of IRAKI and IRAK4.
  • Clause 319 The compound of any one of clauses 301-317, wherein the compound is an inhibitor of IRAKI, IRAK4, and FLT3.
  • Clause 320 The compound of any one of clauses 316, 317, or 319, wherein FLT3 is selected from WT FLT3, activated FLT3, and mutated FLT3.
  • Clause 322 A composition comprising a compound of any one of clauses 301- 321, wherein the composition further comprises a formulary ingredient, an adjuvant, or a carrier.
  • Clause 323. The composition of clause 322, wherein the composition is used in combination with one or more of: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, 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, an mAbs/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 ERK inhibitor including
  • Clause 332244. The composition of clause 323, wherein the composition is used in combination with at least one of a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor.
  • Clause 325 The composition of clause 324, wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof.
  • Clause 326 The composition of clause 324, wherein the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof.
  • Clause 327 The composition of clause 324, wherein the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone, or a pharmaceutically acceptable salt of any one thereof.
  • Clause 328 The composition of clause 324, wherein the CDK inhibitor is a CDK4 inhibitor, a CDK6 inhibitor, a CDK7 inhibitor, and/or a CDK9 inhibitor.
  • Clause 329 The composition of clause 328 wherein the CDK inhibitor is selected from CDK4/6 inhibitor Palbociclib, CDK7 inhibitor THZ1, and/or CDK9 inhibitors BAY 1251152 and Atuveciclib, or a pharmaceutically acceptable salt of any one thereof.
  • Clause 330 The composition of clause 324, wherein the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof.
  • Clause 331 A method of treating a disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of clauses 301-321 or a composition of any one of clauses 322-330.
  • Clause 332 The method of clause 331, wherein the method comprises administering to the subject a composition comprising the therapeutically effective amount of the compound of clause 301 and a formulary ingredient, an adjuvant, or a carrier.
  • Clause 333 The method of clause 331 or 332, wherein the disease or disorder is responsive to at least one of interleukin- 1 receptor-associated kinase (IRAK) inhibition and fins-like tyrosine kinase 3 (FLT3) inhibition.
  • IRAK interleukin- 1 receptor-associated kinase
  • FLT3 fins-like tyrosine kinase 3
  • Clause 334 The method of any one of clauses 331-333, wherein the administration comprises parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration.
  • Clause 335 The method of any one of clauses 331-334, wherein the compound is administered to the subject in an amount of from about 0.005 mg/kg subject body weight to about 1,000 mg /kg subject body weight.
  • Clause 336 The method of any one of clauses 331-335, wherein the disease or disorder comprises a hematopoietic cancer.
  • Clause 337 The method of any one of clauses 331-335, wherein the disease or disorder comprises myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML).
  • MDS myelodysplastic syndrome
  • AML acute myeloid leukemia
  • the disease or disorder comprises lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL with MYD88 mutation, follicular lymphoma, or marginal zone lymphoma.
  • CLL chronic lymphocytic leukemia
  • CML chronic myeloid leukemia
  • ALL acute lymphoblastic leukemia
  • bone marrow cancer non-Hodgkin lymphoma
  • Waldenstrom’s macroglobulinemia B cell lymphoma
  • DLBCL diffuse large B-cell lymphoma
  • DLBCL with MYD88 mutation follicular lymphoma
  • marginal zone lymphoma marginal zone lymphoma
  • Clause 339 The method of any one of clauses 331-335, wherein the disease or disorder comprises at least one cancer selected from glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, Glioma, oral cancer, nasopharyngeal carcinoma, rectal cancer, stomach cancer, and uterine cancer, or one or more inflammatory diseases or autoimmune disease characterized by overactive IRAKI and/or IRAK4, or combinations thereof.
  • the disease or disorder comprises at least one cancer selected from glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma
  • Clause 340 The method of any one of clauses 331-335, wherein the disease or disorder comprises one or more inflammatory diseases or autoimmune disease 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 mellitus, or combinations thereof.
  • inflammatory diseases or autoimmune disease 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 mellitus, or combinations thereof.
  • Clause 34 The method of any one of clauses 331-335, wherein the disease or disorder comprises:
  • MDS, MDS with a splicing factor mutation MDS with a mutation in isocitrate dehydrogenase 1, MDS with a mutation in isocitrate dehydrogenase 2;
  • AML with a splicing factor mutation AML having enhanced IRAK4-Long expression and/or activity relative to IRAK4-Short, and/or wherein the AML is not driven by FLT3 mutations but expresses IRAK4-Long.
  • ABL1/2/SRC/EPHA2/LCK/YES1/KIT/PDGFRB/FYN inhibitor a famesyltransferase inhibitor, a BRAF/MAP2K1/MAP2K2 inhibitor, a Menin-KMT2A/MLL inhibitor, and a multikinase inhibitor.
  • Clause 345 The method of any one of clauses 331-344, wherein the disease or disorder is responsive to at least one of BCL2 inhibition, BTK inhibition, CDK inhibition, and DNA methyltransferase inhibition; or wherein the disease or disorder is sensitive to anti- inflammatory glucocorticoids.
  • Clause 347 The method of clause 346, wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof.
  • Clause 348 The method of any one of clauses 331-347, wherein the disease or disorder is a BCL2 inhibitor resistant disease or disorder.
  • Clause 349 The method of any one of clauses 331-347, wherein the disease or disorder is a venetoclax resistant disease or disorder.
  • Clause 350 The method of any one of clauses 331-347, wherein the disease or disorder is BCL2 inhibitor resistant acute myeloid leukemia (AML).
  • AML BCL2 inhibitor resistant acute myeloid leukemia
  • Clause 35 The method of any one of clauses 331-347, wherein the disease or disorder is venetoclax resistant acute myeloid leukemia (AML).
  • AML venetoclax resistant acute myeloid leukemia
  • Clause 352 The method of any one of clauses 331-347, wherein the disease or disorder is BCL2 inhibitor resistant refractory acute myeloid leukemia (AML).
  • AML BCL2 inhibitor resistant refractory acute myeloid leukemia
  • Clause 354 The method of any one of clauses 331-347, wherein the disease or disorder is BCL2 inhibitor resistant relapsed acute myeloid leukemia (AML).
  • AML BCL2 inhibitor resistant relapsed acute myeloid leukemia
  • Clause 355. The method of any one of clauses 331-347, wherein the disease or disorder is venetoclax resistant relapsed acute myeloid leukemia (AML).
  • AML venetoclax resistant relapsed acute myeloid leukemia
  • Clause 357 The method of any one of clauses 331-347, wherein the disease or disorder is a BTK inhibitor resistant disease or disorder.
  • Clause 361. The method of any one of clauses 331-347, wherein the disease or disorder is a dexamethasone, methylprednisolone, or prednisolone resistant disease or disorder.
  • Clause 364 The method of any one of clauses 331-347, wherein the disease or disorder is a palbociclib, THZ1, BAY 12511152, or atuveciclib resistant disease or disorder.
  • Clause 367 The method of any one of clauses 331-347, wherein the disease or disorder is an azacitidine resistant disease or disorder.
  • Clause 336688 The method of any one of clauses 331-347, wherein the disease or disorder is a BCL2 inhibitor and DNA methyltransferase inhibitor resistant disease or disorder
  • Clause 369 The method of any one of clauses 331-347, wherein the disease or disorder is a venetoclax and azacitidine resistant disease or disorder.
  • Clause 37 The method of any one of clauses 331-347, wherein the disease or disorder is a FLT3 inhibitor resistant disease or disorder.
  • Clause 337722 The method of any one of clauses 331-347, wherein the disease or disorder is FLT3 inhibitor resistant acute myeloid leukemia (AML).
  • AML FLT3 inhibitor resistant acute myeloid leukemia
  • Clause 373 The method of any one of clauses 331-347, wherein the disease or disorder is FLT3 inhibitor resistant refractory acute myeloid leukemia (AML).
  • AML FLT3 inhibitor resistant refractory acute myeloid leukemia
  • Clause 374 The method of any one of clauses 331-347, wherein the disease or disorder is FLT3 inhibitor resistant relapsed acute myeloid leukemia (AML).
  • AML FLT3 inhibitor resistant relapsed acute myeloid leukemia
  • Clause 375 The method of clause 344, wherein the compound of any one of clauses 301-321 or the composition of any one of clauses 322-330 and the one or more additional therapies are administered together in one administration or composition.
  • Clause 376 The method of clause 344, wherein the compound of any one of clauses 301-321 or the composition of any one of clauses 322-330 and the one or more additional therapies are administered separately in more than one administration or more than one composition.
  • Clause 377. The method of any one of clauses 331-376, wherein the disease or disorder is alleviated by inhibiting at least one of IRAKI, IRAK4, and FLT3 in the subject.
  • Clause 378 The method of any one of clauses 331-376, wherein the disease or disorder is alleviated by inhibiting at least two of IRAKI, IRAK4, and FLT3 in the subject.
  • Clause 379 The method of any one of clauses 331-376, wherein the disease or disorder is alleviated by inhibiting IRAKI and IRAK4 in the subject.
  • Clause 380 The method of any one of clauses 331-376, wherein the disease or disorder is alleviated by inhibiting IRAKI, IRAK4, and FLT3 in the subject.
  • Clause 383 The method of any one of clauses 331-382, wherein the compound is a compound of any one of Formula (Ila)-(IIh), Formula (Illa)-(IIIp), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof.
  • R 6 is 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 (-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, wherein 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
  • 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 (- 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, wherein 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,
  • Clause 402. The compound of clause 401, wherein the compound of Formula (I) is a compound of Formula (IIi): or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein:
  • R 20i is selected from C 1 -C 6 alkyl and C 1 -C 6 alkoxy, wherein C 1 -C 6 alkyl and C 1 -C 6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen;
  • R 21i , R 22i , and R 23i are each independently selected from H and halogen; and
  • R 24ia , R 24ib , R 25ia , R 25ib , R 26ia , and R 26ib are each independently selected from H, halogen, - OH, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy, wherein C 1 -C 6 alkyl and C 1 -C 6 alkoxy are each optionally substituted with one or more halogen atoms.
  • Clause 440044 The compound of clause 402, wherein R 21i is halogen, R 22i and R 23i are each H; or R 23i is halogen, R 21i and R 22i are each H.
  • Clause 405. The compound of any one of clauses 402-404, wherein one or more of R 24ia , R 24ib , R 25ia , R 25ib , R 26ia , and R 26ib is halogen.
  • R 21i is F, R 22i and R 23i are each H;
  • R 23i is F, R 21i and R 22i are each H;
  • R 24ia , R 25ia , R 25ib , R 26ia , R 26ib are each H andR 24ib is F.
  • (I) is a compound of Formula (Ilj): or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein:
  • R 20j is selected from C 1 -C 6 alkyl and C 1 -C 6 alkoxy, wherein C 1 -C 6 alkyl and C 1 -C 6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen;
  • R 21j , R 22j , and R 23j are each independently selected from H and halogen;
  • R 24ja , R 24jb , R 25ja , R 25jb , R 26ja , R 26jb , R 27ja , R 27jb , R 25ja , and R 28jb are each independently selected from H, halogen, -OH, and C 1 -C 6 alkyl.
  • Clause 409 The compound of clause 408, with the proviso that when R 20j is R 21j is halogen and R 22j and R 23j are each H; or R 23j is halogen and R 21j and R 22j are each
  • R 21j is F, R 22j and R 23j are each H;
  • R 23j is F
  • R 21j and R 22j are each H
  • each of R 24ja , R 24jb , R 25ja , R 25jb , R 26ja , R 26jb , R 27ja , R 27jb , R 25ja , and R 28jb is H
  • each of R 24ja , R 24jb , R 25ja , R 25jb , R 26ja , R 26jb , R 27ja , R 27jb , and R 25ja is H and R 28jb is F.
  • Clause 413 The compound of any one of clauses 408-412, wherein the compound is selected from:
  • Clause 414 The compound of any one of clauses 401-413, wherein the compound is an inhibitor of at least one of IRAKI, IRAK4, and FLT3.
  • Clause 441155. The compound of any one of clauses 401-414, wherein the compound is an inhibitor of at least two of IRAKI, IRAK4, and FLT3.
  • Clause 416 The compound of any one of clauses 401-415, wherein the compound is an inhibitor of IRAKI and IRAK4.
  • Clause 4417 The compound of any one of clauses 401-415, wherein the compound is an inhibitor of IRAKI, IRAK4, and FLT3.
  • Clause 420 A composition comprising a compound of any one of clauses 401- 419, wherein the composition further comprises a formulary ingredient, an adjuvant, or a carrier.
  • composition of clause 420 wherein the composition is used in combination with one or more of: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, 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, an mAbs/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,
  • Clause 422 The composition of clause 421, wherein the composition is used in combination with at least one of a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor.
  • Clause 423 The composition of clause 422, wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof.
  • Clause 424 The composition of clause 422, wherein the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof.
  • Clause 426 The composition of clause 422, wherein the CDK inhibitor is a CDK4 inhibitor, a CDK6 inhibitor, a CDK7 inhibitor, and/or a CDK9 inhibitor.
  • Clause 427 The composition of clause 422, wherein the CDK inhibitor is selected from CDK4/6 inhibitor Palbociclib, CDK7 inhibitor THZ1, and/or CDK9 inhibitors BAY 1251152 and Atuveciclib, or a pharmaceutically acceptable salt of any one thereof.
  • Clause 428 The composition of clause 422, wherein the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof.
  • Clause 429 A method of treating a disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of clauses 401-419 or a composition of any one of clauses 420-428.
  • Clause 433 The method of any one of clauses 429-432, wherein the compound is administered to the subject in an amount of from about 0.005 mg/kg subject body weight to about 1,000 mg /kg subject body weight.
  • Clause 434 The method of any one of clauses 429-433, wherein the disease or disorder comprises a hematopoietic cancer.
  • Clause 435 The method of any one of clauses 429-433, wherein the disease or disorder comprises myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML).
  • MDS myelodysplastic syndrome
  • AML acute myeloid leukemia

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Abstract

Some embodiments of the disclosure include inventive compounds (e.g., compounds of Formula (I)) and compositions (e.g., pharmaceutical compositions) which inhibit IRAK and/or FLT3 and which can be used for treating, for example, certain diseases. Some embodiments include methods of using the inventive compound (e.g., in compositions or in pharmaceutical compositions) for administering and treating (e.g., diseases such as hematopoietic cancers, myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), etc.). Additional embodiments provide disease treatment using combinations of the inventive IRAK and/or FLT3 inhibiting compounds with other therapies, such as cancer therapies.

Description

MULTI-CYCLIC IRAK AND FLT3 INHIBITING COMPOUNDS AND USES THEREOF
GOVERNMENT RIGHTS
[0001] This invention was made in the performance of a Cooperative Research and Development Agreement with the National Institutes of Health, an Agency of the Department of Health and Human Services. The Government of the United States has certain rights in this invention.
CROSS-REFERENCE TO RELATED APPLICATIONS
[0002] The present application claims priority to U.S. Provisional Application No.
63/354,398, filed June 22, 2022, the entirety of which is incorporated herein by reference.
FIELD OF THE DISCLOSURE
[0003] The present disclosure generally relates to compounds and compositions which are kinase inhibitors and the use of the same in treating diseases and disorders, including cancers.
BACKGROUND
[0004] Myelodysplastic syndromes (MDS) are malignant, potentially fatal blood diseases that arise from a defective hematopoietic stem/progenitor cell, confer a predisposition to acute myeloid leukemia (AML) (Corey et al., 2007; Nimer, 2008), and often progress to chemotherapy-resistant secondary acute myeloid leukemia (sAML). A majority of patients having MDS die of marrow failure, immune dysfunction, and/or transformation to overt leukemia.
[0005] MDS are heterogeneous diseases with few treatment options, as there is a lack of effective medicines capable of providing a durable response. Current treatment options for MDS are limited but include allogeneic HSC transplantation, demethylating agents, and immunomodulatory therapies (Ebert, 2010). While hemopoietic stem cell (HSC) transplantation can be used as a curative treatment for MDS, this option is unavailable to many older patients, who instead receive supportive care and transfusions to ameliorate disease complications. Unfortunately, MDS clones can persist in the marrow even after HSC transplantation, and the disease invariably advances (Tehranchi et al., 2010). For advanced disease or high-risk MDS, patients may also receive immunosuppressive therapy, epigenetic modifying drugs, and/or chemotherapy (Greenberg, 2010). Despite recent progress, most MDS patients exhibit treatment-related toxicities or relapse (Sekeres, 2010a). Overall, the efficacy of these treatments is variable, and generally life expectancies are only slightly improved as compared to supportive care. The complexity and heterogeneity of MDS, and the lack of human xenograft models are obstacles which are challenging for identifying and evaluating novel molecular targets for this disease.
[0006] Approximately 30% of MDS patients also develop aggressive AML due to acquisition of additional mutations in the defective hematopoietic stem/progenitor cell (HSPC) (Greenberg et al., 1997). AML is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute leukemia affecting adults, and its incidence increases with age. Although AML is a relatively rare disease, accounting for approximately 1.2% of cancer deaths in the United States, its incidence is expected to increase as the population ages. Several risk factors and chromosomal abnormalities have been identified, but the specific cause is not clear. As an acute leukemia, AML progresses rapidly and is typically fatal within weeks or months if left untreated. The prognosis for AML that arises from MDS is worse as compared to other types of AML.
[0007] Several compounds are known to treat blood disorders and cancers (e.g. MDS, AML), but do so inadequately. While some known compounds, such as Quizartinib, Gilteritinib, and Crenolanib, can be used to treat AML, some of these treatments do not result in complete remission or partial remission. In some instances, for example, treatment can result in adaptive resistance or selecting mutations that are resistant to inhibitors, as with Quizartinib, in particular, where repeated administration can lead to desensitization in tumor cell suppression of proliferation (Melgar et al., 2019).
[0008] In treating MDS and/or AML, there is a need to develop therapies capable of inhibiting the adaptive resistance mechanism, to improve survival in the context of AML and MDS. There is also an unmet need in AML for drugs that increase overall survival, decrease the length of hospital stay as well as hospital readmission rates, overcome acquired resistance to other treatments, and increase the success rate for hematopoietic stem cell transplant. There is additionally a need for drugs for treating MDS which can slow the conversion rate to AML, and decrease transfusion dependence. [0009] It is therefore necessary to develop treatments and methods of effectively treating MDS and/or AML, and/or other conditions or disorders characterized by dysregulated (e.g., hyperactive) IRAK (e.g., IRAK 1 and/or 4). Additionally, in doing so, it will be important to determine whether a patient is likely to be responsive to a particular treatment or method of treatment. Certain embodiments of the disclosure can address one or more of these issues.
SUMMARY OF THE DISCLOSURE
[0010] In one aspect, the present disclosure provides compound of Formula (I):
Figure imgf000004_0001
(I), or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof, wherein: R2, R3, R4, and R5 are each independently selected from H, halogen, hydroxy, oxo (=O), -CN, amino, amido, -O-aryl, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, wherein amino, amido, -O-aryl, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, -NHCH3, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl which is substituted with cycloalkyl, wherein two adjacent optional substituents can bond or fuse to form a ring; R6 is selected from
Figure imgf000005_0001
and R14 are each independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (- COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, wherein methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more halogen and/or C1-C6 alkyl; R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R29, R29, and R30 are each independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, wherein methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more halogen and/or C1-C6 alkyl; and m, n, o, p, q, r, s, t, u, v, w, and x are each independently selected from 0, 1, 2, 3, 4, or 5; where q+r+s+t is at least 1, and where u+v+w+x is at least 1.
[0011] In one embodiment, the compound of Formula (I) is a compound of Formula (IIi):
Figure imgf000005_0002
Formula (IIi), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R20i is selected from C1-C6 alkyl and C1- C6 alkoxy, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen; R211, R22i, and R23i are each independently selected from H and halogen; and R24ia, R24ib, R25ia, R25ib, R26ia, and R26ib are each independently selected from H, halogen, -OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more halogen atoms. In one embodiment, the compound is a compound of Formula (IIi), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, with the proviso that when R20i is
Figure imgf000006_0001
R21i is halogen and R22i and R23i are each H; or R23i is halogen and R21i and R22i are each H. In one embodiment, R21i is halogen, R22i and R23i are each H; or R23i is halogen, R21i and R22i are each H. In one embodiment, one or more of R24ia, R24ib, R25ia, R25ib, R26ia, and R26ib is halogen. In one embodiment, at least one of (i)-(iv) applies: (i) R20i is (ii) R21i is F, R22i and R23i are
Figure imgf000006_0002
each H; (iii) R23i is F, R21i and R22i are each H; (iv) R24ia, R25ia, R25ib, R26ia, R26ib are each H and R24ib is F. In one embodiment, the compound of Formula (IIi) is selected from:
Figure imgf000006_0003
[0012] In one embodiment, the compound of Formula (I) is a compound of Formula (Ilj):
Formula (Ilj), or a salt, ester, solvate, optical isomer, geometric
Figure imgf000006_0004
isomer, or salt of an isomer thereof; wherein: is selected from and
Figure imgf000006_0006
Figure imgf000006_0005
Figure imgf000006_0007
R20j is selected from C1-C6 alkyl and C1-C6 alkoxy, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen; R21j, R22j, and R23j are each independently selected from H and halogen; and R24ja, R24jb, R25ja, R25jb, R26ja, R26jb, R27ja, R27jb, R28ja, and R28jb are each independently selected from H, halogen, -OH, and C1-C6 alkyl. In one embodiment, the compound is a compound of Formula (IIj) with the proviso that when R20j is , R
Figure imgf000007_0001
j s aogen and R22j and R23j are each H; or R23j is halogen and R21j and R22j are each H. In one embodiment, R21j is halogen, R22j and R23j are each H; or R23j is halogen, R21j and R22j are each H. In one embodiment, one or more of R24ja, R24jb, R25ja, R25jb, R26ja, R26jb, R27ja, R27jb, R28ja, and R28jb is halogen. In one embodiment, at least one of (i)-(v) applies: (i) R20j is F, R22j and R23j are each H; (iii) R23j is F, R21j
Figure imgf000007_0002
R R and R22j are each H; (iv) R24jb, R25ja, R25jb, R26ja, R26jb
Figure imgf000007_0003
, E R27ja, R27jb, R28ja, and R28jb is H; (v) is 4jb, R25ja, R25jb,
Figure imgf000007_0005
R26ja, R26jb, R27ja, R28ja, and R28jb is H and R27jb is F. In one embodiment, the compound of Formula (IIj) is selected from:
Figure imgf000007_0004
. [0013] In one embodiment, the compound of Formula (IIi), (IIj), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, is an inhibitor of at least one of IRAK1, IRAK4, and FLT3. In one embodiment, the compound of Formula (IIi), (IIj), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, is an inhibitor of IRAKI and IRAK4. In one embodiment, the compound of Formula (IIi), (Ilj), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, is an inhibitor of IRAKI, IRAK4, and FLT3.
[0014] In another aspect, the present disclosure provides a composition comprising a compound of any one of Formula (IIi), (Ilj), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, wherein the composition further comprises a formulary ingredient, an adjuvant, or a carrier. In one embodiment, the composition is used in combination with one or more of: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, 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, an mAbs/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, 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, an NEDD8-activator, an MDM2 inhibitor, a PLK1 inhibitor, an Aura A inhibitor, an aurora kinase inhibitor, an EGFR inhibitor, an AuroraB/C/VEGFRl/2/3/FLT3/CSF- IR/Kit/PDGFRA/B inhibitor, aann AKT 1, 2, and/or 3 inhibitor, a
ABL1/2/SRC/EPHA2/LCK/YES1/KIT/PDGFRB/FYN inhibitor, a famesyltransferase inhibitor, a BRAF/MAP2K1/MAP2K2 inhibitor, a Menin-KMT2A/MLL inhibitor, and a multikinase inhibitor. In one embodiment, the composition is used in combination with at least one of a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor. In one embodiment, the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof, the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof, the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone or a pharmaceutically acceptable salt of any one thereof, the CDK inhibitor is selected from CDK4/6 inhibitor Palbociclib, CDK7 inhibitor THZ1, and/or CDK9 inhibitors BAY1251152 and Atuveciclib, or a pharmaceutically acceptable salt of any one thereof, or the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof. [0015] In yet another aspect, the present 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 any one of Formula (IIi), (Ilj), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or a composition comprising a compound of any one of Formula (IIi), (Ilj), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. In one embodiment, the method comprises administering to the subject a composition comprising the therapeutically effective amount of the compound of Formula (I), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and a formulary ingredient, an adjuvant, or a carrier. In one embodiment, the disease or disorder is responsive to at least one of interleukin- 1 receptor-associated kinase (IRAK) inhibition and fms-like tyrosine kinase 3 (FLT3) inhibition. In one embodiment, the disease or 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 myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL with MYD88 mutation, follicular lymphoma, or marginal zone lymphoma. In one embodiment, the disease or disorder comprises at least one cancer selected from glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, Glioma, oral cancer, nasopharyngeal carcinoma, rectal cancer, stomach cancer, and uterine cancer, or combinations thereof. In one embodiment, the disease or disorder comprises one or more inflammatory diseases or autoimmune disease 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 mellitus, Crohn’s disease, colitis, or combinations thereof. In one embodiment, the method further comprises administering to the subject one or more additional therapies selected from: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, 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, an mAbs/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, 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, an NEDD 8 -activator, an MDM2 inhibitor, a PLK1 inhibitor, an Aura A inhibitor, an aurora kinase inhibitor, an EGFR inhibitor, an AuroraB/C/VEGFRl/2/3/FLT3/CSF-lR/Kit/PDGFRA/B inhibitor, an AKT 1, 2, and/or 3 inhibitor, aa ABL1/2/SRC/EPHA2/LCK/YES1/KIT/PDGFRB/FYN inhibitor, a famesyltransferase inhibitor, a BRAF/MAP2K1/MAP2K2 inhibitor, a Menin-KMT2A/MLL inhibitor, and a multikinase inhibitor. In one embodiment, the additional therapy is at least one of a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor. In one embodiment, the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof, the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof, the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone, or a pharmaceutically acceptable salt of any one thereof, the CDK inhibitor is selected from CDK4/6 inhibitor palbociclib, CDK7 inhibitor THZ1, and/or CDK9 inhibitors BAY1251152 and atuveciclib, or a pharmaceutically acceptable salt of any one thereof, and the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof. In one embodiment, the disease or disorder is BCL2 inhibitor resistant acute myeloid leukemia (AML) and/or FLT3 inhibitor resistant AML. In one embodiment, compound of any one of Formula (IIi), (Ilj), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof or the composition comprising a compound of any one of Formula (IIi), (Ilj), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and the one or more additional therapies are administered together in one administration or composition. In one embodiment, the compound of any one of Formula (IIi), (Ilj), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof or the composition comprising a compound of any one of Formula (IIi), (Ilj), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and the one or more additional therapies are administered separately in more than one administration or more than one composition. In one embodiment, the disease or disorder is alleviated by inhibiting at least one of IRAKI, IRAK4, and FLT3 in the subject. In one embodiment, the disease or disorder is alleviated by inhibiting IRAKI and IRAK4 in the subject. In one embodiment, the disease or disorder is alleviated by inhibiting IRAKI, IRAK4, and FLT3 in the subject.
[0016] In yet another aspect, the present disclosure provides a method of increasing survivability in a subject diagnosed with acute myeloid leukemia (AML) or suspected of having AML, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of Formula (IIi), (Ilj), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or a composition comprising a compound of any one of Formula (IIi), (Ilj), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. In one embodiment, the survivability of the subject is increased compared to a subject treated with a therapeutically effective amount of the standard of care for AML. In one embodiment, the standard of care for AML comprises gilteritinib or a pharmaceutically acceptable salt thereof. In one embodiment, the subject is a human. In one embodiment, the subject is a human and the survivability of the subject is increased by about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, about 11 years, about 12 years, about 13 years, about 14 years, about 15 years, about 16 years, about 17 years, about 18 years, about 19 years, or about 20 years compared to a subject treated with a therapeutically effective amount of the standard of care for AML. In one embodiment, the method comprises administering to the subject the therapeutically effective amount of a compound of any one of Formula (IIi), (Ilj), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or a composition comprising a compound of any one of Formula (IIi), (Ilj), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereofabout every 6 hours, every 12 hours, every 18 hours, once a day, every other day, every 3 days, every 4 days, every 5 days, every 6 days, or once a week. In one embodiment, the method further comprises administering to the subject one or more additional therapies selected from: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, 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, an mAbs/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, 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, an NEDD 8 -activator, an MDM2 inhibitor, a PLK1 inhibitor, an Aura A inhibitor, an aurora kinase inhibitor, an EGFR inhibitor, an AuroraB/C/VEGFRl/2/3/FLT3/CSF-lR/Kit/PDGFRA/B inhibitor, an AKT 1, 2, and/or 3 inhibitor, aa ABL1/2/SRC/EPHA2/LCK/YES1/KIT/PDGFRB/FYN inhibitor, a famesyltransferase inhibitor, a BRAF/MAP2K1/MAP2K2 inhibitor, a Menin-KMT2A/MLL inhibitor, and a multikinase inhibitor. In one embodiment, the additional therapy is at least one of a BCL2 inhibitor, a BTK inhibitor, a gluococorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor. In one embodiment, the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof, the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof, the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone, or a pharmaceutically acceptable salt of any one thereof, the CDK inhibitor is selected from CDK4/6 inhibitor palbociclib, CDK7 inhibitor THZ1, and/or CDK9 inhibitors BAY1251152 and atuveciclib, or a pharmaceutically acceptable salt of any one thereof, and the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof. In one embodiment, the AML is BCL2 inhibitor resistant and/or FLT3 inhibitor resistant. In one embodiment, the compound of any one of Formula (IIi), (Ilj), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof or the composition comprising a compound of any one of Formula (IIi), (Ilj), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and the one or more additional therapies are administered together in one administration or composition. In one embodiment, the compound of any one of Formula (IIi), (Ilj), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof or the composition comprising a compound of any one of Formula (IIi), (Ilj), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and the one or more additional therapies are administered separately in more than one administration or more than one composition. In one embodiment, the survivability is increased by inhibiting at least one of IRAKI, IRAK4, and FLT3 in the subject. In one embodiment, the survivability is increased by inhibiting IRAKI and IRAK4 in the subject. In one embodiment, the survivability is increased by inhibiting IRAKI, IRAK4, and FLT3 in the subject. In one embodiment, the compound is a compound of any one of Formula (Ila)-(IIj), Formula (Illa)-(IIIp), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] FIG. 1 depicts the combination outcomes for representative compounds with Venetoclax in the Cell Titer Gio assay in THP1 cells at 48 hours. Panel A depicts the relative Excess HSA values for Compounds 35 and 82 in comparison to representative FLT3 inhibitors. A negative Excess HSA score illustrates that the drug combination is better than either drug alone, wherein greater synergy is observed at larger negative values of the Excess HSA score. Panel B depicts the relative concentration (nM) of CG-806, Compound 82, Compound 35, Gilteritinib hemifumerate, or emavusertib (CA-4948), respectively, to potentiate (<30%) of the 1250 nM Venetoclax Cell Titer Gio response at 48 hours. A smaller concentration indicates higher potency to synergize with Venetoclax. Panels C and D illustrate the concentration ranges over which the combination of Venetoclax and either Compound 82 (Panel C) or Compound 35 (Panel D) are studied in a 10 x 10 combination matrix. The numbers in each cell represent the % response (left) or the Delta Bliss score (right) at each given concentration combination. The number contained within the circle represents the resultant response at which the indicated concentrations of each agent reduce the activity of 1250 nM of Venetoclax to <30%.
[0018] FIG. 2 depicts the combination outcomes for representative compounds with Venetoclax in the Cell Titer Gio assay in MOLM 14 FLT3 ITD (D835Y) cells at 48 hours. Panel A depicts the relative Excess HSA values for Compounds 35 and 82 in comparison to representative FLT3 inhibitors. A negative Excess HSA score illustrates that the drug combination is better than either drug alone, wherein greater synergy is observed at larger negative values of the Excess HSA score. Panel B depicts the relative concentration (nM) of Compound 82, CG-806, Compound 35, Gilteritinib hemifumerate, or emavusertib (CA-4948), respectively, to potentiate (< 10%) of the 125 nM Venetoclax Cell Titer Gio response at 48 hours. A smaller concentration indicates higher potency to synergize with Venetoclax. Panels C and D illustrate the concentration ranges over which the combination of Venetoclax and either Compound 82 (Panel C) or Compound 35 (Panel D) are studied in a 10 x 10 combination matrix. The numbers in each cell represent the % response (left) or the Delta Bliss score (right) at each given concentration combination. The number contained within the circle represents the resultant response at which the indicated concentrations of each agent reduce the activity of 125 nM of Venetoclax to <10%.
[0019] FIG. 3 provides the structures of gilteritinib and emavusertib (CA-4948).
[0020] FIG. 4 demonstrates that mice treated with Compound 82 have improved survival compared to those treated with either vehicle or emavusertib (CA-4948). Survival data for 80 days of mice engrafted survival of mice intravenously engrafted with M0LM14 FLT3-ITD (D835Y) AML cells and treated orally once/day M-F with Compound 82 (at 10 mg/kg) vs. control vehicle, gilteritinib standard of care (SOC, at 30 mg/kg), and emavusertib (CA-4948) (at 30 mg/kg) are illustrated. At the 10 mg/kg dose, enhanced survival is seen with Compound 82 vs. control vehicle as well as vs. emavusertib (CA-4948) but not vs. Gilteritinib.
[0021] FIGS. 5A-5B are charts depicting the leukemic grade of mice studied at the time of necropsy. When adjusting for survival, all treated animals show significant improvement compared to controls. FIG. 5A: Leukemic grade at the time of necropsy (the statistical analysis used was mean with 95% confidence interval). FIG. 5B: Survival-adjusted leukemic grade at the time of necropsy (the statistical analysis used was geometric mean with geometric SD). Gilteritinib and emavusertib (CA-4948) were each administered at 30 mg/kg while Compound 82 was administered at 10 mg/kg.
DETAILED DESCRIPTION OF THE DISCLOSURE
[0022] The following related applications are incorporated by reference herein in their entirety, and 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. WO 2018081738, TREATMENT OF DISEASES ASSOCIATED WITH ACTIVATED IRAK, filed October 30, 2017; U.S. Patent Application No. 16/339,692, TREATMENT OF DISEASES ASSOCIATED WITH ACTIVATED IRAK, filed April 4, 2019; U.S. Patent Application No. 61/826,211, Combination Therapy for MDS, filed May 22, 2013; PCT Patent Publication No. WO 2014190163, Combination Therapy for MDS, filed May 22, 2014; U.S. Patent No. 9,168,257, Combination Therapy for MDS, issued October 27, 2015; U.S. Patent No. 9,504,706, Combination Therapy for MDS, issued November 29, 2016; U.S. Patent No. 9,855,273, Combination Therapy for MDS, issued January 2, 2018; 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. WO 2018038988, 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.
[0023] While embodiments encompassing the general inventive concepts may take diverse forms, various embodiments will be described herein, with the understanding that the present disclosure is to be considered merely exemplary, and the general inventive concepts are not intended to be limited to the disclosed embodiments.
[0024] Some embodiments of the disclosure include inventive compounds (e.g., compounds of Formula (I), Formula (Ila)-(IIj), Formula (IITa)-(IIIp)). Other embodiments include compositions (e.g., pharmaceutical compositions) comprising the inventive compound. Still other embodiments of the disclosure include compositions for treating, for example, certain diseases using the inventive compounds. Some embodiments include methods of using the inventive compound (e.g., in compositions or in pharmaceutical compositions) for administering and treating. Further embodiments include methods for making the inventive compound. Yet further embodiments include methods for determining whether a particular patient is likely to be responsive to such treatment with the inventive compounds and compositions. [0025] Unless otherwise noted, terms are to be understood according to conventional usage by those of ordinary skill in the relevant art.
[0026] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.
[0027] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.
[0028] As used herein, in relation to compounds of Formulae (I), (II), (III), etc., the term “attached” signifies a stable covalent bond, certain preferred points of attachment being apparent to those of ordinary skill in the art.
[0029] As used herein (unless otherwise specified), the term “alkyl” means a monovalent, straight or branched hydrocarbon chain, which can be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e., C1-C10 means one to ten carbons). For example, the terms “C1-C7 alkyl” or “C1- C4 alkyl” refer to straight- or branched-chain saturated hydrocarbon groups having from 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7), or 1 to 4 (e.g., 1, 2, 3, or 4), carbon atoms, respectively. Examples of C1-C7 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i -propyl, n-butyl, s- butyl, t-butyl, n-pentyl, s-pentyl, n-hexyl, and n-heptyl. Examples of C1-C4 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, and t-butyl.
[0030] As used herein (unless otherwise specified), the term “alkenyl” means a monovalent, straight or branched hydrocarbon chain that includes one or more (e.g., 1, 2, 3, or 4) double bonds. Double bonds can occur in any stable point along the chain and the carbon-carbon double bonds can have either the cis or trans configuration. For example, this definition shall include 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, l-pentenyl-3-cyclohexenyl, and the like. Similarly, “heteroalkenyl” refers to 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. [0031] As used herein (unless otherwise specified), the term “alkynyl” means a monovalent, straight or branched hydrocarbon chain that includes one or more (e.g., 1, 2, 3, or 4) triple bonds and that also may optionally include one or more (e.g. 1, 2, 3, or 4) double bonds in 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.
[0032] As used herein (unless otherwise specified), the term “alkoxy” means any of the above alkyl, alkenyl, or alkynyl groups which is 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 shown as MeO-), ethoxy, isopropoxy, propoxy, and butyloxy.
[0033] 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, as exemplified, but not limited by, -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those 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 eight or fewer carbon atoms.
[0034] As used herein (unless otherwise specified), the term “cycloalkyl” means a monovalent, monocyclic or bicyclic, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 membered hydrocarbon group. The rings can be saturated or partially unsaturated. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and bicycloalkyls (e.g., bicyclooctanes such as [2.2.2]bicyclooctane or [3.3.0]bicyclooctane, bicyclononanes such as [4.3.0]bicyclononane, and bicyclodecanes such as [4.4.0]bicyclodecane (decalin), or spiro compounds). For a monocyclic cycloalkyl, the ring is not aromatic. For a bicyclic cycloalkyl, if one ring is aromatic, then the other is not aromatic. For a bicyclic cycloalkyl, one or both rings can be substituted.
[0035] The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, consisting of at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, and wherein the nitrogen and sulfur atoms can optionally be oxidized, and the nitrogen heteroatom can optionally be quatemized. The heteroatom(s) O, N, P, S, and Si can be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH-N-OCH3,
-CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. Up to two heteroatoms can be consecutive, such as, for example, -CH2-NH-OCH3.
[0036] Similarly, the term “heteroalkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)2R'- represents both -C(O)2R'- and -R'C(O)2-. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', -NR'R", -OR', -SR', and/or -SO2R'. Where “heteroalkyl” is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R" or the like, it will be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R" or the like.
[0037] As used herein (unless otherwise specified), the term “halogen” or “halo” means monovalent Cl, F, Br, or I. Additionally, terms such as “haloalkyl” are meant 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.
[0038] As used herein (unless otherwise specified), the term “aryl” means a monovalent, monocyclic or bicyclic, 5, 6, 7, 8, 9, 10, 11, or 12 member aromatic hydrocarbon group and also means polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently. A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tolyl, and xylyl. For an aryl that is bicyclic, one or both rings can be substituted.
[0039] As used herein (unless otherwise specified), the term “heteroaryl” means a monovalent, monocyclic or bicyclic, 5, 6, 7, 8, 9, 10, 11, or 12 membered, hydrocarbon group, where 1, 2, 3, 4, 5, or 6 carbon atoms are replaced by a hetero atom independently selected from nitrogen, oxygen, or sulfur atom, and the monocyclic or bicyclic ring system is aromatic. Heteroaryl groups (or rings) can contain from one to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quatemized. Thus, the term “heteroaryl” includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring). A
5.6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a
6.6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5- fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Examples of heteroaryl groups include, but are not limited to, thienyl (or thiophenyl), furyl, indolyl, pyrrolyl, pyridinyl, pyrazinyl, oxazolyl, thiaxolyl, quinolinyl, pyrimidinyl, imidazolyl, triazolyl, tetrazolyl, lH-pyrazol-4-yl, l-Me-pyrazol-4-yl, pyridin-3-yl, pyridin-4-yl, 3,5- dimethylisoxazolyl, lH-pyrrol-3-yl, 3,5-di-Me-pyrazolyl, and lH-pyrazol-4-yl. For a bicyclic heteroaryl, if one ring is aryl, then the other is heteroaryl. For a bicyclic heteroaryl, one or both rings can have one or more hetero atoms. For a bicyclic heteroaryl, one or both rings can be substituted.
[0040] An “arylene” and a “heteroarylene,” alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. Accordingly, the term "aryl" can represent an unsubstituted, mono-, di- or trisubstituted monocyclic, polycyclic, biaryl and heterocyclic aromatic groups covalently attached at any ring position capable of forming a stable covalent bond, certain preferred points of attachment being apparent to those skilled in the art (e. g. 3-indolyl, 4-imidazolyl). The aryl substituents are independently selected from the group consisting of halo, nitro, cyano, trihalomethyl, C1-16alkyl, aryl C1-16alkyl, C0-16alkyloxyC0-16alkyl, arylC0-16alkyloxyC0-16alkyl, C0- i6alkylthioC0-16alkyl, arylC0-16alkylthioC0-16alkyl, C0- 16alky laminoC0-16alkyl, arylC0-16alkylaminoC0-16alkyl, di(arylC1-16alkyl)aminoC0-16alkyl, C1- 16alky IcarbonylC0-16alkyl, aryl C1-16alkylcarbonylC0-16alkyl, C1-16alkylcarboxyC0-16alkyl, arylC1- 16alky IcarboxyC0-16alkyl, C1-16alkylcarbonylaminoC0-16alkyl, aryl C1-16alky Icarbony laminoC0- 16alkyl,-C0-16alkylCOO R4, -C0-16alkylCONR5R6 wherein R4, R5 and R6 are independently selected from hydrogen, C1-C11 alkyl, arylC0-C11 alkyl, or R5 and R6 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with or without one C1-16alkyl, arylC0-C16alkyl, or C0-CI16alkylaryl substituent. Aryl includes but is not limited to pyrazolyl and triazolyl.
[0041] For brevity, the term “aryl” when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above. Thus, the terms “arylalkyl,” “aralkyl” and the like are meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, and the like) including those 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-(l- naphthyloxy)propyl, and the like), or a sulfur atom. Accordingly, the terms "arylalkyl" and the like (e.g. (4-hydroxyphenyl)ethyl, (2-aminonaphthyl)hexyl, pyridylcyclopentyl) represents an aryl group as defined above attached through an alkyl group as defined above having the indicated number of carbon atoms.
[0042] The terms “cycloalkyl” and “heterocycloalkyl”, also referred to as “heterocyclyl”, by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl,” respectively. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1 -cyclohexenyl, 3 -cyclohexenyl, cycloheptyl, and the like. As used herein (unless otherwise specified), the term “heterocycloalkyl” or “heterocyclyl” means a monovalent, monocyclic or bicyclic, 5, 6, 7, 8, 9, 10, 11, or 12 membered, hydrocarbon, where 1, 2, 3, 4, 5, or 6 carbon atoms are replaced by a hetero atom independently selected from nitrogen atom, oxygen atom, or sulfur atom, and the monocyclic or bicyclic ring system is not aromatic. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of heterocycloalkyl include, but are not limited to, l-(l,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, pyrolidinyl (e.g., pyrrolidin-l-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, or 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, piperadin-2 -yl, piperadin-3 -yl, or piperadin-4-yl), and morpholinyl (e.g., morpholin-l-yl, morpholin-2-yl, morpholin-3-yl, or morpholin-4-yl,). For a bicyclic heterocyclyl, if one ring is aromatic (e.g., monocyclic aryl or heteroaryl), then the other ring is not aromatic. For a bicyclic heterocyclyl, one or both rings can have one or more hetero atoms. For a bicyclic heterocyclyl, one or both rings can be substituted and the like. A “cycloalkylene” and a “heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively.
[0043] As used herein (unless otherwise specified), the term “hetero atom” means an atom selected from nitrogen atom, oxygen atom, or sulfur atom.
[0044] As used herein (unless otherwise specified), the terms “hydroxy” or “hydroxyl” means a monovalent -OH group.
[0045] The term “acyl” means, unless otherwise stated, -C(O)R where R is a 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.
[0046] The term “oxo,” as used herein, means an oxygen that is double bonded to a carbon atom.
[0047] The term “alkylsulfonyl,” as used herein, 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”).
[0048] The term "carbonyloxy" represents a carbonyl group attached through an oxygen bridge.
[0049] In the above definitions, the terms "alkyl" and "alkenyl" can be used interchangeably in so far as a stable chemical entity is formed, as would be apparent to those skilled in the art.
[0050] The term “linker” refers to attachment groups interposed between substituents. In some embodiments, the linker includes amido (-CONH-R11 or -NHCO-Rn), thioamido (-CSNH-R" or -NHCS-R”), carboxyl (-CO2-R11 or -OCORn), carbonyl (-CO-Rn), urea (-NHCONH-Rn), thiourea (-NHCSNH-R11), sulfonamido (-NHSO2-R11 or -SO2NH-R11), ether
(-O-Rn), sulfonyl (-SO2-R11), sulfoxyl (-SO-Rn), carbamoyl (-NHCO2-R11 or -OCONH-Rn), or amino (-NHRn) linking moieties.
[0051 ] Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl,” and “heteroaryl”, and so forth) includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided herein. [0052] As used herein (unless otherwise specified), the term “substituted” (e.g., as in substituted alkyl) means that one or more hydrogen atoms of a chemical group (with one or more hydrogen atoms) can be replaced by one or more non-hydrogen substituents selected from the specified options. The replacement can occur at one or more positions. The term “optionally substituted” means that one or more hydrogen atoms of a chemical group (with one or more hydrogen atoms) can be, but is not required to be substituted.
[0053] A “substituent group,” as used herein, means a non-hydrogen substituent group 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 perfluorinated alkyl, 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 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, 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 perfluorinated alkyl, 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 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, 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 perfluorinated alkyl, 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 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, substituted with at least one substituent selected from: -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 perfluorinated alkyl, unsubstituted C1-C7 alkoxy, unsubstituted C1-C7 haloalkoxy, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl.
[0054] AA “ “ssiizzee--lliimmiitteedd ssuubbssttiittuueenntt”” oorr “ size-limited substituent group,” as used herein, means a group, e.g., selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-20- 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 4-8-membered heterocycloalkyl.
[0055] A “lower substituent” or “lower substituent group,” as used herein, means a group, e.g., selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-8-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 5-7 -membered heterocycloalkyl.
[0056] The term “about” used in the context of a numeric value indicates a range of +/- 10% of the numeric value, unless expressly indicated otherwise.
[0057] Some compounds of the disclosure can have one or more chiral centers and can exist in and be isolated in optically active and racemic forms, for any of the one or more chiral centers. Some compounds can exhibit polymorphism. The compounds of the present disclosure (e.g., Formula I) encompass any optically active, racemate, stereoisomer form, polymorphism, or mixtures thereof. If a chiral center does not provide an indication of its configuration (i.e., R or S) in a chemical structure, it should be considered to represent R, S or a racemate.
[0058] As used herein, the term “sample” encompasses a sample obtained from a subject or patient. The sample can be of any biological tissue or fluid. Such samples include, but are not limited to, sputum, saliva, buccal sample, oral sample, blood, serum, mucus, plasma, urine, blood cells (e.g., white cells), circulating cells (e.g. stem cells or endothelial cells in the blood), tissue, core or fine needle biopsy samples, cell-containing body fluids, free floating nucleic acids, urine, stool, peritoneal fluid, and pleural fluid, tear fluid, or cells therefrom. Samples can also include sections of tissues such as frozen or fixed sections taken for histological purposes or microdissected cells or extracellular parts thereof. A sample to be analyzed can be tissue material from a tissue biopsy obtained by aspiration or punch, excision or by any other surgical method leading to biopsy or resected cellular material. Such a sample can comprise cells obtained from a subject or patient. In some embodiments, the sample is a body fluid that include, for example, blood fluids, serum, mucus, plasma, lymph, ascitic fluids, gynecological fluids, or urine but not limited to these fluids. In some embodiments, the sample can be a non- invasive sample, such as, for example, a saline swish, a buccal scrape, a buccal swab, and the like.
[0059] As used herein, “blood” can include, for example, plasma, serum, whole blood, blood lysates, and the like.
[0060] As used herein, the term “assessing” includes any form of measurement, and includes determining if 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.
[0061 ] As used herein, the term “monitoring” with reference to a type of cancer refers to a method or process of determining the severity or degree of the type of cancer or stratifying the type of cancer based on risk and/or probability of mortality. In some embodiments, monitoring relates to a method or process of determining the therapeutic efficacy of a treatment being administered to a patient.
[0062] As used herein, “outcome” can refer to an outcome studied. In some embodiments, “outcome” can refer to survival / mortality over a given time horizon. For example, “outcome” can refer to survival / mortality over 1 month, 3 months, 6 months, 1 year, 5 years, or 10 years or longer. In some embodiments, an increased risk for a poor outcome indicates that a therapy has had a poor efficacy, and a reduced risk for a poor outcome indicates that a therapy has had a good efficacy. [0063] As used herein, the term “high risk clinical trial” refers to one in which the test agent has “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 drug trial.
[0064] As used herein, the term “low risk clinical trial” refers to one in which the test agent has “minimal risk” (as defined by the terminology used by IRBs). In some embodiments, a low risk clinical trial is one that is not a drug trial. In some embodiments, a low risk clinical trial is one that that involves the use of a monitor or clinical practice process. In some embodiments, a low risk clinical trial is an observational clinical trial.
[0065] As used herein, the terms “modulated” or “modulation,” or “regulated” or ‘regulation” and “differentially regulated” can refer to both up regulation (i.e., activation or stimulation, e.g., by agonizing or potentiating) and down regulation (i.e., inhibition or suppression, e.g., by antagonizing, decreasing or inhibiting), unless otherwise specified or clear from the context of a specific usage.
[0066] 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 mammalian pediatric patient. In the methods, the pediatric patient is a mammalian (e.g., preferably human) patient under 18 years of age, while an adult patient is 18 or older.
[0067] As used herein, the term “treating” (and its variations, such as “treatment”
“treating,” “treat,” and the like) is, unless stated otherwise, to be considered in its broadest context and refers to obtaining a desired pharmacologic and/or physiologic effect. In particular, for example, the term “treating” may not necessarily imply or require that an animal is treated until total recovery. Accordingly, “treating” includes amelioration of the symptoms, relief from the symptoms or effects associated with a condition, decrease in severity of a condition, or preventing, preventively ameliorating symptoms, or otherwise reducing the risk of developing a particular condition. In some aspects, “treating” may not require or include prevention. As used herein, reference to “treating” an animal includes but is not limited to prophylactic treatment and therapeutic treatment. The effect can be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or can be therapeutic in terms of a partial or complete cure for a disease and/or adverse effect attributable to the disease. “Treatment,” as used herein, covers any treatment of a disease in a subject, preferably in a mammal (e.g., in a human), and may include one or more of: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., causing regression or elimination of the disease and/or relieving one or more disease symptoms. In particular aspects of the methods, such as conditions or disorders characterized by dysregulated IRAK expression or dysregulated (e.g., hyperactive) IRAK-mediated signaling pathway(s), treatment may be or include reducing such expression or signaling. “Treatment” can also encompass delivery of an agent or administration of a therapy in order to provide for a pharmacologic 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.
[0068] “Therapeutically effective amount” means 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 appropriate to treat an indication. By treating an indication is meant achieving any desirable effect, such as one or more of palliate, ameliorate, stabilize, reverse, slow, or delay disease progression, increase the quality of life, or to prolong life. Such achievement can be measured by any suitable method, such as measurement of tumor size or blood cell count, or any other suitable measurement.
[0069] As used herein, the term “marker” or “biomarker” refers to a biological molecule, such as, for example, a nucleic acid, peptide, protein, hormone, and the like, whose presence or concentration can be detected and correlated with a known condition, such as a disease state. It can also be used to refer to a differentially expressed gene whose expression pattern can be utilized as part of a predictive, prognostic or diagnostic process in healthy conditions or a disease state, or which, alternatively, can be used in methods for identifying a useful treatment or prevention therapy.
[0070] As used herein, an mRNA “isoform” is an alternative transcript for a specific mRNA or gene. This term includes pre-mRNA, immature mRNA, mature mRNA, cleaved or otherwise truncated, shortened, or aberrant mRNA, modified mRNA (e.g. containing any residue modifications, capping variants, polyadenylation variants, etc.), and the like.
[0071] “Antibody” or “antibody peptide(s)” refer to an intact antibody, or a binding fragment thereof that competes with the intact antibody for specific binding; this definition also encompasses monoclonal and polyclonal antibodies. Binding fragments are produced by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact antibodies. Binding fragments include Fab, Fab', F(ab')2, Fv, and single-chain antibodies. An antibody other than a “bispecific” or “bifunctional” antibody is understood to have each of its binding sites identical. An antibody, for example, substantially inhibits adhesion of a receptor to a counterreceptor when an excess of antibody reduces the quantity of receptor bound to counterreceptor by at least about 20%, 40%, 60% or 80%, and more usually greater than about 85% (as measured in an in vitro competitive binding assay).
[0072] Embodiments of the disclosure set forth herein include inventive compounds (e.g., compounds of Formula (I), such as compounds of Formula (II) and Formula (III), including Formula (Ila)-(IIj) and Formula (Illa)-(IIIp)). Other embodiments include compositions (e.g., pharmaceutical compositions) comprising the inventive compound. Still other embodiments of the disclosure include compositions (e.g., pharmaceutical compositions) for treating, for example, certain diseases using the inventive compounds. Some embodiments include methods of using the inventive compound (e.g., in compositions or in pharmaceutical compositions) for administering and treating (e.g., diseases such as cancer or blood disorders). Some embodiments include methods of determining whether a patient is suitable for, or likely to respond favorably to, a particular treatment. Further embodiments include methods for making the inventive compounds. Additional embodiments of the disclosure are also discussed herein.
Compounds and Compositions, Including Pharmaceutical Compositions
[0073] Some embodiments of the disclosure include compounds having a structure according to Formula (I):
Figure imgf000027_0001
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 a compound of Formula (I). In some embodiments, the compound is not an ester, not a solvate, and not a prodrug. [0074] In exemplary embodiments, R2, R3, R4, and R5 are independently selected from H, halogen, hydroxy, oxo, -CN, amino, amido, -O-aryl, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, which amino, amido, -O-aryl, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, (=O), -O', methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, -NHCH3, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl which is substituted with cycloalkyl, wherein two adjacent optional substituents can bond or fuse to form a ring.
[0075] In some embodiments, R2 can be H, halogen, hydroxy, oxo, -CN, amino, amido, - O-aryl, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, aryl, heteroaryl, or fused ring heteroaryl, which amino, amido, -O-aryl, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2- C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, oxo (=O), -O', methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, -NHCH3, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, - CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 heteroalkyl, C1-C7 haloalkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, aryl, fused ring aryl, heteroaryl, fused ring heteroaryl, or C1-C7 alkyl which is substituted with cycloalkyl; R3, R4, and R5 can be H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (- CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, which methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro- fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), - NH2, -NHCH3, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, - CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl which is substituted with cycloalkyl, wherein two adjacent optional substituents can bond or fuse to form a ring.
[0076] R6 can be
Figure imgf000029_0001
[0077] R7, R8, R9, R10, R11, R12, R13, R14 can be H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, which methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more halogen and/or C1-C6 alkyl; R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R29, R29, and R30 can be H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, which methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more halogen and/or C1-C6 alkyl; and m, n, o, p, q, r, s, t, u, v, w, and x can be 0, 1, 2, 3, 4, or 5, where q+r+s+t is at least 1, and where u+v+w+x is at least 1.
[0078] In some embodiments, R2 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, which O-aryl, amino, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, heterocyclyl, aryl, fused ring aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, (=O), -O', -CN, amino, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, fused ring aryl, fused ring heteroaryl, pyrrolyl, piperidyl, piperazinyl, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl which is substituted with cycloalkyl. In some embodiments, R2 is H, halogen, hydroxy, O-aryl, amino, C1-C7 alkyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, aryl, fused ring aryl, heteroaryl, or fused ring heteroaryl which 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 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl which is substituted with cycloalkyl. In some embodiments, R2 is H, Cl, hydroxy, -NHCH3, -N(CH3)2, -OCH3, -OCF3, -OCHF2, -OPh, -CF3, -CHF2, unsubstituted C1-C7 alkyl, substituted amino, substituted C1-C7 alkyl, substituted cycloalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl, substituted pyrazolyl, substituted fused ring heteroaryl, or unsubstituted fused ring heteroaryl. In some embodiments, R2 is not H.
[0079] In some embodiments, R3 is H, halogen, hydroxy, -CN, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, or C1-C7 alkoxy, which C1-C7 alkyl, or C2-C6 alkoxy, is optionally substituted with one or more of halogen, hydroxy, methanoyl (-COH), carboxy (- CO2H), nitro (-NO2), -NH2, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1- C7 haloalkoxy, or C1-C7 alkyl which is substituted with cycloalkyl. In some embodiments, R3 is H, halogen, hydroxy, -CN, methyl, -CF3, or methoxy.
[0080] In some embodiments, R4 is H, halogen, hydroxy, -CN, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, or C1-C7 alkoxy, which C1-C7 alkyl, or C2-C6 alkoxy, is optionally substituted with one or more of halogen, hydroxy, methanoyl (-COH), carboxy (- CO2H), nitro (-NO2), -NH2, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1- C7 haloalkoxy, or C1-C7 alkyl which is substituted with cycloalkyl. In some embodiments, R4 is H, halogen, hydroxy, -CN, methyl, -CF3, or methoxy.
[0081] In some embodiments, R5 is H, halogen, hydroxy, -CN, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, or C1-C7 alkoxy, which C1-C7 alkyl, or C2-C6 alkoxy, is optionally substituted with one or more of halogen, hydroxy, methanoyl (-COH), carboxy (- CO2H), nitro (-NO2), -NH2, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1- C7 haloalkoxy, or C1-C7 alkyl which is substituted with cycloalkyl. In some embodiments, R5 is H, halogen, hydroxy, -CN, methyl, -CF3, or methoxy.
[0082] In some embodiments, R4 is methyl or -CF3, and at least one of R3 and R5 is H or halogen.
[0083] In some embodiments, there is a chiral center at the R6 attachment carbon. In some embodiments, the chiral center is an R chiral center, an S chiral center, or a racemate. In certain embodiments, the chiral center can be represented by the following bonds ""lllllll
Figure imgf000031_0001
Where a chiral center is possible at other positions of the compounds according to Formula (I), as would appreciated by one skilled in the art, the straight bond shown can also be can be
Figure imgf000031_0002
[0084] In some embodiments, R6 is
Figure imgf000031_0003
[0085] In some embodiments, R7, R8, R9, R10, R11, R12, R 1133, R14 are independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, which methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl which is substituted with cycloalkyl . [0086] In one embodiment, at least one of R7, R8, R9, R10, R11, R12, R13, and R14 is not H. In another embodiment, each of R7, R8, R9, R10, R11, R12, R13, and R14, if present, is H. [0087] In some embodiments, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R29, R29, and R30 are independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (- COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, which methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, - CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl which is substituted with cycloalkyl. [0088] In one embodiment, at least one of R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R29, R29, and R30 is not H. In another embodiment, each of R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R29, R29, and R30, if present, is H. [0089] In some embodiments, m, n, o, p, q, r, s, t, u, v, w, and x are independently selected from 0, 1, 2, 3, 4, or 5, where q+r+s+t is at least 1, and where u+v+w+x is at least 1. [0090] Some embodiments of the disclosure include compounds having a structure according to Formula (I):
Figure imgf000032_0001
wherein the wavy bond from Y to R6 (i.e., ) indicates that, in some instances, there is a chiral center at the R6 attachment carbon. In some embodiments, where there is a chiral center at the R6 attachment carbon, the wavy bond can indicate an R chiral center, an S chiral center, or a racemate. In certain embodiments, can be ,
Figure imgf000032_0002
, , , Where a chiral center is possible at other positions of the compounds according to
Figure imgf000032_0003
Formula (I), as would appreciated by one skilled in the art, the straight bond shown can also be
Figure imgf000033_0001
[0091] In some embodiments, R6 is (la), giving a structure of Formula (II), as follows:
Figure imgf000033_0002
[0092] 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.
[0093] In some embodiments, R7, R8, R9, and R10 are H, and at least one of R11, R12, R13, and R14 is not H, and/or R11, R12, R13, and R14 are H, and at least one of R7, R8, R9, and R10 is not H. In particular embodiments, R7, R8, R9, R10, R11, R12, R13, and R14 are independently selected from H, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C1-C7 alkoxy, cycloalkyl, or spiro-fused cycloalkyl, which methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, or spiro-fused cycloalkyl is optionally substituted with one or more halogen. In some embodiments, R7, R8, R9, and R10 are H, and at least one of R11, R12, R13, and R14 is halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C1-C7 alkoxy, cycloalkyl, or spiro-fused cycloalkyl, which methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, or spiro-fused cycloalkyl is optionally substituted with one or more halogen. In some embodiments, R11, R12, R13, and R14 are H, and at least one of R7, R8, R9, and R10 is halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C1-C7 alkoxy, cycloalkyl, or spiro-fused cycloalkyl, which methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, or spiro-fused cycloalkyl is optionally substituted with one or more halogen. In some embodiments, at least one of R7, R8, R9, and R10 is halogen, hydroxyl, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 alkoxy, cycloalkyl, or spiro-fused cycloalkyl. In some embodiments, at least one of R7, R8, R9, and R10 is F, hydroxyl, methyl, methoxy, -CHF2, - CF3, cyclopropyl, spiro-fused cyclopropyl, spiro-fused cyclobutyl, or spiro-fused cyclopentyl. In some embodiments, both of R7 and R8 or both of R9 and R10 are F, or both of R7 and R8 or both of R9 and R10 are methyl. In some embodiments, at least one of R11, R12, R13, and R14 is halogen, hydroxyl, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 alkoxy, cycloalkyl, or spiro-fused cycloalkyl. In some embodiments, at least one of R11, R12, R13, and R14 is F, hydroxyl, methyl, methoxy, - CHF2, -CF3, cyclopropyl, spiro-fused cyclopropyl, spiro-fused cyclobutyl, or spiro-fused cyclopentyl. In some embodiments, both of R11 and R12 or both of R13 and R14 are F, or wherein both of R11 and R12 or both of R13 and R14 are methyl
[0094] Further to any embodiment above wherein the compound has the structure of Formula (II), the compound can have a structure according to any of (Ila)-(IIe), wherein V, W, X, Y, and Z can independently represent any of R7, R8, R9, R10, R11, R12, R13, or R14, and wherein at least one of V, W, X, Y, and Z is not H.
Figure imgf000034_0001
[0095] In an embodiment, the compound of Formula (II) is a compound of Formula (Ilf)
Figure imgf000035_0001
or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein:
R20f is selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(CH2)a-( C3-C6 cycloalkyl), and C3-C9 heterocyclyl, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen, and C3-C9 heterocyclyl is optionally substituted with one or more substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -OH, and =O;
R21f, R22f, and R23f are each independently selected from H and halogen;
R24fa, R24fb, R25fa, R25fb, R26fa, and R26fb are each independently selected from H, halogen, -OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more halogen atoms; and a is selected from 0, 1, 2, 3, 4, 5, and 6.
[0096] In an embodiment, one or more of R24fa, R24fb, R25fa, R25fb, R26fa, and R26fb is independently selected from halogen, -OH, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy. In another embodiment, each of R24fa, R24fb, R25fa, R25fb, R26fa, and R26fb is H.
[0097] In an embodiment, R20f is H. In another embodiment, R20f is not H. In an embodiment, R20f is unsubstituted C1-C6 alkyl. In one embodiment, R20f is t-butyl. In another embodiment, R20f is C1-C6 alkyl substituted with one or more -OH and/or halogen. In one embodiment, R20f is C1-C6 alkyl substituted with one or more -OH and/or F. In one embodiment,
R20f is selected from
Figure imgf000035_0002
In another embodiment, R20f is unsubstituted C1-C6 alkoxy. In one embodiment, R20f is selected from -OCH3, -OCH2CH3, and In another embodiment, R20f is C1-C6 alkoxy substituted with one or more fluorine
Figure imgf000035_0003
atoms. In one embodiment, R20f is selected from
Figure imgf000036_0001
and
Figure imgf000036_0002
In another embodiment, R20f is C3-C6 cycloalkyl. In one embodiment, R20f is unsubstituted C3 cycloalkyl.
In one embodiment, R20f is C3 cycloalkyl substituted with C1-C6 alkyl. In one embodiment, R20f is In one embodiment, R20f is C3 cycloalkyl substituted with one or more fluorine atoms.
Figure imgf000036_0003
In one embodiment, R20f is
Figure imgf000036_0004
In another embodiment, R20f is -O-(CH2)a-(C3 cycloalkyl).
In one embodiment, R20f is
Figure imgf000036_0005
In another embodiment, R20f is unsubstituted C3-C9 heterocyclyl. In one embodiment, R20f is selected from pyrrolidinyl and
Figure imgf000036_0006
In another embodiment, R20f is C3-C9 heterocyclyl substituted with one or more substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -OH, =O, and -O" wherein adjacent substituents can bond or fuse to form a ring. In one embodiment, R20f is
Figure imgf000036_0007
wherein R20f is selected from C1- C6 alkyl, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are each optionally substituted with one or more halogen and/or -OH. In one embodiment, R20f is wherein R27f is unsubstituted C1-C6 alkyl. In one embodiment, R20f is wherein R27f is -CH3. In one embodiment, R20f is
Figure imgf000036_0011
wherein R27f is
Figure imgf000036_0008
C1-C6 alkyl substituted with one or more -OH and/or F. In one embodiment, R20f is
Figure imgf000036_0009
wherein R27f is selected from
Figure imgf000036_0010
In another embodiment, R20f is pyrrolidinyl substituted with one or more substituents selected from halogen, C1-C6 alkyl, C1- C6 alkoxy, -OH, =O, and -O’ wherein adjacent substituents can bond or fuse to form a ring. In wherein R28f is selected from H and =O, R29fa and R29fb
Figure imgf000036_0012
are each independently selected from H, C1-C6 alkyl, -OH, and halogen, wherein the C1-C6 alkyl is optionally substituted with one or more halogen, and b is 1 or 2. In one embodiment, R29fa and
R29fb are each independently selected from H, -CH3,
Figure imgf000037_0001
-CF3, -OH, and F. In one embodiment, R20f is selected from
Figure imgf000037_0002
Figure imgf000037_0004
In one embodiment, R20f is
Figure imgf000037_0003
wherein R28f is =O and R220fa and R220fb are each independently selected from H, C1-C6 alkyl, and C1-C6 alkoxy wherein C1-C6 alkyl and C1-C6 alkoxy optionally bond or fuse to form a ring. In one embodiment, R20f is
Figure imgf000037_0005
wherein R28f is =O and R220fa and R220fb are each -CH3. In one embodiment, R20f is wherein R28f is =O and R220fa and R220fb bond or fuse to
Figure imgf000037_0006
form oxetanyl. In another embodiment, R20f is
Figure imgf000037_0007
wherein b is 1 or 2. In another embodiment, R20f is selected from
Figure imgf000037_0008
[0098] In an embodiment, each of R21f, R22f, and R23f is H. In an embodiment, R21f and R23f are each independently halogen and R22f is H. In one embodiment, R21f and R23f are each F and R22f is H. In an embodiment, R21f and R23f are each H and R22f is halogen. In one embodiment, R21f and R23f are each H and R22f is F.
[0099] In an embodiment, each of R24fa, R24fb, R25fa, R25fb, R26fa, and R26fb is H. In an embodiment, each of R25fa, R25fb, R26fa, and R26fb is H and R24fa and/or R24fb is halogen. In one embodiment, each of R24fb, R25fa, R25fb, R26fa, and R26fb is H and R24fa is F. In one embodiment, each of R25fa, R25fb, R26fa, and R26fb is H and each of R24fa and R24fb is F. In an embodiment, R25fa, R25fb, R26fa, and R26fb are each H and R24fa and/or R24fb is C1-C6 alkyl. In one embodiment, each of R25fa, R25fb, R26fa, and R26fb is H and each of R24fa and R24fb is -CH3. In one embodiment, each of R24fb, R25fa, R25fb, R26fa, and R26fb is H and R24fa is -CH3. In an embodiment, R25fa, R25fb, R26fa, and R26fb are each H and R24fa and/or R24fb is C1-C6 alkyl substituted with one or more halogen. In an embodiment, R25fa, R25fb, R26fa, and R26fb are each H and R24fa and/or R24fb is Ci alkyl substituted with one or more F. In one embodiment, R24fa, R25fa, R25fb, R26fa, and R26fb are each H andR24fb is -CF3.
[00100] In an embodiment, the compound of Formula (Ilf) has one or more stereocenters. In one embodiment, the compound of Formula (Ilf) comprises a stereocenter where the moiety
Figure imgf000038_0001
connects to the remaining portion of Formula (Ilf). In one embodiment, the compound of Formula (Ilf) comprises a stereocenter at one or more of R24fa, R24fb, R25fa, R25fb, R26fa, and/or R26fb. In one embodiment, the compound of Formula (Ilf) comprises a stereocenter on R20f.
[00101] In an embodiment, the compound of Formula (Ilf) is selected from:
Figure imgf000038_0002
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
[00102] In an embodiment, the compound of Formula (II) is a compound of Formula (Ilg)
Figure imgf000045_0001
or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein:
Figure imgf000045_0002
R20g is selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen, and C3-C9 heterocycyl is optionally substituted with one or more substituents selected from halogen, C1-C6 alkyl, C3-C6-cycloalkyl, - OH, and =O;
R21g, R22g, and R23g are each independently selected from H and halogen; and
R24ga, R24gb, R25ga, R25gb, R26ga, R26gb, R27ga, R27gb, R28ga, and R28gb are each independently selected from H, halogen, -OH, or C1-C6 alkyl.
[00103] In an embodiment, one or more of R24ga, R24gb, R25ga, R25gb, R26ga, R26gb, R27ga, R27gb, R28ga, and R28gb is independently selected from halogen and C1-C6 alkyl. In another embodiment, each of R24ga, R24gb, R25ga, R25gb, R26ga, R26gb, R27ga, R27gb, R28ga, and R28gb is H.
[00104] In an embodiment, R20g is H. In another embodiment, R20g is unsubstituted C1-C6 alkyl. In one embodiment, R20g is t-butyl. In another embodiment, R20g is C1-C6 alkyl substituted with one or more F and/or -OH. In one embodiment, R20g is selected from
Figure imgf000045_0005
Figure imgf000045_0003
In another embodiment, R20g is unsubstituted C1-C6 alkoxy. In one embodiment, R20g is In another embodiment, R20g is C1-C6 alkoxy substituted with one
Figure imgf000045_0004
F or more F and/or -OH. In one embodiment, R20g is selected from
Figure imgf000046_0001
In another embodiment, R20g is unsubstituted C3-C6 cycloalkyl. In one embodiment, R20g is unsubstituted C3 cycloalkyl. In one embodiment, R20g is C3 cycloalkyl substituted with C1-C6 alkyl. In one embodiment, R20g is In one embodiment, R20g is C3 cycloalkyl substituted
Figure imgf000046_0002
with one or more C1-C6 alkyl and one or more fluorine atoms. In one embodiment, R20g is In another embodiment, R20g is C3-C9 heterocycyl substituted with one or more
Figure imgf000046_0003
substituents selected from C1-C6 alkyl, C3-C6-cycloalkyl, C3-C9-heterocyclyl, -OH, -C=O, and halogen. In one embodiment, R20g is
Figure imgf000046_0004
wherein R29g is selected from C1-C6 alkyl, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are each optionally substituted with one or more halogen and/or -OH. In one embodiment, R20g is
Figure imgf000046_0005
wherein R29g is unsubstituted C1-C6 alkyl. In one embodiment, R20g is
Figure imgf000046_0006
wherein R29g is -CH3. In one embodiment, R20g is
Figure imgf000046_0007
wherein R29g is C1-C6 alkyl substituted with one or more -OH and/or F. In one embodiment, R20g is wherein R29g is selected from In one embodiment, R20g is
Figure imgf000046_0009
wherein R29g is unsubstituted C3-C6 cycloalkyl. In one embodiment, R20g is wherein R29g is unsubstituted C3 cycloalkyl. In one embodiment, R20g is
Figure imgf000046_0008
pyrrolidinyl monosubstituted with -C=O. In one embodiment, R20g is
Figure imgf000046_0010
In another embodiment, R20g is piperidinyl monosubstituted with -C=O. In one embodiment, R20g is In another embodiment, R20g is
Figure imgf000047_0002
wherein c is 1 or 2. In another
Figure imgf000047_0001
embodiment, R20g is selected from
Figure imgf000047_0003
[00105] In an embodiment, each of R21g, R22g, and R23g is H. In an embodiment, R21g and R23g are each independently halogen and R22g is H. In one embodiment, R21g and R23g are each F and R22g is H. In an embodiment, R21g and R23g are each H and R22g is halogen, In one embodiment, R21g and R22g are each H and R22g is F.
[00106] In an embodiment, each of R24ga, R24gb, R25ga,
Figure imgf000047_0004
R25gb, R26ga, R26gb, R27ga, and R27gb is H. In an embodiment, each of R25ga, R25gb, R26ga, R26gb, R27ga, and R27gb is H and R24ga and/or R24gb is halogen. In one embodiment, each of R24ga, R25ga, R25gb, R26ga, R26gb, R27ga, and R27gb is H and R24gb is F. In an embodiment, each of R24ga, R24gb, R26ga, R26gb, R27ga, and R27gb is H and R25ga and/or R25gb is unsubstituted C1-C6 alkyl. In one embodiment, each of R24ga, R24gb, R25ga, R26ga, R26gb, R27ga, and R27gb is H and R25gb is -CH3.
[00107] In an embodiment, each of R24ga, R24gb, R26ga,
Figure imgf000047_0005
R26gb, R27ga, R27gb, R28ga, and R28gb is H. In an embodiment, each of R24ga, R24gb, R26ga, R26gb, R28ga, and R28gb is H and R27ga and/or R27gb is halogen. In one embodiment, each of R24ga, R24gb, R26ga, R26gb, R28ga, and R28gb is H and each of R27ga and R27gb is F. In one embodiment, each of R24ga, R24gb, R26ga, R26gb, R27ga, R28ga, and R28gb is H and R27gb is F. In an embodiment, each of R24ga, R24gb, R26ga, R26gb, R28ga, and R28gb is H and R27ga and/or R27gb is unsubstituted C1-C6 alkyl. In one embodiment, each of R24ga, R24gb, R26ga, R26gb, R28ga, and R28gb is H and each of R27ga and R27gb is -CH3. In another embodiment, each of R24ga, R24gb, R27ga, R27gb, R28ga, and R28gb is H and R26ga and/or R26gb is halogen. In one embodiment, each of R24ga, R24gb, R26ga, R27ga, R27gb, R28ga, and R28gb is H and R26gb is F. In an embodiment, each of R24ga, R24gb, R27ga, R27gb, R28ga, and R28gb is H and R26ga and/or R26gb is unsubstituted C1-C6 alkyl. In one embodiment, each of R24ga, R24gb, R26ga, R27ga, R27gb , R28ga, and R28gb is H and R26gb is -CH3.
[00108] In an embodiment, the compound of Formula (Ilg) comprises one or more stereocenters. In one embodiment, the compound of Formula (Ilg) comprises a stereocenter on R20g. In one embodiment, the compound of Formula (Ilg) comprises a stereocenter where the moiety connects to the remaining portion of Formula (Ilg). In one embodiment, one or
Figure imgf000048_0002
more of R24ga, R24gb, R25ga, R25gb, R26ga, R26gb, R27ga, R27gb, R28ga, and/or R28gb comprises a stereocenter.
[00109] In an embodiment, the compound of Formula (Ilg) is selected from:
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
[00110] In an embodiment, the compound of Formula (II) is a compound of Formula (Uh):
Figure imgf000057_0002
or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein:
Figure imgf000057_0003
R2OH is selected from H, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 cycloalkyl, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from halogen and -OH, and C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen; and
R21h, R22h, and R23h are each independently selected from H and halogen. [00111] In an embodiment, R20h is H. In another embodiment, R20h is C1-C6 alkyl substituted with one or more halogen. In one embodiment, R20h is In another embodiment, R20h is C1-C6 alkoxy substituted with one or more halogen.
Figure imgf000058_0004
In one embodiment, R20h is In another embodiment, R20h is unsubstituted C3-C6 cycloalkyl. In one
Figure imgf000058_0005
embodiment, R20h is unsubstituted C3 cycloalkyl. In another embodiment, R20h is C3-C6 cycloalkyl substituted with one or more C1-C6 alkyl. In one embodiment, R20h is in
Figure imgf000058_0006
another embodiment, R20h is C3-C6 cycloalkyl substituted with one or more C1-C6 alkyl and one or more fluorine atoms. In one embodiment, R20h is
Figure imgf000058_0001
[00112] In an embodiment, R21h, R22h, and R23h are each H. In an embodiment, R21h and R23h are each independently halogen and R22h is H. In one embodiment, R21h and R23h are each F and R22h is H. In an embodiment, R21h and R23h are each H and R22h is halogen, In one embodiment, R21h and R23h are each H and R22h is F.
[00113] In an embodiment,
Figure imgf000058_0003
[00114] In an embodiment, the compound of Formula (Ilh) comprises one or more stereocenters. In one embodiment, the compound of Formula (Ilh) comprises a stereocenter on R20h. In one embodiment, the compound of Formula (Ilh) comprises a stereocenter where the
Figure imgf000058_0002
moiety connects to the remaining portion of Formula (Ilh).
[00115] In an embodiment, the compound of Formula (Ilh) is selected from:
Figure imgf000059_0001
[00116] In one embodiment, the compound of Formula (I) is a compound of Formula (IIi):
Figure imgf000059_0002
or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein:
R20i is selected from C1-C6 alkyl and C1-C6 alkoxy, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen;
R21 i, R22i, and R23i are each independently selected from H and halogen; and R24ia, R24ib, R25ia, R25ib, R26ia, and R26ib are each independently selected from H, halogen, - OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more halogen atoms.
[00117] In one embodiment, when R20i is R21i is halogen and R21i and R23i are
Figure imgf000060_0002
each H; or R23i is halogen and R21i and R22i are each H. In one embodiment, when R20i is R21i is F and R22i and R23i are each H; or R23i is F and R21i and R22i are each H.
Figure imgf000060_0003
[00118] In one embodiment, the compound of Formula (IIi) is not one of the following compounds:
Figure imgf000060_0001
ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof
[00119] In one embodiment, R20i is C1-C6 alkyl optionally substituted with one or more -
OH. In one embodiment, R20i is C1-C6 alkyl substituted with one -OH. In one embodiment, R20i is C3 alkyl optionally substituted with one -OH. In one embodiment, R20i is
Figure imgf000060_0004
[00120] In one embodiment, R21i is halogen, R22i and R23i are each H; or R23i is halogen, R21i and R22i are each H. In one embodiment, R21i is F, R22i and R23i are each H; or R23i is F, R21i and R22i are each H.
[00121] In one embodiment, one or more of R24ia, R24ib, R25ia, R25ib, R26ia, and R26ib is halogen. In one embodiment, one or more of R24ia, R24ib, R25ia, R25ib, R26ia, and R26ib is F. In one embodiment, R24ia, R25ia, R25ib, R26ia, R26ib are each H and R24ib is F.
[00122] In one embodiment, the compound of Formula (IIi) is selected from:
Figure imgf000061_0002
Figure imgf000061_0001
or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof.
[00123] In an embodiment, the compound of Formula (IIi) has one or more stereocenters.
In one embodiment, the compound of Formula (IIi) comprises a stereocenter where the moiety
Figure imgf000061_0003
connects to the remaining portion of Formula (IIi). In one embodiment, the compound of Formula (IIi) comprises a stereocenter at one or more of R24ia, R24ib, R25ia, R25ib, R26ia, and/or R26ib. In one embodiment, the compound of Formula (IIi) comprises a stereocenter on R20i
[00124] In one embodiment, the compound of Formula (I) is a compound of Formula (Ilj):
Figure imgf000061_0004
or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein:
Figure imgf000061_0005
R20j is selected from C1-C6 alkyl and C1-C6 alkoxy, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen;
R21j, R22j, and R23j are each independently selected from H and halogen; and
R24ja, R24jb, R25ja, R25jb, R26ja, R26jb, R27ja, R27jb, R28ja, and R28jb are each independently selected from H, halogen, -OH, and C1-C6 alkyl.
[00125] In one embodiment, when R20j is halogen and R22j and R23j are
Figure imgf000062_0004
each H; or R23j is halogen and R21j and R22j are each H. In one embodiment, when R20j is s F and R22j and R23j are each H; or R23j is F and R21j and R22j are each H.
Figure imgf000062_0001
[00126] In one embodiment, the compound of Formula (Ilj) is not one of the following:
Figure imgf000062_0002
Figure imgf000062_0003
or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. [00127] In one embodiment, R20j is C1-C6 alkyl optionally substituted with one or more - OH. In one embodiment, R20j is C1-C6 alkyl substituted with one -OH. In one embodiment, R20j is C3 alkyl optionally substituted with one -OH. In one embodiment, R20j is
Figure imgf000063_0004
[00128] In one embodiment, R21j is halogen, R22j and R23j are each H; or R23j is halogen,
R21j and R22j are each H. In one embodiment, R21j is F, R22j and R23j are each H; or R23j is F, R21j and R22j are each H.
[00129] In one embodiment, one or more of R24ja, R24jb, R25ja, R25jb, R26ja, R26jb, R27ja, R27jb,
R28ja, and R28jb is halogen. In one embodiment, one or more of Rz4ja, R24jb, R25ja, R25jb, R26ja,
R26jb, R27ja, R27jb, R28ja, and R28jb is F. In one embodiment,
Figure imgf000063_0003
wherein each of R24ja, R24jb, R25ja, R25jb, R26ja, R26jb, R27ja, R27jb, R28ja, and R28jb is H. In one embodiment, wherein each of R24ja, R24jb, R25ja, R25jb, R26ja, R26jb, R27ja, R28ja, and
Figure imgf000063_0001
R28jb is H and R27jb is halogen. In one embodiment,
Figure imgf000063_0002
wherein each of
R24ja, R24jb, R25ja, R25jb, R26ja, R26jb, R27ja, R28ja, and R28jb is H and R27jb is F.
[00130] In an embodiment, the compound of Formula (Ilj) comprises one or more stereocenters. In one embodiment, the compound of Formula (Ilj) comprises a stereocenter on
R20j. In one embodiment, the compound of Formula (Ilj) comprises a stereocenter where the
Figure imgf000063_0005
moiety connects to the remaining portion of Formula (Ilj). In one embodiment, one or more of R24ja, R24jb, R25ja, R25jb, R26ja, R26jb, R27ja, R27jb, R28ja, and/or R28jb comprises a stereocenter.
[00131] In one embodiment, the compound of Formula (Ilj) is selected from:
Figure imgf000064_0003
or a salt, ester, solvate, optical isomer,
Figure imgf000064_0002
geometric isomer, or salt of an isomer thereof.
[00132] In some embodiments, R6 is (lb), giving a structure of Formula (III), as follows:
Figure imgf000064_0001
[00133] 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.
[00134] In some embodiments, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R29, R29, and R30 are independently selected from H, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C1-C7 alkoxy, or spiro-fused cycloalkyl, which methanoyl (- COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, or spiro-fiised cycloalkyl is optionally substituted with one or more halogen. In some embodiments, one or more of R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R29, R29, and R30 are H. In some embodiments, all of R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R29, R29, and R30 are H.
[00135] Further to any embodiment above wherein the compound has the structure of Formula (III), the compound can have a structure according to any of (Illa)-(IIIp), as follows:
Figure imgf000065_0001
Figure imgf000066_0001
[00136] In some embodiments, the compounds of Formula (I), such as compounds of Formula (II) or Formula (III), including Formulas (Ila)-(IIj) and Formulas (Illa)-(IIIp), can be any of those specified in Compounds 1-138, as listed in Tables 1-2. 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.
[00137] In some embodiments, the compounds of Formula (I), such as compounds of Formula (II) or Formula (III), including Formulas (Ila)-(IIj) and Formulas (Illa)-(IIIp), 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 hydrochloride, hydrobromide, sulphate, phosphate, nitrate, borate, acetate, maleate, tartrate, and salicylate. In some instances, for acidic compounds, salts can include metals, amines, or organic cations (e.g. quaternary ammonium). In yet other embodiments, simple derivatives of the compounds (e.g., ethers, esters, or amides) which have desirable retention and release characteristics but which are easily hydrolyzed by body pH, enzymes, or other suitable means, can be employed.
[00138] In some embodiments, the compounds of the disclosure having a chiral center and can exist in and be isolated in optically active and racemic forms. In other embodiments, compounds may exhibit polymorphism. Some embodiments of the present disclosure encompass any racemic, optically active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound described herein, including isotopically-labeled and radio-labeled compounds. See e.g., Goding, 1986, Monoclonal Antibodies Principles and Practice; Academic Press, p. 104. Such isomers can be isolated by standard resolution techniques, including e.g., fractional crystallization, chiral chromatography, and the like. See e.g., Eliel, E. L. & Wilen S. H., 1993, Stereochemistry in Organic Compounds; John Wiley & Sons, New York. The preparation of optically active forms can be accomplished by any suitable method, including but not limited to, resolution of the racemic form by recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase.
[00139] In some embodiments, compounds disclosed herein have asymmetric centers and can occur as racemates, racemic mixtures, and as individual enantiomers or diastereoisomers, with all isomeric forms as well as mixtures thereof being contemplated for use in the compounds and methods described herein. The compounds contemplated for use in the compounds and methods described herein do not include those that are known in the art to be too unstable to synthesize and/or isolate.
[00140] The compounds disclosed herein can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds can be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I), or carbon-14 (14C). All isotopic variations of the compounds disclosed herein, whether radioactive or not, are encompassed within the contemplated scope. [00141] In some embodiments, metabolites of the compounds disclosed herein are useful for the methods disclosed herein.
[00142] 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 into a compound (e.g., a biologically active compound) described herein in vivo. Prodrugs can be useful for a variety of reason known in the art, including e.g., ease of administration due e.g., to enhanced bioavailability in oral administration, and the like. The prodrug can also have improved solubility in pharmaceutical compositions over the biologically active compounds. An example, without limitation, of a prodrug is a compound which is administered as an ester (i.e., the "prodrug") to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water solubility is beneficial. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, (ed. H. Bundgaard, Elsevier, 1985), which is hereby incorporated herein by reference for the limited purpose describing procedures and preparation of suitable prodrug derivatives.
[00143] Certain compounds disclosed herein can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of contemplated compounds. Certain compounds of the present disclosure can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the compounds and methods contemplated herein and are intended to be within the scope disclosed herein.
[00144] In certain embodiments, one or more compounds of the disclosure (e.g., Formula (I), a compound of Formula (Ila)-(IIj), or a compound of Formula (Illa)-(IIIp)) can be part of a composition and can be in an amount (by weight of the total composition) 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 75%, at least about 90%, at least about 95%, at least about 99%, at least about 99.99%, no more than about 75%, no more than about 90%, no more than about 95%, no more than about 99%, or no more than about 99.99%, from about 0.0001% to about 99%, from about 0.0001% to about 50%, from about 0.01% to about 95%, from about 1% to about 95%, from about 10% to about 90%, or from about 25% to about 75%.
[00145] In some embodiments, one or more compounds of the disclosure (e.g., Formula (I), compound of any one of Formula (Ila)-(IIj), or a compound of any one of Formula (Illa)- (IIIp)) can be purified or isolated in an amount (by weight of the total composition) 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 75%, at least about 90%, at least about 95%, at least about 99%, at least about 99.99%, no more than about 75%, no more than about 90%, no more than about 95%, no more than about 99%, no more than about 99.99%, from about 0.0001% to about 99%, from about 0.0001% to about 50%, from about 0.01% to about 95%, from about 1% to about 95%, from about 10% to about 90%, or from about 25% to about 75%.
Methods for Preparing Compounds of Formula (I)
[00146] Some embodiments of the present disclosure include methods for the preparation of compounds of Formula (I). In certain embodiments, a compound of Formula (I), such as a compound of any one of Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp), can be prepared comprising one or more of the steps set forth in Example 2 herein. The synthetic routes shown and described in Example 2 can, for example, be used to prepare Compounds 1-138, as set forth in Tables 1-2, and structurally related compounds.
Pharmaceutical Compositions and Formulations
[00147] Some embodiments of the present disclosure include compositions comprising one or more compounds of the disclosure (e.g., Formula (I), a compound of any one of Formula (Ila)-(IIj) or Formula (Illa)-(IIIp)). In one embodiment, the composition comprising a compound of the disclosure further comprises one or more therapeutic agents described elsewhere herein. In one embodiment, the present disclosure includes a separate composition comprising one or more of the therapeutic agents described elsewhere herein. In certain embodiments, the composition is a pharmaceutical composition, such as compositions that are suitable for administration to animals (e.g., mammals, primates, monkeys, humans, canine, feline, porcine, mice, rabbits, rats, etc.). In some embodiments, there is provided a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient. The compound can be a compound of any of Formulae (I)-(III) as disclosed herein, a compound as set forth in Tables 1-2, or a pharmaceutically acceptable salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof. In some embodiments, the compound is set forth in any of Tables 1-2 herein.
[00148] In one embodiment, the present disclosure further relates to a composition comprising a compound of Formula (I), such as a compound of any one of Formula (Ila)-(IIj) or Formula (Illa)-(IIIp), and a composition comprising a therapeutic agent. Exemplary therapeutic agents are described elsewhere herein. In another embodiment, the compound of Formula (I) and the therapeutic agent are co-formulated into a single composition. In one embodiment, the compound of Formula (I), such as a compound of any one of Formula (Ila)-(IIj) or Formula (Illa)-(IIIp), and the therapeutic agent are administered together in one administration or composition. In another embodiment, the compound of Formula (I), such as a compound of any one of Formula (Ila)-(IIj) or Formula (Illa)-(IIIp), and the therapeutic agent are administered separately in more than one administration or more than one composition. In one embodiment, the composition comprising the compound of Formula (I), such as a compound of any one of Formula (Ila)-(IIj) or Formula (Illa)-(IIIp), and the composition comprising the therapeutic agent are administered to a subject at the same time. In another embodiment, the composition comprising the compound of Formula (I), such as a compound of any one of Formula (Ila)-(IIj) or Formula (Illa)-(IIIp), and the composition comprising the therapeutic agent are administered to a subject sequentially. In one embodiment, the composition comprising the compound of Formula (I), such as a compound of any one of Formula (Ila)-(IIj) or Formula (Illa)-(IIIp), and the composition comprising the therapeutic agent are co-administered (or administered within a defined time period) such that the subject is exposed to both inhibitors over a period of time in which they can act synergistically.
[00149] The term “pharmaceutically acceptable salts” is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds disclosed herein contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds disclosed herein contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galacturonic acids and the like (see, for example, Berge et al, “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds disclosed herein contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
[00150] Compounds disclosed herein can exist as salts, such as with pharmaceutically acceptable acids. Accordingly, the compounds contemplated herein include such salts. Examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates, (-) -tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid. These salts can be prepared by methods known to those skilled in the art.
[00151] 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.
[00152] Pharmaceutically acceptable salts of the compounds above, where a basic or acidic group is present in the structure, are also included within the scope of compounds contemplated herein. When an acidic substituent is present, such as -NHSO3H, -COOH and -P(O)(OH)2, there can be formed the ammonium, sodium, potassium, calcium salt, and the like, for use as the dosage form. Basic groups, such as amino or basic heteroaryl radicals, or pyridyl and acidic salts, such as hydrochloride, hydrobromide, acetate, maleate, palmoate, methanesulfonate, p-toluenesulfonate, and the like, can be used as the dosage form.
[00153] Also, in the embodiments in which R-COOH is present, pharmaceutically acceptable esters can be employed, e. g. , methyl, ethyl, tert-butyl, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
[00154] In some instances, the pharmaceutical composition is non-toxic, does not cause side effects, or both. In some embodiments, there may be inherent side effects (e.g., it may harm the patient or may be toxic or harmful to some degree in some patients).
[00155] In some embodiments, one or more compounds of the disclosure (e.g., Formula (I), a compound of any one of Formula (Ila)-(IIj) or Formula (Illa)-(IIIp)) can be part of a pharmaceutical composition and can be 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 75%, at least about 90%, at least about 95%, at least about 99%, at least about 99.99%, no more than about 75%, no more than about 90%, no more than about 95%, no more than about 99%, no more than about 99.99%, from about 0.001% to about 99%, from about 0.001% to about 50%, from about 0.1% to about 99%, from about 1% to about 95%, from about 10% to about 90%, or from about 25% to about 75%. In some embodiments, the pharmaceutical composition can be presented in a dosage form which is suitable for the topical, subcutaneous, intrathecal, intraperitoneal, oral, parenteral, rectal, cutaneous, nasal, vaginal, or ocular administration route. In other embodiments, the pharmaceutical composition can be presented in a dosage form which is suitable for parenteral administration, aa mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration. The pharmaceutical composition can be in the form of, for example, tablets, capsules, pills, powders granulates, suspensions, emulsions, solutions, gels (including hydrogels), pastes, ointments, creams, plasters, drenches, delivery devices, suppositories, enemas, injectables, implants, sprays, aerosols or other suitable forms.
[00156] In some embodiments, the compounds disclosed herein can be administered orally as tablets, aqueous or oily suspensions, lozenges, troches, powders, granules, emulsions, capsules, syrups or elixirs. The composition for oral use can contain one or more agents selected from the group of sweetening agents, flavoring agents, coloring agents and preserving agents in order to produce pharmaceutically elegant and palatable preparations. Accordingly, there are also provided pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and one or more compounds disclosed herein.
[00157] In some embodiments, tablets contain the acting 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 com starch or alginic acid; (3) binding agents, such as starch, gelatin or acacia; and (4) lubricating agents, such as magnesium stearate, stearic acid or talc. These tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
[00158] For preparing pharmaceutical compositions from the compounds disclosed herein, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substance that can also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
[00159] A compound disclosed herein, in the form of a free compound or a pharmaceutically-acceptable pro-drug, metabolite, analogue, derivative, solvate or salt, can be administered, for in vivo application, parenterally by injection or by gradual perfusion over time. Administration can be intravenously, intraperitoneally, intramuscularly, subcutaneously, intracavity, or transdermally. For in vitro studies the compounds can be added or dissolved in an appropriate biologically acceptable buffer and added to a cell or tissue.
[00160] In powders, the carrier is a finely divided solid in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
[00161] The powders and tablets preferably contain from 5% to 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term “preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
[00162] For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
[00163] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
[00164] When parenteral application is needed or desired, particularly suitable admixtures for the compounds disclosed herein are injectable, sterile solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants, including suppositories. This suspension can be formulated according to known methods using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation can also a sterile injectable solution or suspension in a non-toxic parenterally- acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles, carriers, and solvents that can be employed are water, Ringer’s solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. In particular, carriers for parenteral administration include aqueous solutions of dextrose, saline, pure water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene-block polymers, and the like. Ampoules are convenient unit dosages. The compounds disclosed herein can also be incorporated into liposomes or administered via transdermal pumps or patches. Pharmaceutical admixtures suitable for use in the pharmaceuticals compositions and methods disclosed herein include those described, for example, in PHARMACEUTICAL SCIENCES (17th Ed., Mack Pub. Co., Easton, PA) and WO 96/05309, the teachings of both of which are hereby incorporated by reference.
[00165] In some embodiments, preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Frequently used carriers or auxiliaries 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 glycols and solvents, such as sterile water, alcohols, glycerol and polyhydric alcohols. 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 (such as those based on Ringer’s dextrose), and the like. Preservatives and other additives can also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, growth factors and inert gases and the like.
[00166] Preservatives include antimicrobial, anti-oxidants, chelating agents and inert gases. Other pharmaceutically acceptable carriers include aqueous solutions, non-toxic excipients, including salts, preservatives, buffers and the like, as described, for instance, in Remington’s Pharmaceutical Sciences, 15th ed. Easton: Mack Publishing Co. , 1405-1412, 1461- 1487 (1975) and The National Formulary XIV., 14th ed. Washington: American Pharmaceutical Association (1975), the contents of which are hereby incorporated by reference. The pH and exact concentration of the various components of the pharmaceutical composition are adjusted according to routine skills in the art. See e.g., Goodman and Gilman (eds.), 1990, THE PHARMACOLOGICAL BASIS FOR THERAPEUTICS (7th ed.).
[00167] Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, me thylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents. Aqueous suspensions normally contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspension. Such excipients can be (1) suspending agent such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; (2) dispersing or wetting agents which can be (a) naturally occurring phosphatide such as lecithin; (b) a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate ; (c) a condensation product of ethylene oxide with aa long chain aliphatic alcohol, for example, heptadecaethylenoxycetanol; (d) a condensation product of ethylene oxide with a partial ester derived from a fatty acid and hexitol such as polyoxyethylene sorbitol monooleate, or (e) a condensation product of ethylene oxide with a partial ester derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate
[00168] Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations can contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
[00169] The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
[00170] In some embodiments, the pharmaceutical composition can include one or more formulary ingredients. A “formulary ingredient” can be any suitable ingredient (e.g., suitable for the drug(s), for the dosage of the drug(s), for the timing of release of the drugs(s), for the disease, for the disease state, or for the delivery route) including, but not limited to, water (e.g., boiled water, distilled water, filtered water, pyrogen-free water, or water with chloroform), sugar (e.g., sucrose, glucose, mannitol, sorbitol, xylitol, or syrups made therefrom), ethanol, glycerol, glycols (e.g., propylene glycol), acetone, ethers, DMSO, surfactants (e.g., anionic surfactants, cationic surfactants, zwitterionic surfactants, or nonionic surfactants (e.g., polysorbates)), oils (e.g., animal oils, plant oils (e.g., coconut oil or arachis oil), or mineral oils), oil derivatives (e.g., ethyl oleate , glyceryl monostearate, or hydrogenated glycerides), excipients, preservatives (e.g., cysteine, methionine, antioxidants (e.g., vitamins (e.g., A, E, or C), selenium, retinyl palmitate, sodium citrate, citric acid, chloroform, or parabens, (e.g., methyl paraben or propyl paraben)), or combinations thereof.
[00171] In certain embodiments, pharmaceutical compositions can be formulated to release the active ingredient (e.g., one or more compounds of the disclosure such as Formula (I), a compound of any one of Formula (Ila)-(IIj) or Formula (Illa)-(IIIp)) substantially immediately upon the administration or any substantially predetermined time or time after administration. Such formulations can include, for example, controlled release formulations such as various controlled release compositions and coatings.
[00172] Other formulations (e.g., formulations of a pharmaceutical composition) can, in certain embodiments, include those incorporating the drug (or control release formulation) into food, food stuffs, feed, or drink.
[00173] Some compounds can have limited solubility in water and therefore can require a surfactant or other appropriate co-solvent in the composition. Such co-solvents include: Polysorbate 20, 60, and 80; Pluronic F-68, F-84, and P-103; cyclodextrin; and polyoxyl 35 castor oil. Such co-solvents are typically employed at a level between about 0.01 % and about 2% by weight.
[00174] Viscosity greater than that of simple aqueous solutions can be desirable to decrease variability in dispensing the formulations, to decrease physical separation of components of a suspension or emulsion of formulation, and/or otherwise to improve the formulation. Such viscosity building agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose, chondroitin sulfate and salts thereof, hyaluronic acid and salts thereof, and combinations of the foregoing. Such agents are typically employed at a level between about 0.01% and about 2% by weight.
[00175] The compositions disclosed herein can additionally include components to provide sustained release and/or comfort. Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides, and finely-divided drug carrier substrates. These components are discussed in greater detail in U.S. Pat. Nos. 4,911,920; 5,403,841; 5,212,162; and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes.
[00176] There are provided various pharmaceutical compositions useful for ameliorating certain diseases and disorders. The pharmaceutical compositions according to one embodiment are prepared by formulating a compound disclosed herein in the form of a free compound or a pharmaceutically-acceptable pro-drug, metabolite, analogue, derivative, solvate or salt, either alone or together with other pharmaceutical agents, suitable for administration to a subject using carriers, excipients and additives or auxiliaries. Frequently used carriers or auxiliaries include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycols and solvents, such as sterile water, alcohols, glycerol and polyhydric alcohols. Intravenous vehicles include fluid and nutrient replenishers.
[00177] There are provided various pharmaceutical compositions useful for ameliorating certain diseases and disorders. The pharmaceutical compositions according to one embodiment are prepared by formulating a compound disclosed herein in the form of a free compound or a pharmaceutically-acceptable pro-drug, metabolite, analogue, derivative, solvate or salt, either alone or together with other pharmaceutical agents, suitable for administration to a subject using carriers, excipients and additives or auxiliaries. Frequently used carriers or auxiliaries include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycols and solvents, such as sterile water, alcohols, glycerol and polyhydric alcohols. Intravenous vehicles include fluid and nutrient replenishers.
Methods of Treating and Preventing Disease
[00178] In addition to their ability to inhibit IRAK, IRAK inhibitors have been demonstrated to have selectivity for multiple kinases. In some embodiments, compounds described herein according to Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp), such as Compounds 1-138, as listed in Tables 1-2, exhibit have inhibitory action against one or more kinase, such as interleukin- 1 receptor-associated kinase (IRAK) and FMS-like tyrosine kinase 3 (FLT3). The inhibitory action against one or more kinase, such as IRAK and FLT3, can allow for treatment and/or prevention of diseases in an animal (e.g., mammals, porcine, canine, avian (e.g., chicken), bovine, feline, primates, rodents, monkeys, rabbits, mice, rats, and humans) using a compound of the disclosure (e.g., Formula (I), a compound of any one of Formula (Ila)-(IIj) or Formula (Illa)-(IIIp)) including, but not limited to hematopoietic cancers (e.g., disorders of hematopoietic stem cells in the bone marrow or disorders related to myeloid lineage), MDS, AML, myeloproliferative disease, and diseases (e.g., hematopoietic cancers) related to mutations in IRAKI, IRAK4, and/or FLT3 (e.g., mutations in the juxtamembrane region of FLT3, mutations in the kinase domain of FLT3, FLT3 point mutations, FLT3 internal tandem duplication mutations, the FLT3-ITD mutation, the D835Y FLT3 mutation, the D835V FLT3 mutation, the F691L FLT3 mutation, or the R834Q FLT3 mutation).
[00179] In some embodiments, the compounds of the disclosure can inhibit the activity of one or more of FLT3, mutations of FLT3 (e.g., mutations in the juxtamembrane region of FLT3, mutations in the kinase domain of FLT3, FLT3 point mutations, FLT3 internal tandem duplication mutations, the FLT3-ITD mutation, the D835Y FLT3 mutation, the D835V FLT3 mutation, the F691L FLT3 mutation, or the R834Q FLT3 mutation), IRAK4 (interleukin- 1 receptor associated kinase 4), isoforms of IRAK4, mutations of IRAK4, IRAKI (interleukin- 1 receptor associated kinase 1), isoforms of IRAKI, and/or mutations of IRAKI. In some embodiments, the compounds of the disclosure can inhibit the activity of one or both of FLT3 and mutations of FLT3 (e.g., mutations in the juxtamembrane region of FLT3, mutations in the kinase domain of FLT3, FLT3 point mutations, FLT3 internal tandem duplication mutations, the FLT3-ITD mutation, the D835Y FLT3 mutation, the D835V FLT3 mutation, the F691L FLT3 mutation, or the R834Q FLT3 mutation) and optionally inhibits one or more of IRAK4, isoforms of IRAK4, mutations of IRAK4, IRAKI, isoforms of IRAKI, or mutations of IRAKI. In some embodiments, the compounds of the disclosure can inhibit the activity of one or both of FLT3 and mutations of FLT3 (e.g., mutations in the juxtamembrane region of FLT3, mutations in the kinase domain of FLT3, FLT3 point mutations, FLT3 internal tandem duplication mutations, the FLT3-ITD mutation, the D835Y FLT3 mutation, the D835V FLT3 mutation, the F691L FLT3 mutation, or the R834Q FLT3 mutation) and optionally inhibits one or both of IRAK4 and IRAKI, or an isoform or mutation thereof. In some embodiments, the compounds of the disclosure can inhibit FLT3 in combination with IRAK4, IRAKI, or with IRAK4 and IRAKI.
[00180] In some embodiments, compounds exhibit inhibitory activity against IRAK and/or FLT-3 with activities > 1 μM, e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000 nM, or even greater. In some embodiments, the compounds exhibit inhibitory activity against IRAK and/or FLT-3 with activities 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, compounds described herein exhibit inhibitory activity against IRAK and/or FLT-3 with activities > 0.1 μM, e.g., about 1, 2, 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, or 100 nM. Ranges of values using a combination of any 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. It is understood that for purposes of quantification, the terms “activity,” “inhibitory activity,” “biological activity,” “IRAK activity,” “IRAKI activity,” “IRAK4 activity,” “FLT-3 activity,” and the like in the context of an inhibitory compound disclosed herein can be quantified in a variety of ways known in the art. Unless indicated otherwise, as used herein such terms refer to IC50 in the customary sense (i.e., concentration to achieve half-maximal inhibition.
[00181] In some embodiments, hematopoietic cancers that can be treated in an animal (e.g., mammals, porcine, canine, avian (e.g., chicken), bovine, feline, primates, rodents, monkeys, rabbits, mice, rats, and humans) using a compound of the disclosure (e.g., Formula (I), Formulas (Ila)-(IIj), or Formulas (Illa)-(IIIp)) include, but are not limited to hematopoietic cancers and cancers of the myeloid line of blood cells, cancers with an increased risk of occurrence due to other blood disorders, cancers with an increased risk of occurrence due to chemical exposure (e.g., anti-cancer therapies or occupational chemical exposure), cancers with an increased risk of occurrence due to ionizing radiation (e.g., anti-cancer therapies), cancers evolving from myelodysplastic syndromes, cancers evolving from myeloproliferative disease, and cancers of the B cells.
[00182] 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 lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL) (e.g. ABC DLBCL with MYD88 mutation (e.g., L265P)), follicular lymphoma, or marginal zone lymphoma, or combinations thereof. ,
[00183] In some embodiments, cancers characterized by dysregulated IRAK expression (IRAKI and/or IRAK4) and/or IRAK-meidated intracellular signaling, can be treated, and include, but are not limited to, glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, Glioma, oral cancer, nasopharyngeal carcinoma, rectal cancer, stomach cancer, and uterine cancer, and the like, and combinations thereof.
[00184] In some embodiments, compounds of the present disclosure can be used to inhibit targets in the context of additional conditions characterized by overactive IRAKI and/or IRAK4. According to particular aspects of the disclosure, compounds of the present disclosure can be used to inhibit overactive IRAKI and/or IRAK4 in conditions such as inflammatory diseases and autoimmune disease, wherein said inflammatory diseaess and autoimmune diseases are characterized by overactive IRAKI and/or IRAK4. In some embodiments, inflammatory and autoimmune diseases characterized by dysregulated (e.g., hyperactive) IRAK expression (IRAKI and/or IRAK4) and/or IRAK-meidated intracellular signaling, can be treated, and include, but are not limited to, chronic inflammation (i.e., associated with viral and bacterial infection), sepsis, rheumatoid arthritis, hidradenitis suppurativa, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjogren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, and the like, and combinations thereof.
[00185] In certain embodiments, MDS that can be treated in a subject (e.g., mammals, porcine, canine, avian (e.g., chicken), bovine, feline, primates, rodents, monkeys, rabbits, mice, rats, and humans) using a compound of the disclosure (e.g., Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp)) include but are not limited to MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, MDS with a mutation in isocitrate dehydrogenase 2, refractory cytopenia with unilineage dysplasia (e.g., refractory anemia, refractory neutropenia, and refractory thrombocytopenia), refractory anemia with ring sideroblasts, refractory cytopenia with multilineage dysplasia (e.g., refractory cytopenia with multilineage dysplasia and ring sideroblasts and animals/humans with pathological changes not restricted to red cells such as prominent white cell precursor and platelet precursor (megakaryocyte) dysplasia), refractory anemias with excess blasts I and II, 5q-syndrome, megakaryocyte dysplasia with fibrosis, and refractory cytopenia of childhood. In some embodiments, MDS that can be treated include, but are not limited to, MDS that is inherited, MDS with an increased risk of occurrence due to an inherited predisposition, MDS with an increased risk of occurrence due to other blood disorders, MDS with an increased risk of occurrence due to chemical exposure, MDS with an increased risk of occurrence due to ionizing radiation, MDS with an increased risk of occurrence due to cancer treatment (e.g., a combination of radiation and the radiomimetic alkylating agents such as busulfan, nitrosourea, or procarbazine (with a latent period of 5 to 7 years) or DNA topoisomerase inhibitors), MDS evolving from acquired aplastic anemia following immunosuppressive treatment and Fanconi's anemia, MDS with an increased risk due to an mutation in splicing factors, MDS with an increased risk due to a mutation in isocitrate dehydrogenase 1 , and MDS with an increased risk due to a mutation in isocitrate dehydrogenase 2. Animals that can be treated include but are not limited to mammals, rodents, primates, monkeys (e.g., macaque, rhesus macaque, pig tail macaque), humans, canine, feline, porcine, avian (e.g., chicken), bovine, mice, rabbits, and rats. In the methods, the term “subject” may refer to both human and non-human subjects. In some instances, the subject is in need of the treatment (e.g., by showing signs of disease, e.g. MDS, AML, cancer, autoimmune disease, inflammatory condition, etc., or by having a low blood cell count).
[00186] In some embodiments, MDS that can be treated in a subject (e.g., mammals, porcine, canine, avian (e.g., chicken), bovine, feline, primates, rodents, monkeys, rabbits, mice, rats, and humans) using a compound of the disclosure (e.g., Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp)) include, but are not limited to MDS that can be treated by inhibiting one or more of FLT3 (e.g., using FLT3 inhibitors), mutations of FLT3 (e.g., using inhibitors of FLT3 mutants), IRAK4 (e.g., using IRAK4 inhibitors), mutations of IRAK4 (e.g., using inhibitors of IRAK4 mutants), IRAKI (e.g., using IRAK 1 inhibitors), and/or mutations of IRAKI (e.g., using inhibitors of IRAKI mutant). In certain embodiments, MDS that can be treated include, but are not limited to MDS that can be treated by inhibiting IRAK4 (or its mutations), MDS that can be treated by inhibiting and IRAKI (or its mutations), or MDS that can be treated by inhibiting IRAK4 (or its mutations) and IRAKI (or its mutations). In some embodiments, MDS that can be treated include, but are not limited to MDS that can be treated by inhibiting FLT3 in combination with IRAK4, IRAKI, or both IRAK4 and IRAKI. In some embodiments, inhibiting FLT3 in combination with IRAK4, IRAKI, or both IRAK4 and IRAKI provides for treating tumors with FLT3 mutations, which can be or become resistant to FLT3 inhibitors due to adaptive resistance mechanism(s), e.g., driven by IRAK. In some embodiments, MDS that can be treated is characterized by MDS having enhanced IRAK4-Long expression and/or activity relative to IRAK4-Short, and/or wherein the MDS is not driven by FLT3 mutations but expresses IRAK4- Long, based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S (e.g. as described in U.S. Patent Application No. 16/339,692; and Smith, M. A., 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 incorporated by reference herein in their entirety).
[00187] In some embodiments, AML that can be treated in a subject (e.g., mammals, porcine, canine, avian (e.g., chicken), bovine, feline, primates, rodents, monkeys, rabbits, mice, rats, and humans) using a compound of the disclosure (e.g., Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp)) include, but are not limited to AML that is inherited, AML with an increased risk of occurrence due to an inherited predisposition, AML with one or more recurrent genetic abnormality (e.g., with inversions or translocations, such as MLLT3/MLL which is a translocation between chromosome 9 and 11 (“MLL”) AML with translocation between chromosomes 8 and 21, AML with translocation or inversion in chromosome 16, AML with translocation between chromosomes 9 and 11, APL (M3) with translocation between chromosomes 15 and 17, AML with translocation between chromosomes 6 and 9, AML with translocation or inversion in chromosome 3, and the like), AML (megakaryoblastic) with a translocation between chromosomes 1 and 22, AML with myelodysplasia-related changes, AML related to previous chemotherapy or radiation (such as, for example, alkylating agent-related AML, topoisomerase II inhibitor-related AML, and the like), AML not otherwise categorized (does not fall into above categories - similar to FAB classification; such as, for example, AML minimally differentiated (MO), AML with minimal maturation (Ml), AML with maturation (M2), acute myelomonocytic leukemia (M4), acute monocytic leukemia (M5), acute erythroid leukemia (M6), acute megakaryoblastic leukemia (M7), acute basophilic leukemia, acute panmyelosis with fibrosis, and the like), myeloid sarcoma (also known as granulocytic sarcoma, chloroma or extramedullary myeloblastoma), undifferentiated and biphenotypic acute leukemias (also known as mixed phenotype acute leukemias), AML with an increased risk of occurrence due to other blood disorders, AML with an increased risk of occurrence due to chemical exposure, AML with an increased risk of occurrence due to ionizing radiation, AML evolving from myelodysplastic syndromes, AML evolving from myeloproliferative disease, AML with an increased risk due to an FLT3 mutation, AML with an increased risk due to an FLT3 mutation in the juxtamembrane region of FLT3, AML with an increased risk due to an FLT3 mutation of an internal tandem duplication in the juxtamembrane region of FLT3, AML with an increased risk due to an FLT3 mutation in the kinase domain of FLT3, AML with an increased risk due to the FLT3 mutation D835Y, AML with an increased risk due to the FLT3 mutation D835V, AML with an increased risk due to the FLT3 mutation F691L, and AML with an increased risk due to the FLT3 mutation R834Q, and the like. In some embodiments, AML that can be treated include AML that by inhibiting one or more of FLT3 (e.g., using FLT3 inhibitors), mutations of FLT3 (e.g., using inhibitors of FLT3 mutants), IRAK4 (e.g., using IRAK4 inhibitors), mutations of IRAK4 (e.g., using inhibitors of IRAK4 mutants), IRAKI (e.g., using IRAK 1 inhibitors), and/or mutations of IRAKI (e.g., using inhibitors of IRAKI mutant). In certain embodiments, AML that can be treated include, but are not limited to AML that can be treated by inhibiting IRAK4 (or its mutations), MDS that can be treated by inhibiting and IRAKI (or its mutations), or AML that can be treated by inhibiting IRAK4 (or its mutations) and IRAKI (or its mutations). In some embodiments, AML that can be treated include, but are not limited to AML that can be treated by inhibiting FLT3 in combination with IRAK4, IRAKI, or both IRAK4 and IRAKI . In some embodiments, inhibiting FLT3 in combination with IRAK4, IRAKI, or both IRAK4 and IRAKI provides for treating tumors with FLT3 mutations which can be or become resistant to FLT3 inhibitors due to adaptive resistance mechanism(s), e.g. driven by IRAK. In some embodiments, AML that can be treated is characterized by AML having enhanced IRAK4-Long expression and/or activity relative to IRAK4-Short, and/or wherein the AML is not driven by FLT3 mutations but expresses IRAK4-Long, based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S (e.g. as described in U.S. Patent Application No. 16/339,692; and Smith, M. A., 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 incorporated by reference herein in their entirety).
[00188] In some embodiments, hematopoietic cancers that can be treated in a subject (e.g., mammals, porcine, canine, avian (e.g., chicken), bovine, feline, primates, rodents, monkeys, rabbits, mice, rats, and humans) using a compound of the disclosure (e.g., Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp),) include, but are not limited to hematopoietic cancers (e.g. MDS, AML, DLBCL, and the like, as described previously) that can be treated by inhibiting (e.g., reducing the activity or expression of) one or more of FLT3 (e.g., using FLT3 inhibitors), mutations of FLT3 (e.g., using inhibitors of FLT3 mutants), IRAK4 (e.g., using IRAK4 inhibitors), isoforms of IRAK4, mutations of IRAK4 (e.g., using inhibitors of IRAK4 mutants), IRAKI (e.g., using IRAK 1 inhibitors), isoforms of IRAKI, or mutations of IRAKI (e.g., using inhibitors of IRAKI mutants). 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 its mutations) and IRAK4 (or its mutations), hematopoietic cancers that can be treated by inhibiting (e.g., reducing the activity or expression of) FLT3 (or its mutations) and IRAKI (or its mutations), or hematopoietic cancers that can be treated by inhibiting (e.g., reducing the activity or expression of) FLT3 (or its mutations), IRAK4 (or its isoforms or mutations), and IRAKI (or its isoforms mutations). In some embodiments, hematopoietic cancer that can be treated include, but are not limited to hematopoietic cancer that can be treated by inhibiting FLT3 in combination with IRAK4, IRAKI, or both IRAK4 and IRAKI. In some embodiments, inhibiting FLT3 in combination with IRAK4, IRAKI, or both IRAK4 and IRAKI provides for treating tumors with FLT3 mutations which can be or become resistant to FLT3 inhibitors due to adaptive resistance mechanism(s), e.g. driven by IRAK. In some embodiments, hematopoietic cancer that can be treated is characterized by hematopoietic cancer having enhanced IRAK4-Long expression and/or activity relative to IRAK4-Short, and/or wherein the hematopoietic cancer is not driven by FLT3 mutations but expresses IRAK4-Long, based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S (e.g. as described in U.S. Patent Application No. 16/339,692; and Smith, M. A., 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 incorporated by reference herein in their entirety).
[00189] 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, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, Glioma, oral cancer, nasopharyngeal carcinoma, rectal cancer, stomach cancer, and uterine cancer, and the like, and combinations thereof, that can be treated by inhibiting FLT3 in combination with IRAK4, IRAKI, or both IRAK4 and IRAKI. In some embodiments, inhibiting FLT3 in combination with IRAK4, IRAKI, or both IRAK4 and IRAKI provides for treating tumors with FLT3 mutations which can be or become resistant to FLT3 inhibitors due to adaptive resistance mechanism(s), e.g., driven by IRAK. In some embodiments, cancer that can be treated is characterized by cancer having enhanced IRAK4-Long expression and/or activity relative to IRAK4-Short, and/or wherein the cancer is not driven by FLT3 mutations but expresses IRAK4- Long, based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S (e.g. as described in U.S. Patent Application No. 16/339,692; and Smith, M. A., 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 incorporated by reference herein in their entirety).
[00190] In some embodiments, inflammatory and autoimmune diseases characterized by dysregulated (e.g., hyperactive) IRAK expression (IRAKI and/or IRAK4) and/or IRAK- meidated intracellular signaling, that can be treated include, but are not limited to, chronic inflammation (i.e., associated with viral and bacterial infection), sepsis, rheumatoid arthritis, hidradenitis suppurativa, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjogren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, and the like, and combinations thereof, that can be treated by inhibiting FLT3 in combination with IRAK4, IRAKI, or both IRAK4 and IRAKI. In some embodiments, inhibiting FLT3 in combination with IRAK4, IRAKI, or both IRAK4 and IRAKI provides for treating inflammatory and autoimmune diseases with FLT3 mutations which can be or become resistant to FLT3 inhibitors due to adaptive resistance mechanism(s), e.g., driven by IRAK. In some embodiments, inflammatory and autoimmune disease that can be treated is characterized by inflammatory and autoimmune disease having enhanced IRAK4-Long expression and/or activity relative to IRAK4-Short, and/or wherein the inflammatory and autoimmune disease is not driven by FLT3 mutations but expresses IRAK4-Long, based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S (e.g. as described in U.S. Patent Application No. 16/339,692; and Smith, M. A., 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 incorporated by reference herein in their entirety).
[00191] As related to treating 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), treating can include but is not limited to prophylactic treatment and therapeutic treatment. As such, treatment can include, but is not limited to: preventing 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); reducing the risk 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); ameliorating or relieving symptoms 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); eliciting a bodily response against 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 the development 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 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); reducing 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); causing a regression 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) or one or more of the symptoms associated with MDS (e.g., an increase in blood cell count); causing 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); causing 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) by preventing or minimizing FLT3 mutations (e.g., internal tandem duplication mutations or the D835Y mutation); preventing relapse 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); or preventing relapse 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) in animals/humans that have intrinsic or acquired resistance to other MDS treatments. In some embodiments, treating does not include prophylactic treatment of MDS (e.g., preventing or ameliorating future MDS).
[00192] As related to treating hematopoietic cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, or 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, and the like), treating can include but is not limited to prophylactic treatment and therapeutic treatment. As such, treatment can include, but is not limited to: preventing cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, or Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof, and the like); 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 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, and the like); ameliorating or relieving symptoms of cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, or Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof, and the like); eliciting a bodily response against cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, or Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof, and the like); inhibiting the development 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 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, and the like); 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 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, and the like); reducing 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 lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof, and the like); causing a regression of cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone mmaarrrrooww cancer, non-Hodgkin lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof, and the like) or one or more of the symptoms associated with cancer (e.g., a decrease in tumor size); causing 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 lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof, and the like); causing 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 lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof, and the like) by preventing or minimizing FLT3 mutations (e.g., internal tandem duplication mutations or the D835Y mutation); causing remission of acute myeloid leukemia by preventing or minimizing FLT3 mutations (e.g., internal tandem duplication mutations or the D835Y mutation); preventing relapse of cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof, and the like); preventing relapse of cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof, and the like) in animals/humans that have intrinsic or acquired resistance to other cancer treatments (e.g., from some FLT3 inhibitors or from MLL); or preventing relapse of acute myeloid leukemia in animals/humans that have intrinsic or acquired resistance to other cancer treatments (e.g., from some FLT3 inhibitors or from MLL). In some embodiments, treating does not include prophylactic treatment of cancer (e.g., preventing or ameliorating future cancer). [00193] Treatment of a subject can occur using any suitable administration method (such as those disclosed herein) and using any suitable amount of a compound of the disclosure (e.g., Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp)). In some embodiments, methods of treatment comprise 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 comprise treating an animal or human for a hematopoietic cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone mmaarrrrooww cancer, non-Hodgkin lymphoma, Waldenstrom’s macroglobulinemia Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof, and the like). Other embodiments include treatment after one or more of having a blood disorder, having myelodysplastic syndrome, having myeloproliferative disease, an occurrence of chemical exposure, an exposure to ionizing radiation, or a treatment for a hematopoietic cancer (e.g., with chemotherapy, ionizing radiation, or both). Some embodiments of the disclosure include a method for treating a subject (e.g., an animal such as a human or primate) with a composition comprising a compound of the disclosure (e.g., Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp)) (e.g., a pharmaceutical composition) which comprises one or more administrations of one or more such compositions; the compositions may be the same or different if there is more than one administration.
[00194] In some embodiments, the method of treatment includes administering to a subject an effective amount of a composition comprising a compound of the disclosure (e.g., Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp)). As used herein, the term “effective amount” refers to a dosage or a series of dosages sufficient to affect treatment (e.g., to treat MDS such as but not limited to 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); 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), bone marrow cancer, non-Hodgkin lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof, and the like) in a subject. In some embodiments, an effective amount can encompass a therapeutically effective amount, as disclosed herein. In certain embodiments, an effective amount can vary depending on the subject and the particular treatment being affected. The exact amount that is required can, for example, vary from subject to subject, depending on the age and general condition of the subject, the particular adjuvant being used (if applicable), administration protocol, and the like. As such, the effective amount can, for example, vary based on the particular circumstances, and an appropriate effective amount can be determined in a particular case. An effective amount can, for example, include any dosage or composition amount disclosed herein. In some embodiments, an effective amount of at least one compound of the disclosure (e.g., Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp), such as but not limited to Compounds 1-138, as listed in Tables 1-2) (which can be administered to a subject such as mammals, primates, monkeys or humans) can be an amount of about 0.005 to about 50 mg/kg body weight, about 0.01 to about 15 mg/kg body weight, about 0.1 to about 10 mg/kg body weight, about 0.5 to about 7 mg/kg body weight, about 0.005 mg/kg, about 0.01 mg/kg, about 0.05 mg/kg, about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 3 mg/kg, about 5 mg/kg, about 5.5 mg/kg, about 6 mg/kg, about 6.5 mg/kg, about 7 mg/kg, about 7.5 mg/kg, about 8 mg/kg, about 10 mg/kg, about 12 mg/kg, or about 15 mg/kg. In regard to some embodiments, the dosage can be about 0.5 mg/kg body weight or about 6.5 mg/kg body weight. In some instances, an effective amount of at least one compound of the disclosure (e.g., Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp) such as but not limited to Compounds 1-138, as listed in Tables 1-2) (which can be administered to a subject such as mammals, rodents, mice, rabbits, feline, porcine, or canine) can be an amount of about 0.005 to about 50 mg/kg body weight, about 0.01 to about 15 mg/kg body weight, about 0.1 to about 10 mg/kg body weight, about 0.5 to about 7 mg/kg body weight, about 0.005 mg/kg, about 0.01 mg/kg, about 0.05 mg/kg, about 0.1 mg/kg, about 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 disclosure (e.g., Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp), such as but not limited to Compounds 1-138, as listed in Tables 1-2) (which can be administered to an animal such as mammals, primates, monkeys or humans) can be an amount of about 1 to about 1000 mg/kg body weight, about 5 to about 500 mg/kg body weight, about 10 to about 200 mg/kg body weight, about 25 to about 100 mg/kg body weight, about 1 mg/kg, about 2 mg/kg, about 5 mg/kg, about 10 mg/kg, about 25 mg/kg, about 50 mg/kg, about 100 mg/kg, about 150 mg/kg, about 200 mg/kg, about 300 mg/kg, about 400 mg/kg, about 500 mg/kg, about 600 mg/kg, about 700 mg/kg, about 800 mg/kg, about 900 mg/kg, or about 1000 mg/kg. In regard to some conditions, the dosage can be about 20 mg/kg human body weight or about 100 mg/kg human body weight. In some instances, an effective amount of at least one compound of the disclosure (e.g., Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp), such as but not limited to Compounds 1-138, as listed in Tables 1-2) (which can be administered to an animal such as mammals, rodents, mice, rabbits, feline, porcine, or canine) can be an amount of about 1 to about 1000 mg/kg body weight, about 5 to about 500 mg/kg body weight, about 10 to about 200 mg/kg body weight, about 25 to about 100 mg/kg body weight, about 1 mg/kg, about 2 mg/kg, about 5 mg/kg, about 10 mg/kg, about 25 mg/kg, about 50 mg/kg, about 100 mg/kg, about 150 mg/kg, about 200 mg/kg, about 300 mg/kg, about 400 mg/kg, about 500 mg/kg, about 600 mg/kg, about 700 mg/kg, about 800 mg/kg, about 900 mg/kg, or about 1000 mg/kg.
[00195] In some embodiments, the treatments can also include one or more of surgical intervention, chemotherapy, radiation therapy, hormone therapies, immunotherapy, and adjuvant systematic therapies. Adjuvants may include but are not limited to chemotherapy (e.g., temozolomide), radiation therapy, antiangiogenic therapy (e.g., bevacizumab), and hormone therapies, such as administration of LHRH agonists; anti-estrogens, such as tamoxifen; high-dose progestogens; aromatase inhibitors; and/or adrenalectomy. Chemotherapy can be used as a single-agent or as a combination with known or new therapies.
[00196] In some embodiments, the administration to a subject of at least one compound of the disclosure (e.g., Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp)) is an adjuvant cancer therapy or part of an adjuvant cancer therapy. Adjuvant treatments include treatments by the mechanisms disclosed herein and of cancers as disclosed herein, including, but not limited to tumors. Corresponding primary therapies can include, but are not limited to, surgery, chemotherapy, or radiation therapy. In some instances, the adjuvant treatment can be a combination of chemokine receptor antagonists with traditional chemotoxic agents or with immunotherapy that increases the specificity of treatment to the cancer and potentially limits additional systemic side effects. In still other embodiments, a compound of the disclosure (e.g., Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp)) can be used as adjuvant with other chemotherapeutic agents. The use of a compound of the disclosure (e.g., Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp)) may, in some instances, reduce the duration of the dose of both drugs and drug combinations reducing the side effects. [00197] In some embodiments, the administration to a subject may decrease the incidence of one or more symptoms associated with MDS / AML / a type of hematopoietic cancer. In some embodiments, the administration may decrease marrow failure, immune dysfunction, transformation to overt leukemia, or combinations thereof in said subject, as compared to a subject not receiving said composition.
[00198] In some embodiments, the method may decrease a marker of viability of MDS cells AML cells, or cancer cells in a subject. In one aspect, the method may decrease a marker of viability of MDS, AML, and/or cancer cells. The marker may be selected from survival over time, proliferation, growth, migration, formation of colonies, chromatic assembly, DNA binding, RNA metabolism, cell migration, cell adhesion, inflammation, or a combination thereof.
Combination Therapies
[00199] In one embodiment, the compounds of Formula (I), such as the compounds of
Formula (II) or Formula (III), including Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp), are administered with one or more therapeutic agents. Exemplary therapeutic agents include, but are not limited to, a CDK inhibitor, a BCL2 inhibitor, a PTEFb inhibitor, a DNA polymerase inhibitor, a cytidine deaminase inhibitor, a DNA methyltransferase (DNMT) inhibitor, an immunomodulatory imide, a cereblon modulator, a purine nucleoside antimetabolite, a Type II topoisomerase inhibitor, a DNA intercalator, a hedgehog antagonist, an IDH2 inhibitor, an IDH1 inhibitor, a ribonucleotide reductase inhibitor, an adenosine deaminase inhibitor, a Mek 1/2 inhibitor, an ERK 1/2 inhibitor, an AKT inhibitor, a PTPN11 inhibitor, an SHP2 inhibitor, a glucocorticoid steroid, a menin inhibitor, an MDM2 inhibitor, a BTK inhibitor, and a mutant/inactivated p53 reactivator.
[00200] In some embodiments, the treatments disclosed herein can include use of other drugs (e.g., antibiotics) or therapies for treating disease, e.g. MDS / AML / a type of hematopoietic cancer. For example, antibiotics can be used to treat infections and can be combined with a compound of the disclosure to treat disease (e.g., infections). In other embodiments, intravenous immunoglobulin (IVIG) therapy can be used as part of the treatment regime (i.e., in addition to administration of the compound(s) of the disclosure). For example, treatment regimens for various types of cancers can involve one or more elements selected from chemotherapy, targeted therapy, alternative therapy, immunotherapy, and the like.
[00201] Accordingly, in some embodiments, the compounds and/or compositions described herein can be used in one or more administrations to a subject, in combination with one or more BCL2 inhibitor, BTK inhibitor, chemotherapy, targeted therapy, alternative therapy, immunotherapy, DNA methyltransferase inhibitor/hypomethylating agent, anthracycline, histone deacetylase (HD AC) inhibitor, purine nucleoside analogue (antimetabolite), isocitrate dehydrogenase 1 oorr 2 (IDH1 and/or IDH2) inhibitor, antibody-drug conjugate, mAbs/immunotherapy, CAR-T cell therapy, Plk inhibitor, MEK inhibitor, CDK9 inhibitor, CDK8 inhibitor, retinoic acid receptor agonist, TP53 activator, smoothened receptor antagonist, ERK inhibitor, PI3K inhibitor, mTOR inhibitor, glucocorticoid receptor modulator, or EZH2 inhibitor, and the like, or one or more combinations thereof, where the compositions may be the same or different if there is more than one administration. In some embodiments, if there is more than one administration at least one composition used for at least one administration is different from the composition of at least one other administration.
[00202] In one embodiment, the therapeutic agent comprises a BCL2 inhibitor. In one embodiment, the BCL2 inhibitor is venetoclax or a salt thereof. In one embodiment, the therapeutic agent comprises a DNA polymerase inhibitor. In one embodiment, the DNA polymerase inhibitor is cytidine. In one embodiment, the therapeutic agent comprises a cytidine deaminase inhibitor. In one embodiment, the cytidine deaminase inhibitor is zebularine. In one embodiment, the therapeutic agent comprises a DNMT inhibitor. In one embodiment, the DNMT inhibitor is zebularine, decitabine, or azacitidine. In one embodiment, the therapeutic agent comprises an immunomodulatory imide (cereblon modulator). In one embodiment, the immunomodulatory imide (cereblon modulator) is lenalidomide. In one embodiment, the therapeutic agent comprises a purine nucleoside antimetabolite. In one embodiment, the purine nucleoside antimetabolite is clofarabine. In one embodiment, the therapeutic agent comprises a Type II topoisomerase inhibitor/ DNA intercalator. In one embodiment, the Type II topoisomerase inhibitor/ DNA intercalator is vosaroxin. In one embodiment, the therapeutic agent comprises a hedgehog antagonist. In one embodiment, the hedgehog antagonist is glasdegib. In one embodiment, the therapeutic agent comprises an IDH1 inhibitor. In one embodiment, the IDH1 inhibitor is ivosidenib. In one embodiment, the therapeutic agent comprises an IDH2 inhibitor. In one embodiment, the IDH2 inhibitor is enasidenib. In one embodiment, the therapeutic agent comprises a ribonucleotide reductase inhibitor. In one embodiment, the ribonucleotide reductase inhibitor is gemcitabine. In one embodiment, the therapeutic agent comprises an adenosine deaminase inhibitor. In one embodiment, the adenosine deaminase inhibitor is cladribine. In one embodiment, the therapeutic agent comprises a Mek 1/2 inhibitor. In one embodiment, the Mek 1/2 inhibitor is trametinib. In one embodiment, the therapeutic agent comprises an ERK 1/2 inhibitor. In one embodiment, the ERK 1/2 inhibitor is ulixertinib. In one embodiment, the therapeutic agent comprises an AKT inhibitor. In one embodiment, the AKT inhibitor is capivasertib (AZD5363). In one embodiment, the therapeutic agent comprises a PTPN11/SHP2 inhibitor. In one embodiment, the PTPN11/SHP2 inhibitor is TNO-155. In one embodiment, the therapeutic agent comprises a glucocorticoid steroid. In one embodiment, the glucocorticoid steroid is selected from dexamethasone, methylprednisolone, prednisolone, cortisol, prednisone, betamethasone, triamcinolone, deflazacort, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone, and beclometasone. In one embodiment, the glucocorticoid steroid is selected from dexamethasone, methylprednisolone, and prednisolone. In one embodiment, the therapeutic agent comprises a menin inhibitor. In one embodiment, the menin inhibitor is SNDX-5613. In one embodiment, the therapeutic agent comprises an MDM2 inhibitor. In one embodiment, the MDM2 inhibitor is navtemadlin (AMG 232, KRT-232). In one embodiment, the therapeutic agent comprises a BTK inhibitor. In one embodiment, the BTK inhibitor is selected from ibrutinib, acalabrutinib, and zanubrutinib. In one embodiment, the therapeutic agent comprises a mutant/ inactivated p53 reactivator. In one embodiment, the mutant/inactivated p53 reactivator is Eprenetapopt (APR- 246).
[00203] In one embodiment, the therapeutic agent comprises a CDK inhibitor. The CDK inhibitor can be any CDK inhibitor known to a person of ordinary skill in the art. In one embodiment, the CDK inhibitor is a CKD1, CKD2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12, or CDK13 inhibitor or a combination thereof.
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WO 2002053096, US 20030018005, US 6500846, WO 2002100401, US 6486166, WO
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6197804, WO 1999066055, US 6013646, WO 1999043676, US 5767258, US 5733920, and any INPADOC family member of each of the above references, each of which is incorporated herein by reference in its entirety. In another embodiment, the CDK inhibitor comprises an inhibitor described in: Alsfouk, A., Journal of Enzyme Inhibition and Medicinal Chemistry, 2021, 36(l):693-706; Goel, B. et al., Curr. Top. Med. Chem., 2020, 20(17): 1535-1563; Heptinstall, A. B. et al., Future Med. Chem., 2018, 10(11):1369-1388; Sanchez-Martinez, C. et al., Bioorganic & Medicinal Chemistry Letters, 2019, 29:126637; Di Sante, G. et al., Expert Review of Anticancer Therapy, 2019, 19(7): 569-587; Whittaker, S. R. et al., Pharmacology & Therapeutics, 2017, 173:83-105; Chou, J. et al., Cancer Discovery, 2020, 10:351-370; Galbraith, M. D. et al., Transcription, 2019, 10(2):l 18-136; Goel, B. et al., Current Topics in Medicinal Chemistry, 2020, 20:1535-1563; Heptinstall, A. B. et al., Future Medicinal Chemistry, 2018, 10(11): 1369-1388; each of which is incorporated herein by reference in its entirety.
[00205] In one embodiment, the CDK inhibitor is a CDK9 inhibitor. In one embodiment, the CDK9 inhibitor is Atuveciclib (BAY-1143572) or BAY-1251152 (VIP152). In one embodiment, BAY- 1251152 (VIP 152) is a selective CDK9 inhibitor while Atuveciclib (BAY- 1143572) is a CDK9/PTEFb inhibitor. In one embodiment, the CDK inhibitor is a CDK4/6 inhibitor. In one embodiment, the CDK4/6 inhibitor is Palbociclib. In one embodiment, the CDK inhibitor is a CDK7 inhibitor. In one embodiment, the CDK7 inhibitor is THZ1.
[00206] Exemplary CDK inhibitors include, but are not limited to: Compound 21 (PMID 27326333) CYC065; YKL-1-116; i-CDK9; JH-VII-49; JH-XI-10-02; SEL120-34A; MM-D37K; PF-06873600; BEY-1007; BEY-1107; birociclib (XZP-3297); FCN-437; TP-1287; BEBT-209; TQB-3616; AMG-925 (FLX-925); CS3002; HS-10342; terameprocol (EM-1421); NU-6102; CGP-60474; BMS-265246; NU-6027; Purvalanol A; Purvalanol B; RGB-286147; Indirubin; 7- Hydroxystaurosporine; BS-194; PHA-690509; Cdk4/6 Inhibitor IV; FCN437c;
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
wherein X is NH or O;
Figure imgf000123_0001
Figure imgf000123_0002
CH3;
Figure imgf000123_0003
wherein R is -CH3 and X is F, R is H and X is F, or R is -CH3 and X is Cl;
Figure imgf000124_0001
wherein R is tetrahydro-pyran-4-yl and R’ is H, R is -CH2CH3 and R’ is -OCH3, R is isopropyl and R’ is H, or R is - CH2CH3 and R’ is F;
1 0
Figure imgf000124_0002
wherein R is t-butyl carboxyl and n is 1 or R is H and n is 2;
Figure imgf000124_0003
wherein X is NH or O;
Figure imgf000124_0004
wherein R is H and R’ is F, R is F and R’ is F, or R is
H and R’ is H;
Figure imgf000125_0001
wherein R is -OCH3 and R’ is F, R is F and R’ is SF5, or
R is -OCH3 and R’ is -SF5; wherein R is F and R’ is -CH3 or R is -SF5 and R’ is H;
Figure imgf000125_0002
wherein R is -CF3 and R’ is -CH3 or R is H and R’ is cyclopropyl;
Figure imgf000125_0003
wherein R is 3-fluoroailin-lyl and R’ is F or R is phenyl and
R’ is -CH3;
Figure imgf000125_0004
wherein R is H or F and Alkyl is -CH3 or -CH2CH3; wherein R is 3 -fluorophenyl or morpholin-4yl;
Figure imgf000125_0005
Figure imgf000126_0001
wherein R is cyclopropan-l-ol-l-yl, X is Cl, and n is 1 or R is tetrahydrofuran-3yl, X is Cl and n is 1, or R is -CH3, X is F and n is 2, or R is cyclopropane-1- 1- yl, X is F and n is 1, or oxatan-3 -yl, X is -CH3, and n is 1; wherein R is l,2-oxazol-3yl or 3,4-difluorobenzen-lyl;
Figure imgf000126_0002
Figure imgf000126_0003
wherein R is H, C(=O)NHCH3, -SO2NH2, SO2CH3, or 2,3- dihydroxpropan- wherein R is H, CH3, 2-aminoethyan-lyl, 3 -aminopropan- lyl, or
Figure imgf000126_0004
2 3 -dihydroxpropan- wherein R is H or -CH3;
Figure imgf000126_0005
Figure imgf000127_0001
wherein R is H, C(=O)NHCH3, or -SO2CH3;
Figure imgf000127_0002
wherein R is 3 -fluorobenzyl or 3-fluoropyridin-3yl;
Figure imgf000127_0003
wherein Aryl is 4-fluorophenyl, 4-trifluoromethylphenyl, 3- fluorophenyl, 4-methylphenyl, 2 -ethylphenyl, or 3 -pyridyl and R is H, cyclopropyl, cylcopentyl, or cycloheptyl;
Figure imgf000127_0004
wherein R is 2-phenylethan-lyl or (furan-2-yl)methyl; R
Figure imgf000127_0005
wherein R is H or -C(=O)CH2OH;
Figure imgf000127_0006
wherein R is -NHC(=O)CH3 or -NHSO2CH3;
Figure imgf000128_0001
wherein R is H or isobutyl;
Figure imgf000128_0002
wherein R is H and R’ is -CH3 or R is -CN and R’ is H;
Figure imgf000128_0003
wherein R is 3,4-dimethyl-lH-pyrazol-4-yl and R’ is -CH3 or
Figure imgf000128_0004
wherein R is 2,6-dichlorophenyl, 2,3,4,5,6-tetrafluorophenyl, or 3- fluorophenyl;
Figure imgf000128_0005
wherein R is -CH2NCH3 or H;
Figure imgf000128_0006
wherein R is -CH2N(CH3)2 or H;
Figure imgf000129_0001
wherein R is H, -SO2CH3, -CH2C(=O)N(CH3)2, 4-carboxylic acid- cyclobutan-lyl, or (2(hydroxymethy)pyrrolidine-l-yl)-2-one-ethan-lyl, R’ is H or F, and R” is H or -CH2CH3; wherein R1 is -OH, R2 is H, R3 is H, and R4 is H (meridianin A), Ri
Figure imgf000129_0002
is -OH, R2 is H, R3 is Br, and R4 is H (meridianin B), Ri is H, R2 is Br, R3 is H, and R4 is H (meridianin C), Ri is H, R2 is H, R3 is Br, and R4 is H (meridianin D), or Ri is -OH, R2 is H, R3 is H, and R4 is Br (meridianin E); and
Figure imgf000129_0003
wherein R is piperidin-3yl, pyrrolodin-3yl, or morpholin-2yl.
[00209] In one embodiment, the therapeutic agent comprises a BCL2 inhibitor and a DNMT inhibitor. In one embodiment, the therapeutic agent comprises venetoclax, or a salt thereof, and azacitidine, or a salt thereof.
[00210] In some embodiments, the one or more therapeutic agents can be in the form of salts, optical and geometric isomers, and salts of isomers. In other embodiments, the therapeutic agent can be in various forms, such as uncharged molecules, components of molecular complexes, or non-irritating pharmacologically acceptable salts, including but not limited to hydrochloride, hydrobromide, sulphate, phosphate, nitrate, borate, acetate, maleate, tartrate, and salicylate. In some instances, for acidic compounds, salts can include metals, amines, or organic cations (e.g. quaternary ammonium). In yet other embodiments, simple derivatives of the therapeutic agents (e.g., ethers, esters, or amides) which have desirable retention and release characteristics but which are easily hydrolyzed by body pH, enzymes, or other suitable means, can be employed.
[00211] In some embodiments, the therapeutic agent has a chiral center and can exist in and be isolated in optically active and racemic forms. In other embodiments, the therapeutic agent may exhibit polymorphism. Some embodiments of the present disclosure encompass any racemic, optically active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound described herein, including isotopically-labeled and radio-labeled compounds. See e.g., Goding, 1986, Monoclonal Antibodies Principles and Practice; Academic Press, p. 104. Such isomers can be isolated by standard resolution techniques, including e.g., fractional crystallization, chiral chromatography, and the like. See e.g., Eliel, E. L. & Wilen S. H., 1993, Stereochemistry in Organic Compounds; John Wiley & Sons, New York. The preparation of optically active forms can be accomplished by any suitable method, including but not limited to, resolution of the racemic form by recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase.
[00212] In some embodiments, the therapeutic agent has asymmetric centers and can occur as racemates, racemic mixtures, and as individual enantiomers or diastereoisomers, with all isomeric forms as well as mixtures thereof being contemplated for use in the compounds and methods described herein. The compounds contemplated for use in the compounds and methods described herein do not include those that are known in the art to be too unstable to synthesize and/or isolate.
[00213] The therapeutic agents disclosed herein can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds can be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I), or carbon-14 (14C). All isotopic variations of the compounds disclosed herein, whether radioactive or not, are encompassed within the contemplated scope.
[00214] In some embodiments, metabolites of the therapeutic agents disclosed herein are useful for the methods disclosed herein.
[00215] In some embodiments, the therapeutic agents contemplated herein may be provided in the form of a prodrug. The term “prodrug” refers to a compound that can be converted into a compound (e.g., a biologically active compound) described herein in vivo. Prodrugs can be useful for a variety of reason known in the art, including e.g., ease of administration due e.g., to enhanced bioavailability in oral administration, and the like. The prodrug can also have improved solubility in pharmaceutical compositions over the biologically active compounds. An example, without limitation, of a prodrug is a compound which is administered as an ester (i.e., the "prodrug") to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water solubility is beneficial. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, (ed. H. Bundgaard, Elsevier, 1985), which is hereby incorporated herein by reference for the limited purpose describing procedures and preparation of suitable prodrug derivatives.
[00216] Certain the therapeutic agent disclosed herein can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of contemplated compounds. Certain the therapeutic agents of the present disclosure can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the compounds and methods contemplated herein and are intended to be within the scope disclosed herein.
[00217] In particular, IRAK inhibitors have been demonstrated to have synergistic effects when administered in combination with an apoptosis modulator/inhibitor, such as a BCL2 inhibitor. As described in U.S. Patent Application No. 16/804,518 (incorporated herein by reference in its entirety), an exemplary apoptosis/BCL2 inhibitor has been shown to have a synergistic effect when used in combination with an exemplary IRAK inhibitor in multiple AML cell lines. Venetoclax was used as a representative apoptosis/BCL2 inhibitor.
[00218] When a concentration of an exemplary IRAK inhibitor was combined with venetoclax, the potency of venetoclax was increased by an unexpectedly high ~50-fold. According to particular aspects of the disclosure, this synergistic combination allows for increased efficacy of venetoclax at lower doses, to provide for avoiding at least some of the toxicity observed in the clinic. According to particular aspects, the degree of interaction is dependent on the dose ratio combination that is used, with lower concentrations of the exemplary IRAK inhibitor providing larger shifts in the venetoclax IC50. This unexpected and dramatic shift in the venetoclax IC50 is substantially more than an additive response and demonstrates the unexpected synergistic interaction of the two drugs even in cell lines that do not express activated FLT3 mutants. [00219] Accordingly, the present disclosure encompasses methods for treating a disease or disorder which is responsive to inhibition of IRAK, comprising administration to a subject of a composition comprising an IRAK inhibiting compound, wherein some embodiments of the method can further involve administration of an apoptotic modulator. The apoptotic modulator may comprise a BTK and/or a BCL2 inhibitor. BTK and BCL2 inhibitors may be, for example, those known in the art. In some embodiments, the method may comprise the step of administering to the subject an apoptotic modulator. In some embodiments, the apoptotic modulator may comprise a BCL2 inhibitor selected from ABT-263 (Navitoclax), ABT-737, ABT-199 (venetoclax), GDC -0199, GX15-070 (Obatoclax) (all available from Abbott Laboratories), HA14-1, SI, 2-methoxy antimycin A3, gossypol, AT-101, apogossypol, WEHI- 539, A-l 155463, BXI-61, BXL72, TW37, MIMI, UML77, and the like, and combinations thereof. One skilled in the art would appreciate that there are many known BCL2 inhibitors which can be used in accordance with the present disclosure. In some embodiments, the BCL2 inhibitor comprises venetoclax.
[00220] In some embodiments, the administration step comprises administration to a subject of a composition comprising an IRAK inhibiting compound and a BCL2 inhibitor. In some embodiments, the administration step comprises administration of a composition comprising an IRAK inhibiting compound in combination with a composition comprising a BCL2 inhibitor.
[00221] In some embodiments, the IRAK inhibiting compound is selected from Compounds 1-138, or a salt, isomer, derivative or analog thereof, and the BCL2 inhibitor is venetoclax, or a salt, isomer, derivative or analog thereof.
[00222] In some embodiments, the method can further involve administration to a subject of an immune modulator. The immune modulator can include, for example, Lenalidomide (Revlamid; Celgene Corporation). In some embodiments, the method can involve administration of an epigenetic modulator. The epigenetic modulator can include, for example, a hypomethylating agent such as azacitidine, decitabine, or a combination thereof.
[00223] In some embodiments, the compounds and/or compositions described herein can be used in one or more administrations to a subject, together with or in combination with one or more BTK inhibitor, such as, for example, ibrutinib, or a salt, isomer, derivative or analog thereof. [00224] For example, the compounds and/or compositions described herein can be used in one or more administrations, together with or in combination with a DNA methyltransferase inhibitor/hypomethylating agent, such as, for example, azacitidine, decitabine, cytarabine, and/or guadecitabine; an anthracycline, such as, for example, daunorubicin, idarubicin, doxorubicin, mitoxantrone, epirubicin, and/or CPX-351 (a combination cytarabine and daunorubicin in a fixed 5:1 molar ratio), and the like; a histone deacetylase (HD AC) inhibitor, such as, for example, vorinostat, panobinostat, valproic acid, and/or pracinostat, and the like; a purine nucleoside analogue (antimetabolite), such as, for example, fludarabine, cladribine, and/or clofarabine, and the like; an isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor, such as, for example, ivosidenib and/or enasidenib, and the like; an antibody-drug conjugate, such as, for example, Anti-CD33 (e.g. Ac225-lintuzumab, vadastuximab, or gemtuzumab-ozogamicin) and/or Anti- CD45 (e.g. I131-apamistamab), and the like; an mAbs/Immunotherapy, such as, for example, Anti-CD70 (e.g. ARGX-110, cusatuzumab), a bispecific antibody (e.g. floteuzumab (CD 123 x CD3 )), Anti-CTLA4 (e.g. ipilimumab), Anti-PDl/PDLl (e.g. nivolumab, pembrolizumab, atezolizumab, avelumab, PDR001, MBG453), and/or Anti-CD47 (e.g. 5F9 (Magrolimab)), and the like; a Plk inhibitor, such as, for example, volasertib and/or rigosertib, and the like; a MEK inhibitor, such as, for example, trametinib, cobimetinib, selumetinib, pimasertib, and/or refametinib, and the like; a CDK9 inhibitor, such as, for example, alvocidib and/or voruciclib, and the like; a CDK8 inhibitor, such as, for example, SEL120, and the like; a retinoic acid receptor agonist, such as, for example, ATRA (all-trans retinoic acid) and/or SY- 1425 (a selective RARa agonist), and the like; a TP53 activator, such as, for example, APR-246 (Eprenetapopt), and the like; a smoothened receptor antagonist, such as, for example, glasdegib, and the like; an ERK inhibitor, such as, for example, an ERK2/MAPK1 or ERK1/MAPK3 inhibitor, such as, for example, ulixertinib, SCH772984, ravoxertinib, MK-8353, and/or VTX- l le, and the like; a PI3K inhibitor, such as, for example, fimepinostat (CUDC-907), alpelisib, leniolisib (CDZ-173), pilaralisib (XL 147, SAR245408), and/or bimiralisib (PQR-309), and the like; an mTOR inhibitor, such as, for example, bimiralisib (PQR-309), sapanisertib (TAK-228, INK-128), ridaforolimus (MK-8669, AP -23573), everolimus, and/or vistusertib (AZD2014), and the like; a glucocorticoid receptor modulator, such as, for example, an agonist comprising prednisolone, beclometasone, methylprednisolone, prednisone, fluticasone, budesonide, dexamethasone, and/or cortisol, and/or an antagonist comprising mifepristone, miricorilant, and/or onapristone, and/or another binding ligand comprising vamorolone (VBP15), and the like; and/or an EZH2 inhibitor, such as, for example, tazemetostat, and the like, In some embodiments, compounds and pharmaceutical compositions including the same can be used in prevention of secondary malignancies when used in combination with an EZH2 inhibitor. Further therapies are described below and are contemplated in combination therapies in the context of the present disclosure.
Chemotherapy / Targeted Therapy / Alternative Therapy
[00225] Cancers are commonly treated with chemotherapy and/or targeted therapy and/or alternative therapy. Chemotherapies act by indiscriminately targeting rapidly dividing cells, including healthy cells as well as tumor cells, whereas targeted cancer therapies rather act by interfering with specific molecules, or molecular targets, which are involved in cancer growth and progression. Targeted therapy generally targets cancer cells exclusively, having minimal damage to normal cells. Chemotherapies and targeted therapies which are approved and/or in the clinical trial stage are known to those skilled in the art. Any such compound can be utilized in the practice of the present disclosure.
[00226] For example, approved chemotherapies include abitrexate (Methotrexate Injection), abraxane (Paclitaxel Injection), adcetris (Brentuximab Vedotin Injection), adriamycin (Doxorubicin), adrucil Injection (5-FU (fluorouracil)), afmitor (Everolimus), afinitor Disperz (Everolimus), alimta (PEMETREXED), alkeran Injection (Melphalan Injection), alkeran Tablets (Melphalan), aredia (Pamidronate), arimidex (Anastrozole), aromasin (Exemestane), arranon (Nelarabine), arzerra (Ofatumumab Injection), avastin (Bevacizumab), beleodaq (Belinostat Injection), bexxar (Tositumomab), BiCNU (Carmustine), blenoxane (Bleomycin), blincyto (Blinatumoma b Injection), bosulif (Bosutinib), busulfex Injection (Busulfan Injection), campath (Alemtuzumab), camptosar (Irinotecan), caprelsa (Vandetanib), casodex (Bicalutamide), CeeNU (Lomustine), CeeNU Dose Pack (Lomustine), cerubidine (Daunorubicin), clolar (Clofarabine Injection), cometriq (Cabozantinib), cosmegen (Dactinomycin), cotellic (Cobimetinib), cyramza (Ramucirumab Injection), cytosarU (Cytarabine), cytoxan (Cytoxan), cytoxan Injection (Cyclophosphamide Injection), dacogen (Decitabine), daunoXome (Daunorubicin Lipid Complex Injection), decadron (Dexamethasone), depoCyt (Cytarabine Lipid Complex Injection), dexamethasone Intensol (Dexamethasone), dexpak Taperpak (Dexamethasone), docefrez (Docetaxel), doxil (Doxorubicin Lipid Complex Injection), droxia (Hydroxyurea), DTIC (Decarbazine), eligard (Leuprolide), ellence (Ellence (epirubicin)), eloxatin (Eloxatin (oxaliplatin)), elspar (Asparaginase), emcyt (Estramustine), erbitux (Cetuximab), erivedge (Vismodegib), erwinaze (Asparaginase Erwinia chrysanthemi), ethyol (Amifostine), etopophos (Etoposide Injection), eulexin (Flutamide), fareston (Toremifene), farydak (Panobinostat), faslodex (Fulvestrant), femara (Letrozole), firmagon (Degarelix Injection), fludara (Fludarabine), folex (Methotrexate Injection), folotyn (Pralatrexate Injection), FUDR (FUDR (floxuridine)), gazyva (Obinutuzumab Injection), gemzar (Gemcitabine), gilotrif (Afatinib), gleevec (Imatinib Mesylate), Gliadel Wafer (Carmustine wafer), Halaven (Eribulin Injection), Herceptin (Trastuzumab), Hexalen (Altretamine), Hycamtin (Topotecan), Hycamtin (Topotecan), Hydrea (Hydroxyurea), Ibrance (Palbociclib), Iclusig (Ponatinib), Idamycin PFS (Idarubicin), Ifex (Ifosfamide), Imbruvica (Ibrutinib), Inlyta (Axitinib), Intron A alfab (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), Lanvima (Lenvatinib), Leukeran (Chlorambucil), Leukine (Sargramostim), Leustatin (Cladribine), Lonsurf (Trifluridine and Tipiracil), Lupron (Leuprolide), Lupron Depot (Leuprolide), Lupron DepotPED (Leuprolide), Lynparza (Olaparib), Lysodren (Mitotane), Marqibo Kit (Vincristine Lipid Complex Injection), Matulane (Procarbazine), Megace (Megestrol), Mekinist (Trametinib), Mesnex (Mesna), Mesnex (Mesna Injection), Metastron (Strontium-89 Chloride), Mexate (Methotrexate Injection), Mustargen (Mechlorethamine), Mutamycin (Mitomycin), Myleran (Busulfan), Mylotarg (Gemtuzumab Ozogamicin), Navelbine (Vinorelbine), Neosar Injection (Cyclophosphamide Injection), Neulasta (filgrastim), Neulasta (pegfilgrastim), Neupogen (filgrastim), Nexavar (Sorafenib), Nilandron (Nilandron (nilutamide)), Nipent (Pentostatin), Nolvadex (Tamoxifen), Novantrone (Mitoxantrone), Odomzo (Sonidegib), Oncaspar (Pegaspargase), Oncovin (Vincristine), Ontak (Denileukin Diftitox), onxol (Paclitaxel Injection), opdivo (Nivolumab Injection), panretin (Alitretinoin), paraplatin (Carboplatin), perjeta (Pertuzumab Injection), platinol (Cisplatin), platinol (Cisplatin Injection), platinolAQ (Cisplatin), platinolAQ (Cisplatin Injection), pomalyst (Pomalidomide), prednisone Intensol (Prednisone), proleukin (Aldesleukin), purinethol (Mercaptopurine), reclast (Zoledronic acid), revlimid (Lenalidomide), rheumatrex (Methotrexate), rituxan (Rituximab), roferonA alfaa (Interferon alfa-2a), rubex (Doxorubicin), sandostatin (Octreotide), sandostatin LAR Depot (Octreotide), soltamox (Tamoxifen), sprycel (Dasatinib), sterapred (Prednisone), sterapred DS (Prednisone), stivarga (Regorafenib), supprelin LA (Histrelin Implant), sutent (Sunitinib), sylatron (Peginterferon Alfa-2b Injection (Sylatron)), sylvant (Siltuximab Injection), synribo (Omacetaxine Injection), tabloid (Thioguanine), taflinar (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), thiop lex (Thiotepa), TICE BCG (BCG), toposar (Etoposide Injection), torisel (Temsirolimus), treanda (Bendamustine hydrochloride), trelstar (Triptorelin Injection), trexall (Methotrexate), trisenox (Arsenic trioxide), tykerb (lapatinib), unituxin (Dinutuximab Injection), valstar (Valrubicin Intravesical), vantas (Histrelin Implant), vectibix (Panitumumab), velban (Vinblastine), velcade (Bortezomib), vepesid (Etoposide), vepesid (Etoposide Injection), vesanoid (Tretinoin), vidaza (Azacitidine), vincasar PFS (Vincristine), vincrex (Vincristine), votrient (Pazopanib), vumon (Teniposide), wellcovorin IV (Leucovorin Injection), xalkori (Crizotinib), xeloda (Capecitabine), xtandi (Enzalutamide), yervoy (Ipilimumab Injection), yondelis (Trabectedin Injection), zaltrap (Ziv-aflibercept Injection), zzaannoossaarr (Streptozocin), zelboraf (Vemurafenib), zevalin (Ibritumomab Tiuxetan), zoladex (Goserelin), zolinza (Vorinostat), zometa (Zoledronic acid), zortress (Everolimus), zydelig (Idelalisib), zykadia (Ceritinib), zytiga (Abiraterone), and the like, in addition to analogs and derivatives thereof. For example, approved targeted therapies include ado-trastuzumab emtansine (Kadcyla), afatinib (Gilotrif), aldesleukin (Proleukin), alectinib (Alecensa), alemtuzumab (Campath), axitinib (Inlyta), belimumab (Benlysta), belinostat (Beleodaq), bevacizumab (Avastin), bortezomib (Velcade), bosutinib (Bosulif), brentuximab vedotin (Adcetris), cabozantinib (Cabometyx, Cometriq), canakinumab (Haris), carfilzomib (Kyprolis), ceritinib (Zykadia), cetuximab (Erbitux), cobimetinib (Cotellic), crizotinib (Xalkori), dabrafenib (Tafmlar), daratumumab (Darzalex), dasatinib (Sprycel), denosumab (Xgeva), 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 (Portrazza), nilotinib (Tasigna), nivolumab (Opdivo), obinutuzumab (Gazyva), ofatumumab (Arzerra, HuMax-CD20), olaparib (Lynparza),osimertinib (Tagrisso), palbociclib (Ibrance), panitumumab (Vectibix), panobinostat (Farydak), pazopanib (Votrient), pembrolizumab (Keytruda), pertuzumab (Perjeta), ponatinib (Iclusig), ramucirumab (Cyramza), rapamycin, regorafenib (Stivarga), rituximab (Rituxan, Mabthera), romidepsin (Istodax), ruxolitinib (Jakafi), siltuximab (Sylvant), sipuleucel-T (Provenge), sirolimus, sonidegib (Odomzo), sorafenib (Nexavar), sunitinib, tamoxifen, temsirolimus (Torisel), tocilizumab (Actemra), tofacitinib (Xeljanz), tositumomab (Bexxar), trametinib (Mekinist), trastuzumab (Herceptin), vandetanib (Caprelsa), vemurafenib (Zelboraf), venetoclax (Venclexta), vismodegib (Erivedge), vorinostat (Zolinza), ziv-aflibercept (Zaltrap), and the like, in addition to analogs and derivatives thereof.
[00227] Those skilled in the art can determine appropriate chemotherapy and/or targeted therapy and/or alternative therapy options, including treatments that have been approved and those that in clinical trials or otherwise under development. Some targeted therapies are also immunotherapies. Any relevant chemotherapy, target therapy, and alternative therapy treatment strategies can be utilized, alone or in combination with one or more additional cancer therapy, in the practice of the present disclosure.
Immunotherapy
[00228] In some embodiments, immunotherapies include cell-based immunotherapies, such as those involving cells which effect an immune response (such as, for example, lymphocytes, macrophages, natural killer (NK) cells, dendritic cells, cytotoxic T lymphocytes (CTL), antibodies and antibody derivatives (such as, for example, monoclonal antibodies, conjugated monoclonal antibodies, polyclonal antibodies, antibody fragments, radiolabeled antibodies, chemolabeled antibodies, etc.), immune checkpoint inhibitors, vaccines (such as, for example, cancer vaccines (e.g. tumor cell vaccines, antigen vaccines, dendritic cell vaccines, vector-based vaccines, etc.), e.g. oncophage, sipuleucel-T, and the like), immunomodulators (such as, for example, interleukins, cytokines, chemokines, etc.), topical immunotherapies (such as, for example, imiquimod, and the like), injection immunotherapies, adoptive cell transfer, oncolytic virus therapies (such as, for example, talimogene laherparepvec (T-VEC), and the like), immunosuppressive drugs, helminthic therapies, other non-specific immunotherapies, and the like. Immune checkpoint inhibitor immunotherapies are those that 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 immunotherpaies include cytokines, interleukins, interferons, and the like. In some embodiments, an immunotherapy assigned or administered to a subject can include an interleukin, and/or interferon (IFN), and/or one or more suitable antibody-based reagent, such as denileukin diftitox and/or administration of an antibody-based reagent selected from the group consisting of ado-trastuzumab emtansine, alemtuzumab, atezolizumab, bevacizumab, blinatumomab, brentuximab vedotin, cetuximab, catumaxomab, gemtuzumab, ibritumomab tiuxetan, ilipimumab, natalizumab, nimotuzumab, nivolumab, ofatumumab, panitumumab, pembrolizumab, rituximab, tositumomab, trastuzumab, vivatuxin, and the like. In some embodiments, an immunotherapy assigned or administered to a subject can include an indoleamine 2,3-dioxygenase (IDO) inhibitor, adoptive T-cell therapy, virotherapy (T-VEC), and/or any other immunotherapy whose efficacy extensively depends on anti-tumor immunity.
[00229] Those skilled in the art can determine appropriate immunotherapy options, including treatments that have been approved and those that in clinical trials or otherwise under development. Any relevant immunotherapy treatment strategies, alone or in combination with one or more additional cancer therapy, can be utilized in the practice of the present disclosure. Other Cancer Treatments
[00230] In addition to chemotherapies, targeted therapies, alternative therapies, and immunotherapies, cancer can additionally be treated by other strategies. These include surgery, radiation therapy, hormone therapy, stem cell transplant, precision medicine, and the like; such treatments and the compounds and compositions utilized therein are known to those skilled in the art. Any such treatment strategies can be utilized in the practice of the present disclosure.
[00231 ] Alternative treatment strategies have also been used with various types of cancers. Such treatment can be used alone or in combination with any other treatment modality. These include exercise, massage, relaxation techniques, yoga, acupuncture, aromatherapy, hypnosis, music therapy, dietary changes, nutritional and dietary supplements, and the like; such treatments are known to those skilled in the art. Any such treatment strategies can be utilized, alone or in combination with one or more additional cancer therapy, in the practice of the present disclosure.
Dosage and Administration Routes
[00232] Other embodiments of the disclosure can include methods of administering or treating an animal/human, which can involve treatment with an amount of at least one compound of the disclosure (e.g., Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp)) that is effective to treat the disease, condition, or disorder that the organism has, or is suspected of having, or is susceptible to, or to bring about a desired physiological effect. In some embodiments, the composition or pharmaceutical composition comprises at least one compound of the disclosure (e.g., Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp)) which can be administered to an animal (e.g., mammals, primates, monkeys, or humans) 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. In regard to some conditions, the dosage can be about 0.5 mg/kg human body weight or about 6.5 mg/kg human body weight. In some instances, some subjects (e.g., mammals, mice, rabbits, feline, porcine, or canine) can be administered a dosage 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, those skilled in the art will appreciate that it is possible to employ many concentrations in the methods of the present disclosure, and using, in part, the guidance provided herein, will be able to adjust and test any number of concentrations in order to find one that achieves the desired result in a given circumstance. In some embodiments, a dose or a therapeutically effective dose of a compound disclosed herein will be that which is sufficient to achieve a plasma concentration of the compound or its active metabolite(s) within a range 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 even 500-1000 μM, preferably about 1-10 nM, 10-100 nM, or 0.1- 1 μM. Without wishing to be bound by any theory, it is believed that such compounds are indicated in the treatment or management of hematopoietic cancers, such as, for example, MDS and/or AML and/or DLBCL, etc., other types of cancers, inflammatory conditions, and/or autoimmune diseases, as described herein.
[00233] In other embodiments, the compounds and/or pharmaceutical compounds of the disclosure (e.g., compounds of Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp) and pharmaceutical compositions including the same) can be administered in combination with one or more other therapeutic agents for a given disease, condition, or disorder.
[00234] The compounds and pharmaceutical compositions are preferably prepared and administered in dose units. Solid dose units are tablets, capsules and suppositories. For treatment of a subject, depending on activity of the compound, manner of administration, nature and severity of the disease or disorder, age and body weight of the subject, different daily doses can be used.
[00235] Under certain circumstances, however, higher or lower daily doses can be appropriate. The administration of the daily dose can be carried out both by single administration in the form of an individual dose unit or else several smaller dose units and also by multiple administrations of subdivided doses at specific intervals.
[00236] The compounds and pharmaceutical compositions contemplated herein can be administered locally or systemically in a therapeutically effective dose. Amounts effective for this use will, of course, depend on the severity of the disease or disorder and the weight and general state of the subject. Typically, dosages used in vitro can provide useful guidance in the amounts useful for in situ administration of the pharmaceutical composition, and animal models can be used to determine effective dosages for treatment of particular disorders.
[00237] Various considerations are described, e. g. , in Langer, 1990, Science, 249: 1527; Goodman and Gilman's (eds.), 1990, Id., each of which is herein incorporated by reference and for all purposes. Dosages for parenteral administration of active pharmaceutical agents can be converted into corresponding dosages for oral administration by multiplying parenteral dosages by appropriate conversion factors. As to general applications, the parenteral dosage in mg/mL times 1.8 = the corresponding oral dosage in milligrams (“mg”). As to oncology applications, the parenteral dosage in mg/mL times 1.6 = the corresponding oral dosage in mg. An average adult weighs about 70 kg. See e.g., Miller-Keane, 1992, Encyclopedia & Dictionary of Medicine, Nursing & Allied Health, Sth Ed., (W. B. Saunders Co.), pp. 1708 and 1651.
[00238] It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
[00239] In some embodiments, the compounds and/or pharmaceutical compositions can include a unit dose of one or more compounds of the disclosure (e.g., compounds of Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp), and pharmaceutical compositions including the same) in combination with a pharmaceutically acceptable carrier and, in addition, can 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 preservation of the composition. In other embodiments, the one or more carriers, include but are not limited to, saline solutions such as normal saline, Ringer's solution, PBS (phosphate-buffered saline), and generally mixtures of various salts including potassium and phosphate salts with or without sugar additives such as glucose. Carriers can include aqueous and non-aqueous sterile injection solutions that can contain antioxidants, buffers, bacteriostats, bactericidal antibiotics, and solutes that render the formulation isotonic with the bodily 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. Nontoxic auxiliary substances, such as wetting agents, buffers, or emulsifiers may also be added to the composition. Oral formulations can include such normally employed excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, and magnesium carbonate.
[00240] The quantity of active component in a unit dose preparation can be varied or adjusted from 0.1 mg to 10000 mg, more typically 1.0 mg to 1000 mg, most typically 10 mg to 500 mg, according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.
[00241] The compounds of the disclosure (e.g., compounds according to Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp)) can be administered to subjects by any number of suitable administration routes or formulations. The compounds of the disclosure (e.g., Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp)) of the disclosure can also be used to treat subjects for a variety of diseases. Subjects include but are not limited to mammals, primates, monkeys (e.g., macaque, rhesus macaque, or pig tail macaque), humans, canine, feline, bovine, porcine, avian (e.g., chicken), mice, rabbits, and rats. As used herein, the term “subject”, unless stated otherwise, encompasses both human and non-human subjects.
[00242] The route of administration of the compounds of the disclosure (e.g., Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp)) can be of any suitable route. Administration routes can be, but are not limited to the oral route, the parenteral route, the cutaneous route, the nasal route, the rectal route, the vaginal route, and the ocular route. In other embodiments, administration routes can be parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration. The choice of administration route can depend on the compound identity (e.g., the physical and chemical properties of the compound) as well as the age and weight of the animal/human, the particular disease (e.g., cancer or MDS), and the severity of the disease (e.g., stage or severity of cancer or MDS). Of course, combinations of administration routes can be administered, as desired.
[00243] Some embodiments of the disclosure include a method for providing a subject with a composition comprising one or more compounds of the disclosure (e.g., Formula (I), Formulas (Ila)-(IIj) or Formulas (Illa)-(IIIp)) described herein (e.g., a pharmaceutical composition) which comprises one or more administrations of one or more such compositions; the compositions may be the same or different if there is more than one administration.
Methods of Increasing Survivability
[00244] In yet another aspect, the present disclosure provide a method of increasing survivability in a subject diagnosed with acute myeloid leukemia (AML) or suspected of having AML, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of Formulas (I), (Ila)-(IIj), Formulas (Illa)-(IIIp), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or a composition comprising a compound of any one of Formulas (I), (Ila)-(IIj), Formulas (Illa)-(IIIp), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. In one embodiment, the survivability of the subject is increased compared to a subject treated with a therapeutically effective amount of the standard of care for AML. In one embodiment, the standard of care for AML comprises gilteritinib or a pharmaceutically acceptable salt thereof. In one embodiment, the survivability is increased by inhibiting at least one of IRAKI, IRAK4, and FLT3 in the subject. In one embodiment, the survivability is increased by inhibiting IRAKI and IRAK4 in the subject. In one embodiment, the survivability is increased by inhibiting IRAKI, IRAK4, and FLT3 in the subject. In one embodiment, the AML is BCL2 inhibitor resistant and/or FLT3 inhibitor resistant.
[00245] In one embodiment, the method comprises administering to the subject the therapeutically effective amount of a compound of any one of Formulas (I), (Ila)-(IIj), Formulas (Illa)-(IIIp), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or the composition comprising a compound of any one of Formulas (I), (Ila)-(IIj), Formulas (Illa)-(IIIp), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof about every 6 hours, every 12 hours, every 18 hours, once a day, every other day, every 3 days, every 4 days, every 5 days, every 6 days, or once a week.
[00246] In one embodiment, the method further comprise administering to the subject one or more additional therapies selected from: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, 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, an mAbs/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, 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, an NEDD 8 -activator, an MDM2 inhibitor, a PLK1 inhibitor, an Aura A inhibitor, an aurora kinase inhibitor, an EGFR inhibitor, an AuroraB/C/VEGFRl/2/3/FLT3/CSF-lR/Kit/PDGFRA/B inhibitor, an AKT 1, 2, and/or 3 inhibitor, aa ABL1/2/SRC/EPHA2/LCK/YES1/KIT/PDGFRB/FYN inhibitor, a famesyltransferase inhibitor, a BRAF/MAP2K1/MAP2K2 inhibitor, a Menin-KMT2A/MLL inhibitor, and a multikinase inhibitor. In one embodiment, the additional therapy is at least one of a BCL2 inhibitor, a BTK inhibitor, a gluococorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor. In one embodiment, the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof, the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof, the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone, or a pharmaceutically acceptable salt of any one thereof, the CDK inhibitor is selected from CDK4/6 inhibitor palbociclib, CDK7 inhibitor THZ1, and/or CDK9 inhibitors BAY 1251152 and atuveciclib, or a pharmaceutically acceptable salt of any one thereof, and the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of any one of Formulas (I), (Ila)-(IIj), Formulas (Illa)-(IIIp), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or the composition comprising a compound of any one of Formulas (I), (Ila)-(IIj), Formulas (Illa)- (IIIp), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and the one or more additional therapies are administered together in one administration or composition. In another embodiment, the compound of any one of Formulas (I), (Ila)-(IIj), Formulas (Illa)-(IIIp), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, or the composition comprising a compound of any one of Formulas (I), (Ila)- (Ilj), Formulas (Illa)-(IIIp), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof and the one or more additional therapies are administered separately in more than one administration or more than one composition.
[00247] In one embodiment, the subject is a human. In one embodiment, the subject is a human and the survivability of the subject is increased by about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, about 11 years, about 12 years, about 13 years, about 14 years, about 15 years, about 16 years, about 17 years, about 18 years, about 19 years, or about 20 years compared to a subject treated with a therapeutically effective amount of the standard of care for AML. In another embodiment, the subject is a non-human mammal engrafted with AML cells. In one embodiment, the subject is a mouse engrafted with AML cells. In one embodiment, the AML cells are MOLM14-FLT3-ITD(D835Y) cells. In one embodiment, the subject is a mouse engrafted with AML cells wherein the survivability of the subject is increased by about 1 day, about 2 days, about 5 days, about 10 days, about 15 days, about 20 days, about 25 days, about 30 days, about 35 days, about 40 days, about 45 days, about 50 days, about 55 days, about 60 days, about 65 days, about 70 days, about 75 days, about 80 days, about 85 days, or about 90 days compared to a subject treated with a therapeutically effective amount of the standard of care for AML.
Toxicity
[00248] The ratio between toxicity and therapeutic effect for a particular compound is its therapeutic index and can be expressed as the ratio between LD50 (the amount of compound lethal in 50% of the population) and EDso (the amount of compound effective in 50% of the population). Compounds that exhibit high therapeutic indices are preferred. Therapeutic index data obtained from in vitro assays, cell culture assays and/or animal studies can be used in formulating a range of dosages for use in humans. The dosage of such compounds preferably lies within a range of plasma concentrations that include the ED50 with little or no toxicity. The dosage can vary within this range depending upon the dosage form employed and the route of administration utilized. See, e.g., Fingl et al., In: THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, Ch.l, p.l, 1975. The exact formulation, route of administration, and dosage can be chosen by the individual practitioner in view of 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 chosen by the individual practitioner in view of the patient’s condition and the particular method in which the compound is used.
[00249] Having described the disclosure in detail, it will be apparent that modifications, variations, and equivalent embodiments are possible without departing from the scope of the disclosure defined in the appended claims. Furthermore, it should be appreciated that all examples in the present disclosure are provided as non-limiting examples.
[00250] The following clauses describe certain embodiments.
[00251] Clause 1. A compound selected from Formula (I)
Figure imgf000145_0001
or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof, wherein:
R2 is H, halogen, hydroxy, oxo, -CN, amino, -O-aryl, methanoyl (-COH), carboxy (-CO2H), C1- C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, aryl, heteroaryl, or fused ring heteroaryl, which amino, -O-aryl, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, oxo (=O), -O', methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NHz, -NHCH3, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 heteroalkyl, C1-C7 haloalkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, cycloalkyl, heterocyclyl, spiro-fused cycloalkyl, aryl, fused ring aryl, heteroaryl, fused ring heteroaryl, or C1-C7 alkyl which is substituted with cycloalkyl wherein two adjacent optional substituents can bond or fuse to form a ring; R3, R4, and R5 are independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (- COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, which methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, -NHCH3, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl which is substituted with cycloalkyl;
R6 is
Figure imgf000146_0001
R7, R8, R9, R10, R11, R12, R13, R14 are independently selected from H, halogen, hydroxy, oxo, - CN, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, which methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more halogen;
R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R29, R29, and R30 are independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, which methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more halogen; and m, n, o, p, q, r, s, t, u, v, w, and x are independently selected from 0, 1, 2, 3, 4, or 5, where q+r+s+t is at least 1, and where u+v+w+x is at least 1.
[00252] Clause 2. The compound of clause 1, wherein R2 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, which O-aryl, amino, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, heterocyclyl, aryl, fused ring aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, -CN, amino, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, fused ring aryl, fused ring heteroaryl, pyrrolyl, piperidyl, piperazinyl, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl which is substituted with cycloalkyl.
[00253] Clause 33.. The compound of clause 1 or clause 2, wherein R2 is H, halogen, hydroxy, O-aryl, amino, C1-C7 alkyl, C1-C7 alkoxy, cycloalkyl, heterocyclyl, aryl, fused ring aryl, heteroaryl, or fused ring heteroaryl which 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 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl which is substituted with cycloalkyl.
[00254] Clause 4. The compound of any of clauses 1-3, wherein R2 is H, Cl, hydroxy, - NHCH3, -N(CH3)2, -OCH3, -OCF3, -OCHF2, -OPh, -CF3, -CHF2, unsubstituted C1-C7 alkyl, substituted amino, substituted C1-C7 alkyl, substituted cycloalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl, substituted pyrazolyl, substituted fused ring heteroaryl, or unsubstituted fused ring heteroaryl.
[00255] Clause 5. The compound of any of clauses 1-4, wherein R2 is not H.
[00256] Clause 66.. The compound of any of clauses 1-5, wherein R3 is H, halogen, hydroxy, -CN, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, or C1-C7 alkoxy, which C1-C7 alkyl, or C2-C6 alkoxy, is optionally substituted with one or more of halogen, hydroxy, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, -N(CH3)2, cyano (-CN), ethynyl (- CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl which is substituted with cycloalkyl.
[00257] Clause 77.. The compound of any of clauses 1-6, wherein R3 is H, halogen, hydroxy, -CN, methyl, -CF3, or methoxy.
[00258] Clause 8. The compound of any of clauses 1-5, wherein R4 is H, halogen, hydroxy, -CN, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, or C1-C7 alkoxy, which C1-C7 alkyl, or C2-C6 alkoxy, is optionally substituted with one or more of halogen, hydroxy, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, -N(CH3)2, cyano (-CN), ethynyl (- CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl which is substituted with cycloalkyl.
[00259] Clause 9. The compound of any of clauses 1-8, wherein R4 is H, halogen, hydroxy, -CN, methyl, -CF3, or methoxy.
[00260] Clause 10. The compound of any of clauses 1-9, wherein R5 is H, halogen, hydroxy, -CN, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, or C1-C7 alkoxy, which C1-C7 alkyl, or C2-C6 alkoxy, is optionally substituted with one or more of halogen, hydroxy, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, -N(CH3)2, cyano (-CN), ethynyl (- CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl which is substituted with cycloalkyl.
[00261] Clause 11. The compound of any of clauses 1-10, wherein R5 is H, halogen, hydroxy, -CN, methyl, -CF3, or methoxy.
[00262] Clause 12. The compound of any of clauses 1-11, wherein R4 is methyl or -CF3, and wherein at least one of R3 and R5 is H or halogen.
[00263] Clause 13. The compound of any of clauses 1-12, wherein R6 is
Figure imgf000148_0001
[00264] Clause 14. The compound of any of clauses 1-13, wherein m is 0 or 1, wherein n is 0 or 1 , wherein o is 0 or 1 , and wherein p is 0 or 1.
[00265] Clause 15. The compound of any of clauses 1-14, wherein R7, R8, R9, and R10 are H, and wherein at least one of R11, R12, R13, and R14 is not H.
[00266] Clause 16. The compound of any of clauses 1-15, wherein R11, R12, R13, and R14 are H, and wherein at least one of R7, R8, R9, and R10 is not H.
[00267] Clause 17. The compound of any of clauses 1-14, wherein all of R7, R8, R9, R10,
Rn, R12 :, R13, and R14 are H.
[00268] Clause 18. The compound of any of clauses 1-17, wherein R7, R8, R9, R10, R11, R12, R13, and R14 are independently selected from H, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C1-C7 alkoxy, cycloalkyl, or spiro-fused cycloalkyl, which methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, or spiro-fused cycloalkyl is optionally substituted with one or more halogen.
[00269] Clause 19. The compound of clause 18, wherein R7, R8, R9, and R10 are H, and wherein at least one of R11, R12, R13, and R14 is halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C1-C7 alkoxy, cycloalkyl, or spiro-fused cycloalkyl, which methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, or spiro-fused cycloalkyl is optionally substituted with one or more halogen.
[00270] Clause 20. The compound of clause 18, wherein R11, R12, R13, and R14 are H, and wherein at least one of R7, R8, R9, and R10 is halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C1-C7 alkoxy, cycloalkyl, or spiro-fused cycloalkyl, which methanoyl (- COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, cycloalkyl, or spiro-fused cycloalkyl is optionally substituted with one or more halogen.
[00271] Clause 21. The compound of any of clauses 1-20, wherein at least one of R7, R8,
R9, and R10 is halogen, hydroxyl, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 alkoxy, cycloalkyl, or spiro-fused cycloalkyl.
[00272] Clause 22. The compound of clause 20, wherein at least one of R7, R8, R9, and
R10 is F, hydroxyl, methyl, methoxy, -CHF2, -CF3, spiro-fused cyclopropyl, spiro-fused cyclobutyl, or spiro-fused cyclopentyl.
[00273] Clause 23. The compound of clause 22, wherein both of R7 and R8 or both of R9 and R10 are F, or wherein both of R7 and R8 or both of R9 and R10 are methyl. [00274] Clause 24. The compound of any of clauses 1-23, wherein at least one of R11, R12, R13, and R14 is halogen, hydroxyl, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 alkoxy, cycloalkyl, or spiro-fused cycloalkyl.
[00275] Clause 25. The compound of clause 24, wherein at least one of R11, R12, R13, and
R14 is F, hydroxyl, methyl, methoxy, -CHF2, -CF3, spiro-fused cyclopropyl, spiro-fused cyclobutyl, or spiro-fused cyclopentyl.
[00276] Clause 26. The compound of clause 25, wherein both of R11 and R12 or both of R13 and R14 are F, or wherein both of R11 and R12 or both of R13 and R14 are methyl.
[00277] Clause 27. The compound of any of clauses 1-12, wherein R6 is
Figure imgf000150_0001
[00278] Clause 28. The compound of clause 27, wherein q, r, s, t, u, v, w, and x are independently 0, 1, or 2.
[00279] Clause 29. The compound of clause 27 or clause 28, wherein q is 0 or 1, wherein r is 0 or 1, wherein s is 0 or 1, wherein t is 0 or 1, wherein u is 0 or 1, wherein v is 0 or 1, wherein w is 0 or 1, and wherein x is 0 or 1 .
[00280] Clause 30. The compound of any of clauses 27-29, wherein R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R29, R29, and R30 are independently selected from H, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C1-C7 alkoxy, or spiro-fused cycloalkyl, which methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 alkoxy, or spiro-fused cycloalkyl is optionally substituted with one or more halogen.
[00281] Clause 31. The compound of any of clauses 27-30, wherein one or more of R15, R16, R17,, RR18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R29, R29, and R30 are H, or wherein all of R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R29, R29, and R30 are H.
[00282] Clause 32. The compound of any of clauses 27-31, wherein R6 is:
Figure imgf000151_0001
[00283] Clause 33. The compound of any of clauses 27-32, wherein R6 is:
Figure imgf000151_0002
[00284] Clause 34. The compound of any of clauses 1-33, wherein the compound is selected from Compounds 1-64, as listed in Example 1 and Tables 1.
[00285] Clause 35. The compound of any of clauses 1-34, 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.
[00286] Clause 36. The compound of any of clauses 1-35, 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.
[00287] Clause 37. A composition comprising a compound of any of clauses 1-36.
[00288] Clause 38. The composition of clause 37, wherein the amount of the compound is from about 0.0001% (by weight total composition) to about 99%.
[00289] Clause 39. The composition of clause 37 or clause 38, further comprising a formulary ingredient, an adjuvant, or a carrier.
[00290] Clause 40. The composition of any of clauses 37-39, wherein the composition further comprises a BCL2 inhibitor.
[00291] Clause 41. The composition of any of clauses 37-40, wherein the composition is used in combination with a second composition comprising a BCL2 inhibitor.
[00292] Clause 42. The composition of any of clauses 37-41, wherein the BCL2 comprises venetoclax, or a salt, isomer, derivative or analog thereof.
[00293] Clause 43. The composition of any of clauses 37-42, wherein the composition is used in combination with oonnee oorr mmoorree chemotherapy, DNA methyltransferase inhibitor/hypomethylating agent, anthracycline, histone deacetylase (HDAC) inhibitor, purine nucleoside analogue (antimetabolite), isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor, antibody-drug conjugate, mAbs/immunotherapy, CAR-T cell therapy, Plk inhibitor, MEK inhibitor, CDK9 inhibitor, CDK8 inhibitor, retinoic acid receptor agonist, TP53 activator, smoothened receptor antagonist, ERK inhibitor, PI3K inhibitor, mTOR inhibitor, glucocorticoid receptor modulator, or EZH2 inhibitor, or one or more combinations thereof.
[00294] Clause 44. The composition of clause 43, wherein the DNA methyltransferase inhibitor/hypomethylating agent comprises azacitidine, decitabine, cytarabine, and/or guadecitabine; wherein the anthracycline comprises daunorubicin, idarubicin, doxorubicin, mitoxantrone, epirubicin, and/or CPX-351 (a combination cytarabine and daunorubicin in a fixed 5:1 molar ratio); wherein the histone deacetylase (HDAC) inhibitor comprises vorinostat, panobinostat, valproic acid, and/or pracinostat; wherein the purine nucleoside analogue (antimetabolite) comprises fludarabine, cladribine, and/or clofarabine; wherein the isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor comprises ivosidenib and/or enasidenib; wherein the antibody-drug conjugate comprises Anti-CD33 (e.g. Ac225-lintuzumab, vadastuximab, or gemtuzumab-ozogamicin) and/or Anti-CD45 (e.g. I131-apamistamab); wherein the mAbs/immunotherapy comprises Anti-CD70 (e.g. ARGX-110, cusatuzumab), a bispecific antibody (e.g. floteuzumab (CD 123 x CD3 )), Anti-CTLA4 (e.g. ipilimumab), Anti-PDl/PDLl (e.g. nivolumab, pembrolizumab, atezolizumab, avelumab, PDR001, MBG453), and/or Anti- CD47 (e.g. 5F9 (Magrolimab)); wherein the Plk inhibitor comprises volasertib and/or rigosertib; wherein the MEK inhibitor comprises trametinib, cobimetinib, selumetinib, pimasertib, and/or refametinib; wherein the CDK9 inhibitor comprises alvocidib and/or voruciclib; wherein the CDK8 inhibitor comprises SEL120; wherein the retinoic acid receptor agonist comprises ATRA (all-trans retinoic acid) and/or SY- 1425 (a selective RARa agonist); wherein the TP53 activator comprises APR-246 (Eprenetapopt); wherein the smoothened receptor antagonist comprises glasdegib; wherein the ERK inhibitor comprises an ERK2/MAPK1 or ERK1/MAPK3 inhibitor comprising ulixertinib, SCH772984, ravoxertinib, MK-8353, and/or VTX-1 le; wherein the PI3K inhibitor comprises fimepinostat (CUDC-907), alpelisib, leniolisib (CDZ-173), pilaralisib (XL 147, SAR245408), and/or bimiralisib (PQR-309); wherein the mTOR inhibitor comprises bimiralisib (PQR-309), sapanisertib (TAK-228, INK-128), ridaforolimus (MK-8669, AP -23573), everolimus, and/or vistusertib (AZD2014); wherein the glucocorticoid receptor modulator comprises an agonist comprising prednisolone, beclometasone, methylprednisolone, prednisone, fluticasone, budesonide, dexamethasone, and/or cortisol, and/or an antagonist comprising mifepristone, miricorilant, and/or onapristone, and/or another binding ligand comprising vamorolone (VBP15); and/or wherein the EZH2 inhibitor comprises tazemetostat.
[00295] Clause 45. A method for providing a subject with a compound comprising one or more administrations of one or more compositions comprising the compound of any of clauses 1- 36, wherein the compositions may be the same or different if there is more than one administration.
[00296] Clause 46. The method of clause 45, wherein at least one of the one or more compositions further comprises a formulary ingredient.
[00297] Clause 47. The method of clause 45 or clause 46, wherein at least one of the one or more compositions comprises the composition of any of clauses 37-44.
[00298] Clause 48. The method of any of clauses 45-47, wherein at least one of the one or more administrations comprises parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration. [00299] Clause 49. The method of any of clauses 45-48, wherein if there is more than one administration at least one composition used for at least one administration is different from the composition of at least one other administration.
[00300] Clause 50. The method of any of clauses 45-49, wherein the compound of at least one of the one or more compositions is administered to the subject in an amount of from about 0.005 mg/kg subject body weight to about 50 mg /kg subject body weight.
[00301] Clause 51. The method of any of clauses 45-50, wherein the subject is a mammal, preferably wherein the subject is a human, a rodent, or a primate.
[00302] Clause 52. A method for treating a disease or disorder, comprising one or more administrations to a subject of one or more compositions comprising the compound of any of clauses 1-36, wherein the compositions may be the same or different if there is more than one administration.
[00303] Clause 53. The method of clause 52, wherein the disease or disorder is responsive to at least one of interleukin- 1 receptor-associated kinase (IRAK) inhibition or fms-like tyrosine kinase 3 (FLT3) inhibition.
[00304] Clause 54. The method of clause 52 or clause 53, wherein at least one of the one or more compositions further comprises a formulary ingredient.
[00305] Clause 55. The method of clause 53 or clause54, wherein at least one of the one or more compositions comprises the composition of any of clauses 37-44.
[00306] Clause 56. The method of any of clauses 52-55, wherein at least one of the one or more administrations comprises parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, transdermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration.
[00307] Clause 57. The method of any of clauses 52-56, wherein at least one of the one or more administrations comprises an oral administration.
[00308] Clause 58. The method of any of clauses 52-57, wherein if there is more than one administration at least one composition used for at least one administration is different from the composition of at least one other administration.
[00309] Clause 59. The method of any of clauses 52-58, wherein the compound of at least one of the one or more compositions is administered to the subject in an amount of from about 0.005 mg/kg subject body weight to about 50 mg /kg subject body weight. [00310] Clause 60. The method of any of clauses 52-59, wherein the subject is a mammal, preferably wherein the subject is a human, a rodent, or a primate.
[00311] Clause 61. The method of any of clauses 52-60, wherein the subject is in need of the treatment.
[00312] Clause 62. The method of any of clauses 52-61, wherein the method is for treating a hematopoietic cancer.
[00313] Clause 63. The method of any of clauses 52-62, wherein the method is for treating a myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML).
[00314] Clause 64. The method of any of clauses 52-62, 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 lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL with MYD88 mutation, follicular lymphoma, or marginal zone lymphoma.
[00315] Clause 6655.. The method of any of clauses 52-61, wherein the method is for treating at least one cancer selected from glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, Glioma, oral cancer, nasopharyngeal carcinoma, rectal cancer, stomach cancer, and uterine cancer, or one or more inflammatory diseases or autoimmune disease characterized by overactive IRAKI and/or IRAK4, or combinations thereof.
[00316] Clause 66. The method of clause 65, wherein the method is for treating one or more inflammatory diseases or autoimmune disease selected from chronic inflammation (i.e., associated with viral and bacterial infection), sepsis, rheumatoid arthritis, hidradenitis suppurativa, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjogren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, or combinations thereof.
[00317] Clause 67. The method of any of clauses 52-63, wherein the method is for treating MDS, MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, MDS with a mutation in isocitrate dehydrogenase 2, or wherein the method is for treating AML having enhanced IRAK4-Long expression and/or activity relative to IRAK4- Short, and/or wherein the AML is not driven by FLT3 mutations but expresses IRAK4-Long.
[00318] Clause 68. The method of clause 64, wherein the method is for treating DLBCL, and wherein the DLBCL comprises a L265P MYD88 mutant (ABC) subtype of DLBCL.
[00319] Clause 69. The method of clause 68, wherein the method further comprises administration of a composition comprising a BTK inhibitor.
[00320] Clause 70. The method of clause 69, wherein the BTK inhibitor comprises ibrutinib.
[00321] Clause 71. The method of any of clauses 52-70, wherein the subject is susceptible to AML and/or MDS, and/or wherein the method prevents or ameliorates future AML and/or MDS.
[00322] Clause 72. The method of any of clauses 52-71, wherein the method occurs after one or more of having MDS, having myeloproliferative disease, an occurrence of chemical exposure, an exposure to ionizing radiation, or a treatment for cancer.
[00323] Clause 73. The method of any of clauses 52-71, wherein the method further comprises administration of a composition comprising a BCL2 inhibitor, or wherein the at least one or more compositions comprises the compound of any of clauses 1-36 and further comprises a BCL2 inhibitor.
[00324] Clause 74. The method of clause 73 wherein the compound of any of clauses 1- 36 and the BCL2 inhibitor may be administered together or separately, in one or more administrations of one or more compositions.
[00325] Clause 75. The method of clause 73 or clause 74, wherein the BCL2 inhibitor comprises venetoclax, or a salt, isomer, derivative or analog thereof.
[00326] Clause 76. The method of any of clauses 52-75, wherein the method further comprises administration of one or more additional therapy selected from one or more chemotherapy, DNA methyltransferase inhibitor/hypomethylating agent, anthracycline, histone deacetylase (HD AC) inhibitor, purine nucleoside analogue (antimetabolite), isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor, antibody-drug conjugate, mAbs/immunotherapy, CAR-T cell therapy, Plk inhibitor, MEK inhibitor, CDK9 inhibitor, CDK8 inhibitor, retinoic acid receptor agonist, TP53 activator, smoothened receptor antagonist, ERK inhibitor, PI3K inhibitor, mTOR inhibitor, glucocorticoid receptor modulator, or EZH2 inhibitor, or one or more combinations thereof. [00327] Clause 77.. The method of clause 76, wherein the DNA methyltransferase inhibitor/hypomethylating agent comprises azacitidine, decitabine, cytarabine, and/or guadecitabine; wherein the anthracycline comprises daunorubicin, idarubicin, doxorubicin, mitoxantrone, epirubicin, and/or CPX-351 (a combination cytarabine and daunorubicin in a fixed 5:1 molar ratio); wherein the histone deacetylase (HD AC) inhibitor comprises vorinostat, panobinostat, valproic acid, and/or pracinostat; wherein the purine nucleoside analogue (antimetabolite) comprises fludarabine, cladribine, and/or clofarabine; wherein the isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor comprises ivosidenib and/or enasidenib; wherein the antibody-drug conjugate comprises Anti-CD33 (e.g. Ac225-lintuzumab, vadastuximab, or gemtuzumab-ozogamicin) and/or Anti-CD45 (e.g. I131-apamistamab); wherein the mAbs/Immunotherapy comprises Anti-CD70 (e.g. ARGX-110, cusatuzumab), a bispecific antibody (e.g. floteuzumab (CD 123 x CD3 )), Anti-CTLA4 (e.g. ipilimumab), Anti-PDl/PDLl (e.g. nivolumab, pembrolizumab, atezolizumab, avelumab, PDR001, MBG453), and/or Anti- CD47 (e.g. 5F9 (Magrolimab)); wherein the Plk inhibitor comprises volasertib and/or rigosertib; wherein the MEK inhibitor comprises trametinib, cobimetinib, selumetinib, pimasertib, and/or refametinib; wherein the CDK9 inhibitor comprises alvocidib and/or voruciclib; wherein the CDK8 inhibitor comprises SEL120; wherein the retinoic acid receptor agonist comprises ATRA (all-trans retinoic acid) and/or SY- 1425 (a selective RARa agonist); wherein the TP53 activator comprises APR-246 (Eprenetapopt); wherein the smoothened receptor antagonist comprises glasdegib; wherein the ERK inhibitor comprises an ERK2/MAPK1 or ERK1/MAPK3 inhibitor comprising ulixertinib, SCH772984, ravoxertinib, MK-8353, and/or VTX-1 le; wherein the PI3K inhibitor comprises fimepinostat (CUDC-907), alpelisib, leniolisib (CDZ-173), pilaralisib (XL 147, SAR245408), and/or bimiralisib (PQR-309); wherein the mTOR inhibitor comprises bimiralisib (PQR-309), sapanisertib (TAK-228, INK-128), ridaforolimus (MK-8669, AP -23573), everolimus, and/or vistusertib (AZD2014); wherein the glucocorticoid receptor modulator comprises an agonist comprising prednisolone, beclometasone, methylprednisolone, prednisone, fluticasone, budesonide, dexamethasone, and/or cortisol, and/or an antagonist comprising mifepristone, miricorilant, and/or onapristone, and/or another binding ligand comprising vamorolone (VBP15); and/or wherein the EZH2 inhibitor comprises tazemetostat.
[00328] Clause 78. A compound according to any one of clauses 1-36, 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, wherein the compositions may be the same or different if there is more than one administration.
[00329] Clause 79. The compound for use of clause 78, wherein the disease or disorder is responsive to at least one of interleukin- 1 receptor-associated kinase (IRAK) inhibition or fms- like tyrosine kinase 3 (FLT3) inhibition.
[00330] Clause 80. The compound for use of clause 78 or clause 79, wherein at least one of the one or more compositions further comprises a formulary ingredient.
[00331] Clause 81. The compound for use of any one of clauses 78-80, wherein at least one of the one or more compositions comprises the composition of any of clauses 37-44.
[00332] Clause 82. The compound for use of any one of clauses 78-81, wherein at least one of the one or more administrations comprises parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, transdermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration.
[00333] Clause 83. The compound for use of any one of clauses 78-82, wherein at least one of the one or more administrations comprises an oral administration.
[00334] Clause 84. The compound for use of any one of clauses 78-83, wherein if there is more than one administration at least one composition used for at least one administration is different from the composition of at least one other administration.
[00335] Clause 85. The compound for use of any one of clauses 78-84, wherein the compound is administered to the subject in an amount of from about 0.005 mg/kg subject body weight to about 50 mg /kg subject body weight.
[00336] Clause 86. The compound for use of any one of clauses 78-85, wherein the subject is a mammal, preferably wherein the subject is a human, a rodent, or a primate.
[00337] Clause 8877.. The compound for use of any one of clauses 78-86, wherein the subject is in need of the treatment.
[00338] Clause 88. The compound for use of any one of clauses 78-87, wherein the method is for treating a hematopoietic cancer.
[00339] Clause 89. The compound for use of any one of clauses 78-88, wherein the method is for treating MDS and/or AML.
[00340] Clause 90. The compound for use of any one of clauses 78-88, 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 lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B- cell lymphoma (DLBCL), DLBCL with MYD88 mutation, follicular lymphoma, or marginal zone lymphoma.
[00341] Clause 91. The compound for use of any one of clauses 78-87, wherein the method is for treating at least one cancer selected from glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular ccaarrcciinnoommaa,, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, Glioma, oral cancer, nasopharyngeal carcinoma, rectal cancer, stomach cancer, and uterine cancer, or one or more inflammatory diseases or autoimmune disease characterized by overactive IRAKI and/or IRAK45 or combinations thereof.
[00342] Clause 92. The compound for use of clause 91, wherein the method is for treating one or more inflammatory diseases or autoimmune disease selected from chronic inflammation (i.e., associated with viral and bacterial infection), sepsis, rheumatoid arthritis, hidradenitis suppurativa, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjogren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, or combinations thereof.
[00343] Clause 93. The compound for use of any one of clauses 78-89, wherein the method is for treating MDS, MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, MDS with a mutation in isocitrate dehydrogenase 2, or wherein the method is for treating AML having enhanced IRAK4-Long expression and/or activity relative to IRAK4-Short, and/or wherein the AML is not driven by FLT3 mutations but expresses IRAK4- Long.
[00344] Clause 94. The compound for use of clause 90, wherein the method is for treating DLBCL, and wherein the DLBCL comprises a L265P MYD88 mutant (ABC) subtype of DLBCL.
[00345] Clause 9955.. The compound for use of clause 94, wherein the method further comprises administration of a composition comprising a BTK inhibitor.
[00346] Clause 96. The compound for use of clause 95, wherein the BTK inhibitor comprises ibrutinib. [00347] Clause 97.. The compound for use of any one of clauses 78-96, wherein the subject is susceptible to AML and/or MDS, and/or wherein the method prevents or ameliorates future AML and/or MDS.
[00348] Clause 98. The compound for use of any one of clauses 78-97, wherein the method occurs after one or more of having MDS, having myeloproliferative disease, an occurrence of chemical exposure, an exposure to ionizing radiation, or a treatment for cancer.
[00349] Clause 99. The compound for use of any one of clauses 78-98, wherein the method further comprises administration of a composition comprising a BCL2 inhibitor, or wherein the at least one or more compositions comprises the compound of any of clauses 1-36 and further comprises a BCL2 inhibitor.
[00350] Clause 100. The compound for use of clause 99, wherein the compound of any of clauses 1-36 and the BCL2 inhibitor may be administered together or separately, in one or more administrations of the one or more compositions.
[00351] Clause 101. The compound for use of clause 99 or clause 100, wherein the BCL2 inhibitor comprises venetoclax, or a salt, isomer, derivative or analog thereof.
[00352] Clause 102. The compound for use of any one of clauses 78-101, wherein the method further comprises administration of one or more additional therapy selected from one or more chemotherapy, DNA methyltransferase inhibitor/hypomethylating agent, anthracycline, histone deacetylase (HDAC) inhibitor, purine nucleoside analogue (antimetabolite), isocitrate dehydrogenase 1 oorr 2 (IDH1 and/or IDH2) inhibitor, antibody-drug conjugate, mAbs/immunotherapy, CAR-T cell therapy, Plk inhibitor, MEK inhibitor, CDK9 inhibitor, CDK8 inhibitor, retinoic acid receptor agonist, TP53 activator, smoothened receptor antagonist, ERK inhibitor, PI3K inhibitor, mTOR inhibitor, glucocorticoid receptor modulator, or EZH2 inhibitor, or one or more combinations thereof.
[00353] Clause 103. The compound for use of any one of clauses 78-102, wherein the DNA methyltransferase inhibitor/hypomethylating agent comprises azacitidine, decitabine, cytarabine, and/or guadecitabine; wherein the anthracycline comprises daunorubicin, idarubicin, doxorubicin, mitoxantrone, epirubicin, and/or CPX-351 (a combination cytarabine and daunorubicin in a fixed 5:1 molar ratio); wherein the histone deacetylase (HDAC) inhibitor comprises vorinostat, panobinostat, valproic acid, and/or pracinostat; wherein the purine nucleoside analogue (antimetabolite) comprises fludarabine, cladribine, and/or clofarabine; wherein the isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor comprises ivosidenib and/or enasidenib; wherein the antibody-drug conjugate comprises Anti-CD33 (e.g. Ac225- lintuzumab, vadastuximab, or gemtuzumab-ozogamicin) and/or Anti-CD45 (e.g. I131- apamistamab); wherein the mAbs/Immunotherapy comprises Anti-CD70 (e.g. ARGX-110, cusatuzumab), a bispecific antibody (e.g. floteuzumab (CD123 x CD3 )), Anti-CTLA4 (e.g. ipilimumab), Anti-PDl/PDLl (e.g. nivolumab, pembrolizumab, atezolizumab, avelumab, PDR001, MBG453), and/or Anti-CD47 (e.g. 5F9 (Magrolimab)); wherein the Plk inhibitor comprises volasertib and/or rigosertib; wherein the MEK inhibitor comprises trametinib, cobimetinib, selumetinib, pimasertib, and/or refametinib; wherein the CDK9 inhibitor comprises alvocidib and/or voruciclib; wherein the CDK8 inhibitor comprises SEL120; wherein the retinoic acid receptor agonist comprises ATRA (all-trans retinoic acid) and/or SY- 1425 (a selective RARa agonist); wherein the TP53 activator comprises APR-246 (Eprenetapopt); wherein the smoothened receptor antagonist comprises glasdegib; wherein the ERK inhibitor comprises an ERK2/MAPK1 or ERK1/MAPK3 inhibitor comprising ulixertinib, SCH772984, ravoxertinib, MK-8353, and/or VTX-l le; wherein the PI3K inhibitor comprises fimepinostat (CUDC-907), alpelisib, leniolisib (CDZ-173), pilaralisib (XL147, SAR245408), and/or bimiralisib (PQR-309); wherein the mTOR inhibitor comprises bimiralisib (PQR-309), sapanisertib (TAK-228, INK- 128), ridaforolimus (MK-8669, AP-23573), everolimus, and/or vistusertib (AZD2014); wherein the glucocorticoid receptor modulator comprises an agonist comprising prednisolone, beclometasone, methylprednisolone, prednisone, fluticasone, budesonide, dexamethasone, and/or cortisol, and/or an antagonist comprising mifepristone, miricorilant, and/or onapristone, and/or another binding ligand comprising vamorolone (VBP15); and/or wherein the EZH2 inhibitor comprises tazemetostat.
[00354] Clause 201. A compound of Formula (I):
Figure imgf000161_0001
or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof, wherein: R2, R3, R4, and R5 are each independently selected from H, halogen, hydroxy, oxo (=O), -CN, amino, amido, -O-aryl, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, spiro-fiised cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, wherein amino, amido, -O-aryl, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fiised cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, oxo, methanoyl (-C0H), carboxy (-CO2H), nitro (-NO2), -NH2, -NHCH3, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, - CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl which is substituted with cycloalkyl, wherein two adjacent optional substituents can bond or fuse to form a ring;
R6 is selected from
Figure imgf000162_0001
R7, R8, R9, R10, R11, R12, R13, and R14 are each independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fiised cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, wherein methanoyl (-C0H), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fiised cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more halogen and/or C1-C6 alkyl;
R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R29, R29, and R30 are each independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (- CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fiised cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, wherein methanoyl (-C0H), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro- fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more halogen and/or C1-C6 alkyl; and m, n, o, p, q, r, s, t, u, v, w, and x are each independently selected from 0, 1, 2, 3, 4, or 5; where q+r+s+t is at least 1, and where u+v+w+x is at least 1.
[00355] Clause 202. The compound of clause 201, wherein the compound of Formula
(I) is a compound of Formula (Ilf):
Figure imgf000163_0001
or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein:
R20f is selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 cycloalkyl, -O-(CH2)a-(C3-C6 cycloalkyl), and C3-C9 heterocyclyl, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, wherein C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen, and wherein C3-C9 heterocyclyl is optionally substituted with one or more substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -OH, and =O wherein two adjacent optional substituents can bond or fuse to form a ring;
R21f, R22f, and R23f are each independently selected from H and halogen;
R24fa, R24fb, R25fa, R25fb, R26fa, and R26fb are each independently selected from H, halogen, -OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more halogen atoms; and a is selected from 0, 1, 2, 3, 4, 5, and 6.
[00356] Clause 203. The compound of clause 2, wherein one or more of R24fa, R24fb, R25fa, R25fb, R26fa, and R26fb is independently selected from halogen, -OH, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy.
[00357] Clause 204. The compound of clause 202 or 203, wherein R20f is H.
[00358] Clause 220055.. The compound of clause 202 or 203, wherein at least one of (i)-
(viii) applies: (i) R20f is selected from t-butyl, unsubstituted C3 cycloalkyl, pyrrolidinyl, -OCH3, -OCH2CH3,
Figure imgf000164_0004
Figure imgf000164_0005
(ii) R20f is
Figure imgf000164_0001
wherein R27f is selected from -CH3,
Figure imgf000164_0002
(iii) R20f is wherein R28f is =O and R220fa and R220fb are each -CH3 or R220fa and
Figure imgf000164_0003
R220fb bond or fuse to form oxetanyl;
(iv) R21f, R22f, and R23f are each H;
(v) R21f and R23f are each F and R22f is H;
(vi) R21f and R23f are each H and R22f is F;
(vii) R24fa, R24fb, R25fa, R25fb, R26fa, and R26fb are each H;
(viii) R25fa, R25fb, R26fa, and R26fb are each H and R24fa and/or R24fb are selected from F, -CH3, and -CF3.
[00359] Clause 220066.. The compound of any one of clauses 202-205, wherein the compound is selected from:
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
[00360] Clause 207. The compound of clause 201, wherein the compound of Formula
(I) is a compound of Formula (Ilg):
Figure imgf000168_0002
or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein:
Figure imgf000168_0003
R20g is selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, wherein C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen, and wherein C3-C9 heterocyclyl is optionally substituted with one or more substituents selected from halogen, C1-C6 alkyl, C3-C6-cycloalkyl, -OH, and =O; R21g, R22g, and R23g are each independently selected from H and halogen; and R24ga, R24gb, R28ga, R25gb, R26ga, R26gb, R27ga, R27gb, R28ga, and R28gb are each independently selected from H, halogen, -OH, and C1-C6 alkyl.
[00361] Clause 208. The compound of clause 207, wherein one or more of R24ga, R24gb, R25ga, R25gb, R26ga, R26gb, R27ga, R27gb, R28ga, and R28gb is independently selected from halogen, - OH, and C1-C6 alkyl.
[00362] Clause 209. The compound of clause 207 or 208, wherein R20g is H.
[00363] Clause 210. The compound of any one of clauses 207-209, wherein at least one of (i)-(xi) applies:
(i) R20g is selected from t-butyl, unsubstituted C3 cycloalkyl,
Figure imgf000169_0001
Figure imgf000169_0002
Figure imgf000169_0003
wherein c is 1 or 2;
(ii) R20g is
Figure imgf000169_0004
29g wherein R29g is selected from unsubstituted C3 cycloalkyl, -CH3,
Figure imgf000169_0005
(iii) R21g, R22g, and R23g are each H;
(iv) R21g and R23g are each F and R22g is H;
(v) R21g and R23g are each H and R22g is F;
(vi) each of R24ga, R24gb, R25ga, R25gb, R26ga, R26gb, R27ga, and
Figure imgf000169_0006
R27gb is H;
Figure imgf000170_0001
[00364] Clause 211. The compound of any one of clauses 207-210, wherein the compound is selected from:
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
[00365] Clause 212.. The compound of clause 201, wherein the compound of Formula
(I) is a compound of Formula (Uh):
Figure imgf000175_0002
or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein:
Figure imgf000175_0003
R20h is selected from H, C1-C6 alkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from halogen and -OH, and wherein C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen; and
R21h, R22h, and R.23H are each independently selected from H and halogen.
[00366] Clause 213. The compound of clause 212, wherein R20h is H.
[00367] Clause 214. The compound of clause 212 or 213, wherein at least one of (i)-(v) applies: (i) R20h is selected from
Figure imgf000176_0003
(ii) R21h, R22h, and R23h are each H;
(iii) R21h and R23h are each F and R22his H;
(iv) R21h and R23h are each H and R22h is F;
Figure imgf000176_0002
[00368] Clause 221155.. The compound of any one of clauses 212-214, wherein the compound is selected from:
Figure imgf000176_0001
[00369] Clause 221166.. The compound of any one of clauses 201-215, wherein the compound is an inhibitor of at least one of IRAKI, IRAK4, and FLT3.
[00370] Clause 217. The compound of any one of clauses 201-216, wherein the compound is an inhibitor of at least two of IRAKI, IRAK4, and FLT3.
[00371] Clause 218. The compound of any one of clauses 201-217, wherein the compound is an inhibitor of IRAKI and IRAK4.
[00372] Clause 219. The compound of any one of clauses 201-217, wherein the compound is an inhibitor of IRAKI, IRAK4, and FLT3.
[00373] Clause 220. The compound of any one of clauses 216, 217, or 219, wherein FLT3 is selected from WT FLT3, activated FLT3, and mutated FLT3.
[00374] Clause 221. The compound of clause 220, wherein the mutated FLT3 is D835Y mutated FLT3 or F691L mutated FLT3. [00375] Clause 222. A composition comprising a compound of any one of clauses 201- 221, wherein the composition further comprises a formulary ingredient, an adjuvant, or a carrier.
[00376] Clause 223. The composition of clause 222, wherein the composition is used in combination with one or more of: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, 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, an mAbs/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 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, an NEDD8-activator, an MDM2 inhibitor, a PLK1 inhibitor, an Aura A inhibitor, an aurora kinase inhibitor, an EGFR inhibitor, an AuroraB/C/VEGFRl/2/3/FLT3/CSF- IR/Kit/PDGFRA/B inhibitor, aann AKT 1, 2, and/or 3 inhibitor, a
ABL1/2/SRC/EPHA2/LCK/YES1/KIT/PDGFRB/FYN inhibitor, a famesyltransferase inhibitor, a BRAF/MAP2K1/MAP2K2 inhibitor, a Menin-KMT2A/MLL inhibitor, and a multikinase inhibitor.
[00377] Clause 222244.. The composition of clause 223, wherein the composition is used in combination with a BCL2 inhibitor.
[00378] Clause 222255.. The composition of clause 224, wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof.
[00379] Clause 226. A method of treating a disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of clauses 201-221 or a composition of any one of clauses 222-225.
[00380] 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 201 and a formulary ingredient, an adjuvant, or a carrier. [00381] Clause 228.. The method of clause 226 or 227, wherein the disease or disorder is responsive to at least one of interleukin- 1 receptor-associated kinase (IRAK) inhibition and fins-like tyrosine kinase 3 (FLT3) inhibition.
[00382] Clause 229. The method of any one of clauses 226-228, wherein the administration comprises parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration.
[00383] Clause 230. The method of any one of clauses 226-229, wherein the compound is administered to the subject in an amount of from about 0.005 mg/kg subject body weight to about 1,000 mg /kg subject body weight.
[00384] Clause 231. The method of any one of clauses 226-230, wherein the disease or disorder comprises a hematopoietic cancer.
[00385] Clause 232. The method of any one of clauses 226-230, wherein the disease or disorder comprises myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML).
[00386] Clause 233. The method of any one of clauses 226-230, wherein the disease or disorder comprises lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL with MYD88 mutation, follicular lymphoma, or marginal zone lymphoma.
[00387] Clause 223344.. The method of any one of clauses 226-230, wherein the disease or disorder comprises at least one cancer selected from glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, Glioma, oral cancer, nasopharyngeal carcinoma, rectal cancer, stomach cancer, and uterine cancer, or one or more inflammatory diseases or autoimmune disease characterized by overactive IRAKI and/or IRAK4, or combinations thereof.
[00388] Clause 223355.. The method of any one of clauses 226-230, wherein the disease or disorder comprises one or more inflammatory diseases or autoimmune disease 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 mellitus, or combinations thereof.
[00389] Clause 236. The method of any one of clauses 226-230, wherein the disease or disorder comprises:
(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) AML with a splicing factor mutation, AML having enhanced IRAK4-Long expression and/or activity relative to IRAK4-Short, and/or wherein the AML is not driven by FLT3 mutations but expresses IRAK4-Long.
[00390] Clause 223377.. The method of clause 236, wherein 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 U2 AF 1 or SF3B 1.
[00391] Clause 238. The method of any one of clauses 226-230, wherein the disease or disorder comprises DLBCL, and wherein the DLBCL comprises a L265P MYD88 mutant (ABC) subtype of DLBCL or a S219C MYD88 mutant (GCB) subtype of DLBCL.
[00392] Clause 239. The method of any one of clauses 226-238, further comprising administering to the subject one or more additional therapies selected from: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, a BTK inhibitor, a DNA methyltransferase inhibitor/hypomethylating agent, an anthracycline, a histone deacetylase (HD AC) inhibitor, a purine nucleoside analogue (antimetabolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor, an antibody-drug conjugate, an mAbs/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 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, an NEDD 8 -activator, an MDM2 inhibitor, a PLK1 inhibitor, an Aura A inhibitor, an aurora kinase inhibitor, an EGFR inhibitor, an AuroraB/C/VEGFRl/2/3/FLT3/CSF-lR/Kit/PDGFRA/B inhibitor, an AKT 1, 2, and/or 3 inhibitor, aa ABL1/2/SRC/EPHA2/LCK/YES1/KIT/PDGFRB/FYN inhibitor, a famesyltransferase inhibitor, a BRAF/MAP2K1/MAP2K2 inhibitor, a Menin-KMT2A/MLL inhibitor, and a multikinase inhibitor.
[00393] Clause 240. The method of clause 239, wherein the additional therapy is a BCL2 inhibitor.
[00394] Clause 224411.. The method of clause 240, wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof.
[00395] Clause 242. The method of any one of clauses 226-241, wherein the disease or disorder is a BCL2 inhibitor resistant disease or disorder.
[00396] Clause 243. The method of any one of clauses 226-241, wherein the disease or disorder is a venetoclax resistant disease or disorder.
[00397] Clause 224444.. The method of any one of clauses 226-241, wherein the disease or disorder is a FLT3 inhibitor resistant disease or disorder.
[00398] Clause 245. The method of any one of clauses 226-241, wherein the disease or disorder is BCL2 inhibitor resistant acute myeloid leukemia (AML).
[00399] Clause 246. The method of any one of clauses 226-241, wherein the disease or disorder is venetoclax resistant acute myeloid leukemia (AML).
[00400] Clause 247. The method of any one of clauses 226-241, wherein the disease or disorder is FLT3 inhibitor resistant acute myeloid leukemia (AML).
[00401] Clause 248. The method of any one of clauses 226-241, wherein the disease or disorder is BCL2 inhibitor resistant refractory acute myeloid leukemia (AML).
[00402] Clause 249. The method of any one of clauses 226-241, wherein the disease or disorder is venetoclax resistant refractory acute myeloid leukemia (AML).
[00403] Clause 250. The method of any one of clauses 226-241, wherein the disease or disorder is FLT3 inhibitor resistant refractory acute myeloid leukemia (AML).
[00404] Clause 251. The method of any one of clauses 226-241, wherein the disease or disorder is BCL2 inhibitor resistant relapsed acute myeloid leukemia (AML).
[00405] Clause 252. The method of any one of clauses 226-241, wherein the disease or disorder is venetoclax resistant relapsed acute myeloid leukemia (AML).
[00406] Clause 253. The method of any one of clauses 226-241, wherein the disease or disorder is FLT3 inhibitor resistant relapsed acute myeloid leukemia (AML). [00407] Clause 254.. The method of clause 239, wherein the compound of any one of clauses 201-221 or the composition of any one of clauses 222-225 and the one or more additional therapies are administered together in one administration or composition.
[00408] Clause 255. The method of clause 239, wherein the compound of any one of clauses 201-221 or the composition of any one of clauses 222-225 and the one or more additional therapies are administered separately in more than one administration or more than one composition.
[00409] Clause 256. The method of any one of clauses 226-255, wherein the disease or disorder is alleviated by inhibiting at least one of IRAKI, IRAK4, and FLT3 in the subject.
[00410] Clause 257. The method of any one of clauses 226-256, wherein the disease or disorder is alleviated by inhibiting at least two of IRAKI, IRAK4, and FLT3 in the subject.
[00411] Clause 258. The method of any one of clauses 226-255, wherein the disease or disorder is alleviated by inhibiting IRAKI and IRAK4 in the subject.
[00412] Clause 259. The method of any one of clauses 226-255, wherein the disease or disorder is alleviated by inhibiting IRAKI, IRAK4, and FLT3 in the subject.
[00413] Clause 260. The method of any one of clauses 256, 257, or 259, wherein FLT3 is selected from WT FLT3, activated FLT3, and mutated FLT3.
[00414] Clause 261. The method of clause 260, wherein the mutated FLT3 is D835Y mutated FLT3 or F691L mutated FLT3.
[00415] Clause 301. A compound of Formula (I):
Figure imgf000181_0001
or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof, wherein:
R2, R3, R4, and R5 are each independently selected from H, halogen, hydroxy, oxo (=O), - CN, amino, amido, -O-aryl, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, wherein amino, amido, -O-aryl, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro- fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), - NHz, -NHCH3, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, - CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl which is substituted with cycloalkyl, wherein two adjacent optional substituents can bond or fuse to form a ring;
R6 is selected from
Figure imgf000182_0001
R7, R8, R9, R10, R11, R12, R13, and R14 are each independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, wherein methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more halogen and/or C1-C6 alkyl;
R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R29, R29, and R30 are each independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (- CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, wherein methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro- fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more halogen and/or C1-C6 alkyl; and m, n, o, p, q, r, s, t, u, v, w, and x are each independently selected from 0, 1, 2, 3, 4, or 5; where q+r+s+t is at least 1, and where u+v+w+x is at least 1. [00416] Clause 302.. The compound of clause 301, wherein the compound of Formula
(I) is a compound of Formula (Ilf):
Figure imgf000183_0001
or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein:
R20f is selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -O-(CH2)a- (C3-C6 cycloalkyl), and C3-C9 heterocyclyl, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, wherein C3- C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen, and wherein C3-C9 heterocyclyl is optionally substituted with one or more substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -OH, and =O wherein two adjacent optional substituents can bond or fuse to form a ring;
R21f, R22f, and R23f are each independently selected from H and halogen;
R24fa, R24fb, R25fa, R25fb, R26fa, and R26fb are each independently selected from H, halogen, -OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more halogen atoms; and a is selected from 0, 1, 2, 3, 4, 5, and 6.
[00417] Clause 303. The compound of clause 302, wherein one or more of R24fa, R24fb,
R25fa, R25fb, R26fa, and R26fb is independently selected from halogen, -OH, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy.
[00418] Clause 330044.. The compound of clause 302 or 303, wherein R2of is H.
[00419] Clause 330055.. The compound of clause 302 or 303, wherein at least one of (i)-(x) applies:
(i) R20f is selected from t-butyl, unsubstituted C3 cycloalkyl, pyrrolidinyl, -OCH3, -
Figure imgf000183_0002
Figure imgf000184_0001
(ii) R20f is
Figure imgf000184_0002
wherein R27f is selected from -CH3,
Figure imgf000184_0003
(iii) R20f
Figure imgf000184_0004
wherein R28f is =O and R220fa and R220fb are each -CH3 or
R220fa and R220fb bond or fuse to form oxetanyl;
(iv) R21f, R22f, and R23f are each H;
(v) R21f and R23f are each F and R22f is H;
(vi) R21f and R23f are each H and R22f is F;
(vii) R22f and R23f are each H and R21f is F;
(viii) R21f and R22f are each H and R23f is F;
(ix) R24fa, R24fb, R25fa, R25fb, R26fa, and R26fb are each H; and
(x) R25fa, R25fb, R26fa, and R26fb are each H andR24fa and/or R24fb are selected from F, -CH3, and -CF3.
[00420] Clause 330066.. The compound of any one of clauses 302-305, wherein the compound is selected from:
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
[00421] Clause 307.. The compound of clause 301, wherein the compound of Formula
(I) is a compound of Formula (Ilg):
Figure imgf000188_0002
or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein:
Figure imgf000188_0003
R20g is selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C9 heterocyclyl, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, wherein C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen, and wherein C3-C9 heterocyclyl is optionally substituted with one or more substituents selected from halogen, C1-C6 alkyl, Ca-C6-cycloalkyl, -OH, and =O;
R21g, R22g, and R23g are each independently selected from H and halogen; and R24ga, R24gb, R25ga, R25gb, R26ga, R26gb, R27ga, R27gb, R28ga, and R28gb are each independently selected from H, halogen, -OH, and C1-C6 alkyl.
[00422] Clause 308. The compound of clause 307, wherein one or more of R24ga, R24gb, R25ga, R25gb, R26ga, R26gb, R27ga, R27gb, R28ga, and R28gb is independently selected from halogen, - OH, and C1-C6 alkyl.
[00423] Clause 309. The compound of clause 307 or 308, wherein R20g is H.
[00424] Clause 310. The compound of any one of clauses 307-309, wherein at least one of (i)-(xiii) applies:
(i) R20g is selected from t-butyl, unsubstituted C3 cycloalkyl,
Figure imgf000189_0001
Figure imgf000189_0002
Figure imgf000189_0003
wherein c is 1 or 2; wherein R29g is selected from unsubstituted C3 cycloalkyl, -
Figure imgf000189_0004
(iii) R21g, R22g, and R22g are each H;
(iv) R21g and R23g are each F and R22g is H;
(v) R21g and R23g are each H and R22g is F;
(vi) R22g and R23g are each H and R21g is F;
(vii) R21g and R22g are each H and R23g is F;
(viii)
Figure imgf000189_0005
, and R27gb is H;
Figure imgf000190_0001
R28gbisH andR26gb isF or-CH3.
[00425] Clause311. The compound of any one of clauses 307-310, wherein the compoundisselectedfrom:
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
[00426] Clause 312.. The compound of clause 301, wherein the compound of Formula
(I) is a compound of Formula (Ilh):
Figure imgf000195_0002
Formula (Ilh), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein:
Figure imgf000195_0004
is selected from
Figure imgf000195_0003
R20h is selected from H, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 cycloalkyl, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from halogen and -OH, and wherein C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen; and R21h, R22h, and R23h are each independently selected from H and halogen.
[00427] Clause 313. The compound of clause 312, wherein R20h is H.
[00428] Clause 314. The compound of clause 312 or 313, wherein at least one of (i)-(v) applies:
(i) R20h is selected from
Figure imgf000196_0001
(ii) R21h, R22h, and R23h are each H;
(iii) R21h and R23h are each F and R22his H;
(iv) R2111 and R23hare each H and R22h is F; and
Figure imgf000196_0002
[00429] Clause 315. The compound of any one of clauses 312-314, wherein the compound is selected from:
Figure imgf000196_0003
[00430] Clause 331166.. The compound of any one of clauses 301-315, wherein the compound is an inhibitor of at least one of IRAKI, IRAK4, and FLT3.
[00431] Clause 317. The compound of any one of clauses 301-316, wherein the compound is an inhibitor of at least two of IRAKI, IRAK4, and FLT3.
[00432] Clause 318. The compound of any one of clauses 301-317, wherein the compound is an inhibitor of IRAKI and IRAK4.
[00433] Clause 319. The compound of any one of clauses 301-317, wherein the compound is an inhibitor of IRAKI, IRAK4, and FLT3. [00434] Clause 320.. The compound of any one of clauses 316, 317, or 319, wherein FLT3 is selected from WT FLT3, activated FLT3, and mutated FLT3.
[00435] Clause 321. The compound of clause 320, wherein the mutated FLT3 is D835Y mutated FLT3 or F691L mutated FLT3.
[00436] Clause 322. A composition comprising a compound of any one of clauses 301- 321, wherein the composition further comprises a formulary ingredient, an adjuvant, or a carrier.
[00437] Clause 323. The composition of clause 322, wherein the composition is used in combination with one or more of: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, 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, an mAbs/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, 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, an NEDD 8 -activator, an MDM2 inhibitor, a PLK1 inhibitor, an Aura A inhibitor, an aurora kinase inhibitor, an EGFR inhibitor, an AuroraB/C/VEGFRl/2/3/FLT3/CSF-lR/Kit/PDGFRA/B inhibitor, an AKT 1, 2, and/or 3 inhibitor, aa ABL1/2/SRC/EPHA2/LCK/YES1/KIT/PDGFRB/FYN inhibitor, a famesyltransferase inhibitor, a BRAF/MAP2K1/MAP2K2 inhibitor, a Menin-KMT2A/MLL inhibitor, and a multikinase inhibitor.
[00438] Clause 332244.. The composition of clause 323, wherein the composition is used in combination with at least one of a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor.
[00439] Clause 325. The composition of clause 324, wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof.
[00440] Clause 326. The composition of clause 324, wherein the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof. [00441] Clause 327.. The composition of clause 324, wherein the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone, or a pharmaceutically acceptable salt of any one thereof.
[00442] Clause 328. The composition of clause 324, wherein the CDK inhibitor is a CDK4 inhibitor, a CDK6 inhibitor, a CDK7 inhibitor, and/or a CDK9 inhibitor.
[00443] Clause 329. The composition of clause 328 wherein the CDK inhibitor is selected from CDK4/6 inhibitor Palbociclib, CDK7 inhibitor THZ1, and/or CDK9 inhibitors BAY 1251152 and Atuveciclib, or a pharmaceutically acceptable salt of any one thereof.
[00444] Clause 330. The composition of clause 324, wherein the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof.
[00445] Clause 331. A method of treating a disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of clauses 301-321 or a composition of any one of clauses 322-330.
[00446] Clause 332. The method of clause 331, wherein the method comprises administering to the subject a composition comprising the therapeutically effective amount of the compound of clause 301 and a formulary ingredient, an adjuvant, or a carrier.
[00447] Clause 333. The method of clause 331 or 332, wherein the disease or disorder is responsive to at least one of interleukin- 1 receptor-associated kinase (IRAK) inhibition and fins-like tyrosine kinase 3 (FLT3) inhibition.
[00448] Clause 334. The method of any one of clauses 331-333, wherein the administration comprises parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration.
[00449] Clause 335.. The method of any one of clauses 331-334, wherein the compound is administered to the subject in an amount of from about 0.005 mg/kg subject body weight to about 1,000 mg /kg subject body weight.
[00450] Clause 336. The method of any one of clauses 331-335, wherein the disease or disorder comprises a hematopoietic cancer.
[00451] Clause 337. The method of any one of clauses 331-335, wherein the disease or disorder comprises myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML). [00452] Clause 338.. The method of any one of clauses 331-335, wherein the disease or disorder comprises lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL with MYD88 mutation, follicular lymphoma, or marginal zone lymphoma.
[00453] Clause 339. The method of any one of clauses 331-335, wherein the disease or disorder comprises at least one cancer selected from glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, Glioma, oral cancer, nasopharyngeal carcinoma, rectal cancer, stomach cancer, and uterine cancer, or one or more inflammatory diseases or autoimmune disease characterized by overactive IRAKI and/or IRAK4, or combinations thereof.
[00454] Clause 340.. The method of any one of clauses 331-335, wherein the disease or disorder comprises one or more inflammatory diseases or autoimmune disease 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 mellitus, or combinations thereof.
[00455] Clause 341. The method of any one of clauses 331-335, wherein the disease or disorder comprises:
(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) AML with a splicing factor mutation, AML having enhanced IRAK4-Long expression and/or activity relative to IRAK4-Short, and/or wherein the AML is not driven by FLT3 mutations but expresses IRAK4-Long.
[00456] Clause 342. The method of clause 341, wherein 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 U2 AF 1 or SF3B 1. [00457] Clause 343.. The method of any one of clauses 331-335, wherein the disease or disorder comprises DLBCL, and wherein the DLBCL comprises a L265P MYD88 mutant (ABC) subtype of DLBCL or a S219C MYD88 mutant (GCB) subtype of DLBCL.
[00458] Clause 344. The method of any one of clauses 331-343, further comprising administering to the subject one or more additional therapies selected from: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, 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, an mAbs/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, a steroid or glucocorticoid receptor modulator, an EZH2 inhibitor, a hedgehog (Hh) inhibitor, a Topoisomerase I inhibitor, aa Topoisomerase II inhibitor, an aminopeptidase/Leukotriene A4 hydrolase inhibitor, aa FLT3/Axl/ALK inhibitor, a FLT3/KIT/PDGFR, PKC, and/or KDR inhibitor, a Syk inhibitor, an E-selectin inhibitor, an NEDD 8 -activator, an MDM2 inhibitor, a PLK1 inhibitor, an Aura A inhibitor, an aurora kinase inhibitor, aann EEGGFFRR iinnhhiibbiittoorr,, an AuroraB/C/VEGFRl/2/3/FLT3/CSF-lR/Kit/PDGFRA/B inhibitor, aann A AKKTT 1, 2, aanndd//oorr 3 inhibitor, a
ABL1/2/SRC/EPHA2/LCK/YES1/KIT/PDGFRB/FYN inhibitor, a famesyltransferase inhibitor, a BRAF/MAP2K1/MAP2K2 inhibitor, a Menin-KMT2A/MLL inhibitor, and a multikinase inhibitor.
[00459] Clause 345.. The method of any one of clauses 331-344, wherein the disease or disorder is responsive to at least one of BCL2 inhibition, BTK inhibition, CDK inhibition, and DNA methyltransferase inhibition; or wherein the disease or disorder is sensitive to anti- inflammatory glucocorticoids.
[00460] Clause 346. The method of clause 344, wherein the additional therapy is at least one of a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor.
[00461] Clause 347. The method of clause 346, wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof. [00462] Clause 348.. The method of any one of clauses 331-347, wherein the disease or disorder is a BCL2 inhibitor resistant disease or disorder.
[00463] Clause 349. The method of any one of clauses 331-347, wherein the disease or disorder is a venetoclax resistant disease or disorder.
[00464] Clause 350.. The method of any one of clauses 331-347, wherein the disease or disorder is BCL2 inhibitor resistant acute myeloid leukemia (AML).
[00465] Clause 351. The method of any one of clauses 331-347, wherein the disease or disorder is venetoclax resistant acute myeloid leukemia (AML).
[00466] Clause 352. The method of any one of clauses 331-347, wherein the disease or disorder is BCL2 inhibitor resistant refractory acute myeloid leukemia (AML).
[00467] Clause 353. The method of any one of clauses 331-347, wherein the disease or disorder is venetoclax resistant refractory acute myeloid leukemia (AML).
[00468] Clause 354. The method of any one of clauses 331-347, wherein the disease or disorder is BCL2 inhibitor resistant relapsed acute myeloid leukemia (AML).
[00469] Clause 355. The method of any one of clauses 331-347, wherein the disease or disorder is venetoclax resistant relapsed acute myeloid leukemia (AML).
[00470] Clause 356. The method of clause 346, wherein the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof.
[00471] Clause 357. The method of any one of clauses 331-347, wherein the disease or disorder is a BTK inhibitor resistant disease or disorder.
[00472] Clause 358. The method of any one of clauses 331-347, wherein the disease or disorder is an ibrutinib resistant disease or disorder.
[00473] Clause 335599.. The method of clause 346, wherein the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone, or a pharmaceutically acceptable salt of any one thereof.
[00474] Clause 360.. The method of any one of clauses 331-347, wherein the disease or disorder is sensitive to anti-inflammatory glucocorticoids.
[00475] Clause 361. The method of any one of clauses 331-347, wherein the disease or disorder is a dexamethasone, methylprednisolone, or prednisolone resistant disease or disorder.
[00476] Clause 362.. The method of clause 346, wherein the CDK inhibitor is selected from CDK4/6 inhibitor palbociclib, CDK7 inhibitor THZ1, and/or CDK9 inhibitors BAY 1251152 and atuveciclib, or a pharmaceutically acceptable salt of any one thereof. [00477] Clause 363.. The method of any one of clauses 331-347, wherein the disease or disorder is a CDK inhibitor resistant disease or disorder.
[00478] Clause 364. The method of any one of clauses 331-347, wherein the disease or disorder is a palbociclib, THZ1, BAY 12511152, or atuveciclib resistant disease or disorder.
[00479] Clause 365. The method of clause 346, wherein the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof.
[00480] Clause 366. The method of any one of clauses 331-347, wherein the disease or disorder is a DNA methyltransferase inhibitor resistant disease or disorder
[00481] Clause 367. The method of any one of clauses 331-347, wherein the disease or disorder is an azacitidine resistant disease or disorder.
[00482] Clause 336688.. The method of any one of clauses 331-347, wherein the disease or disorder is a BCL2 inhibitor and DNA methyltransferase inhibitor resistant disease or disorder
[00483] Clause 369. The method of any one of clauses 331-347, wherein the disease or disorder is a venetoclax and azacitidine resistant disease or disorder.
[00484] Clause 370.. The method of clause 346, wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof and the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof.
[00485] Clause 371. The method of any one of clauses 331-347, wherein the disease or disorder is a FLT3 inhibitor resistant disease or disorder.
[00486] Clause 337722.. The method of any one of clauses 331-347, wherein the disease or disorder is FLT3 inhibitor resistant acute myeloid leukemia (AML).
[00487] Clause 373. The method of any one of clauses 331-347, wherein the disease or disorder is FLT3 inhibitor resistant refractory acute myeloid leukemia (AML).
[00488] Clause 374. The method of any one of clauses 331-347, wherein the disease or disorder is FLT3 inhibitor resistant relapsed acute myeloid leukemia (AML).
[00489] Clause 375. The method of clause 344, wherein the compound of any one of clauses 301-321 or the composition of any one of clauses 322-330 and the one or more additional therapies are administered together in one administration or composition.
[00490] Clause 376. The method of clause 344, wherein the compound of any one of clauses 301-321 or the composition of any one of clauses 322-330 and the one or more additional therapies are administered separately in more than one administration or more than one composition. [00491] Clause 377.. The method of any one of clauses 331-376, wherein the disease or disorder is alleviated by inhibiting at least one of IRAKI, IRAK4, and FLT3 in the subject.
[00492] Clause 378. The method of any one of clauses 331-376, wherein the disease or disorder is alleviated by inhibiting at least two of IRAKI, IRAK4, and FLT3 in the subject.
[00493] Clause 379. The method of any one of clauses 331-376, wherein the disease or disorder is alleviated by inhibiting IRAKI and IRAK4 in the subject.
[00494] Clause 380. The method of any one of clauses 331-376, wherein the disease or disorder is alleviated by inhibiting IRAKI, IRAK4, and FLT3 in the subject.
[00495] Clause 381. The method of any one of clauses 377, 378, or 380, wherein FLT3 is selected from WT FLT3, activated FLT3, and mutated FLT3
[00496] Clause 382. The method of clause 381, wherein the mutated FLT3 is D835Y mutated FLT3 or F691L mutated FLT3.
[00497] Clause 383. The method of any one of clauses 331-382, wherein the compound is a compound of any one of Formula (Ila)-(IIh), Formula (Illa)-(IIIp), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof.
[00498] Clause 401. A compound of Formula (I):
Figure imgf000203_0001
or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof, wherein:
R2, R3, R4, and R5 are each independently selected from H, halogen, hydroxy, oxo (=O), - CN, amino, amido, -O-aryl, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, wherein amino, amido, -O-aryl, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro- fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), - NH2, -NHCH3, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, - CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl which is substituted with cycloalkyl, wherein two adjacent optional substituents can bond or fuse to form a ring;
R6 is selected from
Figure imgf000204_0001
R7, R8, R9, R10, R11, R12, R13, and R14 are each independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, wherein methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more halogen and/or C1-C6 alkyl;
R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R29, R29, and R30 are each independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (- CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, wherein methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro- fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more halogen and/or C1-C6 alkyl; and m, n, 0, p, q, r, s, t, u, v, w, and x are each independently selected from 0, 1, 2, 3, 4, or 5; where q+r+s+t is at least 1, and where u+v+w+x is at least 1 .
[00499] Clause 402. The compound of clause 401, wherein the compound of Formula (I) is a compound of Formula (IIi):
Figure imgf000205_0003
or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein:
R20i is selected from C1-C6 alkyl and C1-C6 alkoxy, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen; R21i, R22i, and R23i are each independently selected from H and halogen; and
R24ia, R24ib, R25ia, R25ib, R26ia, and R26ib are each independently selected from H, halogen, - OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more halogen atoms.
[00500] Clause 403. The compound of clause 402, with the proviso that when R20i is R21i is halogen and R22i and R23i are each H; or R23i is halogen and R21i and R22i are each
Figure imgf000205_0001
H.
[00501] Clause 440044.. The compound of clause 402, wherein R21i is halogen, R22i and R23i are each H; or R23i is halogen, R21i and R22i are each H.
[00502] Clause 405. The compound of any one of clauses 402-404, wherein one or more of R24ia, R24ib, R25ia, R25ib, R26ia, and R26ib is halogen.
[00503] Clause 406. The compound of any one of clauses 402-405, wherein at least one of (i)-(iv) applies:
Figure imgf000205_0002
(ii) R21i is F, R22i and R23i are each H;
(iii) R23i is F, R21i and R22i are each H;
(iv) R24ia, R25ia, R25ib, R26ia, R26ib are each H andR24ib is F.
[00504] Clause 407. The compound of any one of clauses 402-406, wherein the compound is selected from:
Figure imgf000206_0001
[00505] Clause 408. The compound of clause 401, wherein the compound of Formula
(I) is a compound of Formula (Ilj):
Figure imgf000206_0002
or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein:
Figure imgf000206_0003
R20j is selected from C1-C6 alkyl and C1-C6 alkoxy, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen;
R21j, R22j, and R23j are each independently selected from H and halogen; and
R24ja, R24jb, R25ja, R25jb, R26ja, R26jb, R27ja, R27jb, R25ja, and R28jb are each independently selected from H, halogen, -OH, and C1-C6 alkyl.
[00506] Clause 409. The compound of clause 408, with the proviso that when R20j is
Figure imgf000206_0004
R21j is halogen and R22j and R23j are each H; or R23j is halogen and R21j and R22j are each
H.
[00507] Clause 441100.. The compound of clause 408, wherein R21j is halogen, R22j and R23j are each H; or R23j is halogen, Rzij and R22j are each H.
[00508] Clause 411. The compound of any one of clauses 408-410, wherein one or more of R24ja, R24jb, R25ja, R25jb, R26ja, R26jb, R27ja, R27jb, R28ja, and R28jb is halogen.
[00509] Clause 412. The compound of any one of clauses 408-411, wherein at least one of (i)-(v) applies: (i) R20j is
(ii) R21j is
Figure imgf000207_0001
F, R22j and R23j are each H;
(iii) R23j is F, R21j and R22j are each H; each of R24ja, R24jb, R25ja, R25jb, R26ja, R26jb, R27ja, R27jb,
Figure imgf000207_0002
R25ja, and R28jb is H; each of R24ja, R24jb, R25ja, R25jb, R26ja, R26jb, R27ja, R27jb,
Figure imgf000207_0003
and R25ja is H and R28jb is F.
[00510] Clause 413. The compound of any one of clauses 408-412, wherein the compound is selected from:
Figure imgf000207_0004
[00511] Clause 414. The compound of any one of clauses 401-413, wherein the compound is an inhibitor of at least one of IRAKI, IRAK4, and FLT3.
[00512] Clause 441155.. The compound of any one of clauses 401-414, wherein the compound is an inhibitor of at least two of IRAKI, IRAK4, and FLT3.
[00513] Clause 416. The compound of any one of clauses 401-415, wherein the compound is an inhibitor of IRAKI and IRAK4. [00514] Clause 4417.. The compound of any one of clauses 401-415, wherein the compound is an inhibitor of IRAKI, IRAK4, and FLT3.
[00515] Clause 418. The compound of any one of clauses 414, 415, or 417, wherein FLT3 is selected from WT FLT3, activated FLT3, and mutated FLT3.
[00516] Clause 419. The compound of clause 418, wherein the mutated FLT3 is D835Y mutated FLT3 or F691L mutated FLT3.
[00517] Clause 420.. A composition comprising a compound of any one of clauses 401- 419, wherein the composition further comprises a formulary ingredient, an adjuvant, or a carrier.
[00518] Clause 421. The composition of clause 420, wherein the composition is used in combination with one or more of: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, 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, an mAbs/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, 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, an NEDD 8 -activator, an MDM2 inhibitor, a PLK1 inhibitor, an Aura A inhibitor, an aurora kinase inhibitor, an EGFR inhibitor, an AuroraB/C/VEGFRl/2/3/FLT3/CSF-lR/Kit/PDGFRA/B inhibitor, an AKT 1, 2, and/or 3 inhibitor, aa ABL1/2/SRC/EPHA2/LCK/YES1/KIT/PDGFRB/FYN inhibitor, a famesyltransferase inhibitor, a BRAF/MAP2K1/MAP2K2 inhibitor, a Menin-KMT2A/MLL inhibitor, and a multikinase inhibitor.
[00519] Clause 422. The composition of clause 421, wherein the composition is used in combination with at least one of a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor.
[00520] Clause 423. The composition of clause 422, wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof. [00521] Clause 424.. The composition of clause 422, wherein the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof.
[00522] Clause 425. The composition of clause 422, wherein the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone, or a pharmaceutically acceptable salt of any one thereof.
[00523] Clause 426.. The composition of clause 422, wherein the CDK inhibitor is a CDK4 inhibitor, a CDK6 inhibitor, a CDK7 inhibitor, and/or a CDK9 inhibitor.
[00524] Clause 427. The composition of clause 422, wherein the CDK inhibitor is selected from CDK4/6 inhibitor Palbociclib, CDK7 inhibitor THZ1, and/or CDK9 inhibitors BAY 1251152 and Atuveciclib, or a pharmaceutically acceptable salt of any one thereof.
[00525] Clause 428. The composition of clause 422, wherein the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof.
[00526] Clause 429. A method of treating a disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of clauses 401-419 or a composition of any one of clauses 420-428.
[00527] Clause 430. The method of clause 429, wherein the method comprises administering to the subject a composition comprising the therapeutically effective amount of the compound of clause 401 and a formulary ingredient, an adjuvant, or a carrier.
[00528] Clause 431. The method of clause 429 or 430, wherein the disease or disorder is responsive to at least one of interleukin- 1 receptor-associated kinase (IRAK) inhibition and fins-like tyrosine kinase 3 (FLT3) inhibition.
[00529] Clause 432. The method of any one of clauses 429-431, wherein the administration comprises parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration.
[00530] Clause 433. The method of any one of clauses 429-432, wherein the compound is administered to the subject in an amount of from about 0.005 mg/kg subject body weight to about 1,000 mg /kg subject body weight.
[00531] Clause 434. The method of any one of clauses 429-433, wherein the disease or disorder comprises a hematopoietic cancer. [00532] Clause 435.. The method of any one of clauses 429-433, wherein the disease or disorder comprises myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML).
[00533] Clause 436. The method of any one of clauses 429-433, wherein the disease or disorder comprises lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL with MYD88 mutation, follicular lymphoma, or marginal zone lymphoma.
[00534] Clause 437.. The method of any one of clauses 429-433, wherein the disease or disorder comprises at least one cancer selected from glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, Glioma, oral cancer, nasopharyngeal carcinoma, rectal cancer, stomach cancer, and uterine cancer, or one or more inflammatory diseases or autoimmune disease characterized by overactive IRAKI and/or IRAK4, or combinations thereof.
[00535] Clause 438. The method of any one of clauses 429-433, wherein the disease or disorder comprises one or more inflammatory diseases or autoimmune disease 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 mellitus, Crohn’s disease, colitis, or combinations thereof.
[00536] Clause 439.. The method of any one of clauses 429-433, wherein the disease or disorder comprises: (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) AML with a splicing factor mutation, AML having enhanced IRAK4-Long expression and/or activity relative to IRAK4-Short, and/or wherein the AML is not driven by FLT3 mutations but expresses IRAK4-Long.
[00537] Clause 440. The method of clause 439, wherein 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 U2 AF 1 or SF3B 1. [00538] Clause 441.. The method of any one of clauses 429-433, wherein the disease or disorder comprises DLBCL, and wherein the DLBCL comprises a L265P MYD88 mutant (ABC) subtype of DLBCL or a S219C MYD88 mutant (GCB) subtype of DLBCL.
[00539] Clause 442. The method of any one of clauses 429-441, further comprising administering to the subject one or more additional therapies selected from: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, 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, an mAbs/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, a steroid or glucocorticoid receptor modulator, an EZH2 inhibitor, a hedgehog (Hh) inhibitor, a Topoisomerase I inhibitor, aa Topoisomerase II inhibitor, an aminopeptidase/Leukotriene A4 hydrolase inhibitor, aa FLT3/Axl/ALK inhibitor, a FLT3/KIT/PDGFR, PKC, and/or KDR inhibitor, a Syk inhibitor, an E-selectin inhibitor, an NEDD 8 -activator, an MDM2 inhibitor, a PLK1 inhibitor, an Aura A inhibitor, an aurora kinase inhibitor, aann EEGGFFRR iinnhhiibbiittoorr,, an AuroraB/C/VEGFRl/2/3/FLT3/CSF-lR/Kit/PDGFRA/B inhibitor, aann A AKKTT 1, 2, aanndd//oorr 3 inhibitor, a
ABL1/2/SRC/EPHA2/LCK/YES1/KIT/PDGFRB/FYN inhibitor, a famesyltransferase inhibitor, a BRAF/MAP2K1/MAP2K2 inhibitor, a Menin-KMT2A/MLL inhibitor, and a multikinase inhibitor.
[00540] CCllaauussee 444433.. The method of any one of clauses 429-442, wherein the disease or disorder is responsive to at least one of BCL2 inhibition, BTK inhibition, CDK inhibition, and DNA methyltransferase inhibition; or wherein the disease or disorder is sensitive to anti- inflammatory glucocorticoids.
[00541] Clause 444. The method of clause 442, wherein the additional therapy is at least one of a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor.
[00542] Clause 445. The method of clause 444, wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof. [00543] Clause 446.. The method of any one of clauses 429-444, wherein the disease or disorder is a BCL2 inhibitor resistant disease or disorder.
[00544] Clause 447. The method of any one of clauses 429-444, wherein the disease or disorder is a venetoclax resistant disease or disorder.
[00545] Clause 448.. The method of any one of clauses 429-444, wherein the disease or disorder is BCL2 inhibitor resistant acute myeloid leukemia (AML).
[00546] Clause 449. The method of any one of clauses 429-444, wherein the disease or disorder is venetoclax resistant acute myeloid leukemia (AML).
[00547] Clause 450. The method of any one of clauses 429-444, wherein the disease or disorder is BCL2 inhibitor resistant refractory acute myeloid leukemia (AML).
[00548] Clause 451. The method of any one of clauses 429-444, wherein the disease or disorder is venetoclax resistant refractory acute myeloid leukemia (AML).
[00549] Clause 452. The method of any one of clauses 429-444, wherein the disease or disorder is BCL2 inhibitor resistant relapsed acute myeloid leukemia (AML).
[00550] Clause 453. The method of any one of clauses 429-444, wherein the disease or disorder is venetoclax resistant relapsed acute myeloid leukemia (AML).
[00551] Clause 454. The method of clause 444, wherein the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof.
[00552] Clause 455. The method of any one of clauses 429-444, wherein the disease or disorder is a BTK inhibitor resistant disease or disorder.
[00553] Clause 456. The method of any one of clauses 429-444, wherein the disease or disorder is an ibrutinib resistant disease or disorder.
[00554] Clause 457.. The method of clause 444, wherein the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone, or a pharmaceutically acceptable salt of any one thereof.
[00555] Clause 458.. The method of any one of clauses 429-444, wherein the disease or disorder is sensitive to anti-inflammatory glucocorticoids.
[00556] Clause 459. The method of any one of clauses 429-444, wherein the disease or disorder is a dexamethasone, methylprednisolone, or prednisolone resistant disease or disorder.
[00557] Clause 446600.. The method of clause 459, wherein the CDK inhibitor is selected from CDK4/6 inhibitor palbociclib, CDK7 inhibitor THZ1, and/or CDK9 inhibitors BAY 1251152 and atuveciclib, or a pharmaceutically acceptable salt of any one thereof. [00558] Clause 461. The method of any one of clauses 429-444, wherein the disease or disorder is a CDK inhibitor resistant disease or disorder.
[00559] Clause 462. The method of any one of clauses 429-444, wherein the disease or disorder is a palbociclib, THZ1, BAY 12511152, or atuveciclib resistant disease or disorder.
[00560] Clause 463. The method of clause 444, wherein the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof.
[00561] Clause 464. The method of any one of clauses 429-444, wherein the disease or disorder is a DNA methyltransferase inhibitor resistant disease or disorder.
[00562] Clause 465. The method of any one of clauses 429-444, wherein the disease or disorder is an azacitidine resistant disease or disorder.
[00563] Clause 466.. The method of any one of clauses 429-444, wherein the disease or disorder is a BCL2 inhibitor and DNA methyltransferase inhibitor resistant disease or disorder.
[00564] Clause 467. The method of any one of clauses 429-444, wherein the disease or disorder is a venetoclax and azacitidine resistant disease or disorder.
[00565] Clause 468.. The method of clause 444, wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof and the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof.
[00566] Clause 469. The method of any one of clauses 429-444, wherein the disease or disorder is a FLT3 inhibitor resistant disease or disorder.
[00567] Clause 447700.. The method of any one of clauses 429-444, wherein the disease or disorder is FLT3 inhibitor resistant acute myeloid leukemia (AML).
[00568] Clause 471. The method of any one of clauses 429-444, wherein the disease or disorder is FLT3 inhibitor resistant refractory acute myeloid leukemia (AML).
[00569] Clause 472. The method of any one of clauses 429-444, wherein the disease or disorder is FLT3 inhibitor resistant relapsed acute myeloid leukemia (AML).
[00570] Clause 473. The method of clause 442, wherein the compound of any one of clauses 401-419 or the composition of any one of clauses 420-428 and the one or more additional therapies are administered together in one administration or composition.
[00571] Clause 474. The method of clause 442, wherein the compound of any one of clauses 401-419 or the composition of any one of clauses 420-428 and the one or more additional therapies are administered separately in more than one administration or more than one composition. [00572] Clause 475.. The method of any one of clauses 429-474, wherein the disease or disorder is alleviated by inhibiting at least one of IRAKI, IRAK4, and FLT3 in the subject.
[00573] Clause 476. The method of any one of clauses 429-475, wherein the disease or disorder is alleviated by inhibiting at least two of IRAKI, IRAK4, and FLT3 in the subject.
[00574] Clause 477. The method of any one of clauses 429-475, wherein the disease or disorder is alleviated by inhibiting IRAKI and IRAK4 in the subject.
[00575] Clause 478. The method of any one of clauses 429-475, wherein the disease or disorder is alleviated by inhibiting IRAKI, IRAK4, and FLT3 in the subject.
[00576] Clause 479. The method of any one of clauses 475, 476, or 478, wherein FLT3 is selected from WT FLT3, activated FLT3, and mutated FLT3.
[00577] Clause 480. The method of clause 479, wherein the mutated FLT3 is D835Y mutated FLT3 or F691L mutated FLT3.
[00578] Clause 481. A method of increasing survivability in a subject diagnosed with acute myeloid leukemia (AML) or suspected of having AML, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of clauses 401-419 or a composition of any one of clauses 420-428.
[00579] Clause 482. The method of clause 481, wherein the survivability of the subject is increased compared to a subject treated with a therapeutically effective amount of the standard of care for AML.
[00580] Clause 448833.. The method of clause 482, wherein the standard of care for AML comprises gilteritinib or a pharmaceutically acceptable salt thereof.
[00581] Clause 484. The method of any one of clauses 481 -483, wherein the subject is a human.
[00582] Clause 485. The method of clause 484, wherein the survivability of the subject is increased by about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, about 11 years, about 12 years, about 13 years, about 14 years, about 15 years, about 16 years, about 17 years, about 18 years, about 19 years, or about 20 years compared to a subject treated with a therapeutically effective amount of the standard of care for AML.
[00583] Clause 448866.. The method of any one of clauses 481 -483, wherein the subject is a non-human mammal engrafted with AML cells. [00584] Clause 487. The method of clause 486, wherein the subject is a mouse engrafted with AML cells.
[00585] Clause 488. The method of clause 486 or 487, wherein the AML cells are MOLM14-FLT3-ITD(D835Y) cells.
[00586] Clause 489. The method of any one of clauses 486-488, wherein the survivability of the subject is increased by about 1 day, about 2 days, about 5 days, about 10 days, about 15 days, about 20 days, about 25 days, about 30 days, about 35 days, about 40 days, about 45 days, about 50 days, about 55 days, about 60 days, about 65 days, about 70 days, about 75 days, about 80 days, about 85 days, or about 90 days compared to a subject treated with a therapeutically effective amount of the standard of care for AML.
[00587] Clause 490. The method of any one of clauses 481-489, comprising administering to the subject the therapeutically effective amount of a compound of any one of clauses 401-419 or the composition of any one of clauses 420-428 about every 6 hours, every 12 hours, every 18 hours, once a day, every other day, every 3 days, every 4 days, every 5 days, every 6 days, or once a week.
[00588] Clause 491. The method of any one of clauses 481-490, wherein the administration comprises parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration.
[00589] Clause 492.. The method of any one of clauses 481-491, wherein the compound is administered to the subject in an amount of from about 0.005 mg/kg subject body weight to about 1,000 mg /kg subject body weight.
[00590] Clause 493. The method of any one of clauses 481-492, wherein the AML comprises AML with a splicing factor mutation, AML having enhanced IRAK4-Long expression and/or activity relative to IRAK4-Short, and/or AML which is not driven by FLT3 mutations but expresses IRAK4-Long.
[00591] Clause 494. The method of any one of clauses 481-493, further comprising administering to the subject one or more additional therapies selected from: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, 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, an mAbs/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, a steroid or glucocorticoid receptor modulator, an EZH2 inhibitor, a hedgehog (Hh) inhibitor, aa 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, an NEDD 8 -activator, an MDM2 inhibitor, a PLK1 inhibitor, an Aura A inhibitor, an aurora kinase inhibitor, an EGFR inhibitor, an AuroraB/C/VEGFRl/2/3/FLT3/CSF-lR/Kit/PDGFRA/B inhibitor, aann AKT 1, 2, and/or 3 inhibitor, a
ABL1/2/SRC/EPHA2/LCK/YES1/KIT/PDGFRB/FYN inhibitor, a famesyltransferase inhibitor, a BRAF/MAP2K1/MAP2K2 inhibitor, a Menin-KMT2A/MLL inhibitor, and a multikinase inhibitor.
[00592] Clause 495.. The method of any one of clauses 481-494, wherein the AML is responsive to at least one of BCL2 inhibition, BTK inhibition, CDK inhibition, and DNA methyltransferase inhibition; or wherein the AML is sensitive to anti-inflammatory glucocorticoids.
[00593] Clause 496. The method of clause 494, wherein the additional therapy is at least one of a BCL2 inhibitor, a BTK inhibitor, a gluococorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor.
[00594] Clause 497. The method of clause 496, wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof.
[00595] Clause 498. The method of any one of clauses 481-496, wherein the AML is
BCL2 inhibitor resistant.
[00596] Clause 499. The method of any one of clauses 481-496, wherein the AML is venetoclax resistant.
[00597] Clause 500. The method of any one of clauses 481-496, wherein the AML is BCL2 inhibitor resistant refractory AML.
[00598] Clause 501. The method of any one of clauses 481-496, wherein the AML is venetoclax resistant refractory AML. [00599] Clause 0022.. The method of any one of clauses 481-496, wherein the AML is BCL2 inhibitor resistant relapsed AML.
[00600] Clause 503. The method of any one of clauses 481-496, wherein the AML is venetoclax resistant relapsed AML.
[00601] Clause 504. The method of clause 496, wherein the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof.
[00602] Clause 505. The method of any one of clauses 481-496, wherein the AML is
BTK inhibitor resistant.
[00603] Clause 506. The method of any one of clauses 481-496, wherein the AML is ibrutinib resistant.
[00604] Clause 507. The method of clause 496, wherein the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone, or a pharmaceutically acceptable salt of any one thereof.
[00605] Clause 508.. The method of any one of clauses 481-496, wherein the AML is sensitive to anti-inflammatory glucocorticoids.
[00606] Clause 509. The method of any one of clauses 481-496, wherein the AML is dexamethasone, methylprednisolone, or prednisolone resistant.
[00607] Clause 510. The method of clause 496, wherein the CDK inhibitor is selected from CDK4/6 inhibitor palbociclib, CDK7 inhibitor THZ1, and/or CDK9 inhibitors BAY 1251152 and atuveciclib, or a pharmaceutically acceptable salt of any one thereof.
[00608] Clause 511. The method of any one of clauses 481-496, wherein the AML is CDK inhibitor resistant.
[00609] Clause 512.. The method of any one of clauses 481-496, wherein the AML is palbociclib, THZ1, BAY 12511152, or atuveciclib resistant.
[00610] Clause 513. The method of clause 496, wherein the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof.
[00611] Clause 514. The method of any one of clauses 481-496, wherein the AML is DNA methyltransferase inhibitor resistant.
[00612] Clause 515. The method of any one of clauses 481-496, wherein the AML is azacitidine resistant.
[00613] Clause 516. The method of any one of clauses 481-496, wherein the AML is BCL2 inhibitor and DNA methyltransferase inhibitor resistant. [00614] Clause 517.. The method of any one of clauses 481-496, wherein the AML is venetoclax and azacitidine resistant.
[00615] Clause 518. The method of clause 496, wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof and the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof.
[00616] Clause 519. The method of any one of clauses 481-496, wherein the AML is
FLT3 inhibitor resistant.
[00617] Clause 552200.. The method of any one of clauses 481-496, wherein the AML is FLT3 inhibitor resistant refractory AML.
[00618] Clause 521. The method of any one of clauses 481-496, wherein the AML is
FLT3 inhibitor resistant relapsed AML.
[00619] Clause 522. The method of clause 494, wherein the compound of any one of clauses 401-419 or the composition of any one of clauses 420-428 and the one or more additional therapies are administered together in one administration or composition.
[00620] Clause 523. The method of clause 494, wherein the compound of any one of clauses 401-419 or the composition any one of clauses 420-428 and the one or more additional therapies are administered separately in more than one administration or more than one composition.
[00621] Clause 524.. The method of any one of clauses 481-523, wherein the survivability is increased by inhibiting at least one of IRAKI, IRAK4, and FLT3 in the subject.
[00622] Clause 525. The method of any one of clauses 481-524, wherein the survivability is increased by inhibiting at least two of IRAKI, IRAK4, and FLT3 in the subject.
[00623] Clause 526. The method of any one of clauses 481-525, wherein the survivability is increased by inhibiting IRAKI and IRAK4 in the subject.
[00624] Clause 527. The method of any one of clauses 481-525, wherein the survivability is increased by inhibiting IRAKI, IRAK4, and FLT3 in the subject.
[00625] Clause 528. The method of any one of clauses 524, 525, or 527, wherein FLT3 is selected from WT FLT3, activated FLT3, and mutated FLT3.
[00626] Clause 529. The method of clause 528, wherein the mutated FLT3 is D835Y mutated FLT3 or F691L mutated FLT3. [00627] Clause 530.. The method of any one of clauses 481-529, wherein the compound is a compound of any one of Formula (Ila)-(IIj), Formula (Illa)-(IIIp), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof.
EXAMPLES
[00628] The following non-limiting examples are provided to further illustrate embodiments of the disclosure disclosed herein. It should be appreciated by those of skill in the art that the techniques disclosed in the examples that follow represent approaches that have been found to function well in the practice of the disclosure, and thus can be considered to constitute examples of modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments that are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure.
List of Abbreviations.
[00629] In the accompanying procedures and schemes, abbreviations are used with the following meanings unless otherwise indicated: Ac = acetate; aq, aq. = aqueous; Ar = aryl; BOC, Boc = t-butyloxycarbonyl; Bn = benzyl; BSA = bovine serum albumin; Bu = butyl, Z-Bu = tert-butyl; BuLi, n-BuLi - n-butyllithium; CBZ, Cbz - Benzyloxycarbonyl; cone, cone. = concentrated; c-Bu = cyclobutyl; c-Pr = cyclopropyl; Cy = cyclohexyl; DAST = (diethylamino)sulfur trifluoride; dba = dibenzylideneacetone; DCM = dichloromethane; DIAD = diisopropylazodicarboxylate; DIBAL, DIBAL-H = diisobutylaluminum hydried; DIEA = diisopropylethylamine; DMAC, DMA = dimethylacetamide; DME = 1,2-dimethoxyethane; DMEM = Dulbecco’s modified eagle medium; DMAP = 4-dimethylaminopyridine; DMF = N,N- dimethylformamide; DMSO = dimethylsulfoxide; eq. = equivalent(s); EDC = N-[3- (dimethylamino)propyl]-N-ethylcarbodiimide; EDTA = ethylenediaminetetraacetic acid; ESI = electrospray ionization; Et = ethyl; EtOAc = ethyl acetate; EtOH = ethanol; FBS = Fetal Bovine Serum; h, hr = hour; HATU - N-[(dimethylamino)-lH-l,2,3-triazolo[4,5-b]pyridin-l- ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide; HOAc = acetic acid; HOAt = 3H-[l,2,3]-triazolo[4,5-b]pyridin-3-ol; HOBt = IH-benzotriazol-l-ol; HPLC = High pressure liquid chromatography; HTRF = homogenous time resolved fluorescence; IP A, i-PrOH = isopropanol; iPr = isopropyl; LAH = lithium aluminum hydried; LCMS = liquid chromatography - mass spectroscopy; LHMDS — lithium bis(trimethylsilyl)amide; Me — methyl; MeOH methanol; min, min. = minute; ?? WW = 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(dibenzylidineacetone)dipalladium; Pd/C = palladium on activated carbon;
Ph = phenyl; PMB = 4-methoxybenzyl; PMBC1 = l-(chloromethyl)-4-methoxybenzene; Pr = propyl; Py = pyridyl; RT, 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; Z-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; 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).
General Methods.
[00630] Unless otherwise stated, all reactions were carried out under an atmosphere of dry nitrogen in dried glassware. Indicated reaction temperatures refer to those of the reaction bath, while room temperature (rt) is noted as 25 °C. Unless otherwise noted, all solvents were of anhydrous quality purchased from Aldrich Chemical Co. and were used as received. Commercially available starting materials and reagents were purchased from commercial suppliers and were used as received.
[00631] Analytical thin layer chromatography (TLC) was performed with Sigma Aldrich TLC plates (5 x 20 cm, 60 A, 250 μm). Visualization was accomplished by irradiation under a 254 nm UV lamp. Chromatography on silica gel was performed using forced flow (liquid) of the indicated solvent system on Biotage KP-Sil pre-packed cartridges and using the Biotage SP-1 automated chromatography system. 1H NMR spectra were recorded on a Varian Inova 400 MHz spectrometer. Chemical shifts are reported in ppm with the solvent resonance as the internal standard (DMSO-d6 2.50 ppm for 1H). 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 constants, and number of protons. Low resolution mass spectra (electrospray ionization) were acquired on an Agilent Technologies 6130 quadrupole spectrometer coupled to the HPLC system. Unless otherwise noted, all LCMS ions listed are [M+H] . If needed, products were purified via semi-preparative HPLC using the columns and mobile phases noted. Samples were analyzed for purity on an Agilent 1200 series LC/MS equipped with a Luna® Cl 8 reverse phase (3 micron, 3 x 75 mm) column having a flow rate of 0.8 - 1.0 mL/min over a 7 minute gradient and an 8.5 minute run time (Method 1). Unless otherwise noted, the mobile phase was a mixture of acetonitrile (0.025% TFA) and H2O (0.05% TFA), with temperature maintained at 50 °C. Purity of final compounds was determined to be >95% using a 3 μL injection with quantitation by AUC at 220 and 254 nm (Agilent Diode Array Detector).
Example 1
Compounds of the Disclosure (Compounds 1 - 132)
[00632] The compounds in Table 1 were prepared using the synthetic procedures described elsewhere herein.
Figure imgf000221_0001
Figure imgf000222_0001
Figure imgf000223_0001
Figure imgf000224_0001
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
Figure imgf000230_0001
Figure imgf000231_0001
Figure imgf000232_0001
Figure imgf000233_0001
Figure imgf000234_0001
Figure imgf000235_0001
Figure imgf000236_0001
Figure imgf000237_0001
Figure imgf000238_0001
Example 2 Exemplary Synthetic Procedure #1 (Compounds 133 - 138)
Compound 133, 2-(3-(5-fluoro-6-(((3S,4S)-4-fluoropiperidin-3-yl)amino)pyridin-2- yl)imidazo[ 1 ,2-a]pyrazin-6-yl)propan-2-ol
Figure imgf000239_0001
Step A. 6-(l-ethoxyvinyl)imidazo[l,2-a]pyrazine
Figure imgf000239_0002
[00633] A mixture of 6-bromoimidazo[l,2-a]pyrazine (15.00 g, 75.75 mmol), tributyl(l- ethoxyvinyl)stannane (41.04 g, 113.6 mmol, 38.35 mL), [1,1- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5.54 g, 7.57 mmol), and copper(I) iodide (1.44 g, 7.57 mmol) in dioxane (200 mL) was purged with nitrogen, and was then heated at 100 °C for 16 hours. The reaction was then cooled to room temperature, quenched by addition of saturated aqueous potassium fluoride solution (60 mL), diluted with water (300 mL), and extracted with ethyl acetate (2 x 150 mL). The organic extracts were combined, washed with saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel (0 - 60% ethyl acetate in petroleum ether) to provide the title compound: LCMS m/z 190.0 [M+H]+; ’H NMR (400 MHz, CD3OD) δ 8.92 (s, 1 H), 8.68 (s, 1 H), 8.03 (s, 1 H), 7.76 (s, 1 H), 5.40 (d, J= 1.8 Hz, 1 H), 4.49 (d, J= 1.6 Hz, 1 H), 4.02 (q, J = 7.0 Hz, 2 H), 1.46 (t, 6.9 Hz, 3 H).
Step B. l-(imidazo[l,2-a]pyrazin-6-yl)ethanone
Figure imgf000240_0001
[00634] To a solution of 6-(l-ethoxyvinyl)imidazo[l,2-a]pyrazine (5.60 g, 29.6 mmol) in acetonitrile (30 mL) was added hydrochloric acid (2.0 M, 83.9 mL). The resulting reaction was stirred at room temperature for 2 hours, and was then filtered and concentrated under reduced pressure. The crude product thus obtained was purified by flash chromatography on silica gel (0 - 50% ethyl acetate in petroleum ether) to provide the title compound: LCMS m/z 162.1 [M+H]+; *H NMR (400 MHz, CD3OD) δ 9.21 (d, J = 1.4 Hz, 1 H), 9.06 (d, J = 0.6 Hz, 1 H), 8.20 (s, 1 H), 7.91 (d, J= 1.1 Hz, 1 H), 2.74 - 2.70 (m, 3 H).
Step C. 5-isopropenyl-N,N-bis[(4-methoxyphenyl)methyl]pyrazin-2-amine
Figure imgf000240_0002
[00635] To a cooled 0 °C solution of l-imidazo[l,2-a]pyrazin-6-ylethanone (0.901 g, 5.58 mmol) in dichloromethane (20 mL) 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, and was then quenched by addition of water (10 mL) and extracted with dichloromethane (3 x lOmL). The organic extracts were combined, washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel (0 - 100% ethyl acetate in petroleum ether) to provide the title compound: LCMS m/z 178.2 [M+H]+. Step D. 2-(3-(6-bromo-3-fluoropyridin-2-yl)imidazo[l,2-a]pyrazin-6-yl)propan-2-ol & 2-(3-(6- bromo-5-fhioropyridin-2-yl)imidazo[ 1 ,2-a]pyrazin-6-yl)propan-2-ol
Figure imgf000240_0003
[00636] A mixture of 2-imidazo[l,2-a]pyrazin-6-ylpropan-2-ol (1.00 g, 5.64 mmol), 2,6- dibromo-3 -fluoro-pyridine (2.88 g, 11.3 mmol), palladium(II)acetate (0.127 g, 0.564 mmol), triphenylphosphine (0.222 g, 0.846 mmol), 2,2-dimethylpropanoic acid (0.173 g, 1.69 mmol) and potassium carbonate (2.34 g, 16.9 mmol) in toluene (15.0 mL) was degassed and purged with nitrogen, and was then heated at 100 °C for 12 hours under nitrogen atmosphere. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel (0 - 100 % ethyl acetate in petroleum ether). The resulting product was then further purified by HPLC (Phenomenex Luna C18 column, 3 micron, 75 x 30 mm; 30 - 50% acetonitrile in aqueous 10 mM ammonium bicarbonate) to provide the title compounds:
2-(3-(6-bromo-3-fluoropyridin-2-yl)imidazo[l,2-a]pyrazin-6-yl)propan-2-ol: LCMS m/z 351.0 [M+H]+; 1H NMR (400 MHz, CD3OD) δ 10.14 - 10.09 (s, 1 H), 9.10 - 9.05 (s, 1 H), 8.41 (s, 1 H), 7.76 (dd, J= 8.3, 10.8 Hz, 1 H), 7.63 (dd, J= 3.0, 8.3 Hz, 1 H), 1.67 (s, 6 H).
2-(3-(6-bromo-5-fhioropyridin-2-yl)imidazo[l,2-a]pyrazin-6-yl)propan-2-ol: LCMS m/z 351.0 [M+H]+; 'H NMR (400 MHz, CD3OD) δ 9.80 - 9.75 (s, 1 H), 8.90 - 8.85 (s, 1 H), 8.32 (s, 1 H), 7.83 (dd, J- 8.3, 8.3 Hz, 1 H), 7.60 (dd, J= 3.0, 10.8 Hz, 1 H), 1.67 (s, 6 H).
Step E. (3S,4S)-tert-butyl 4-fluoro-3-((3-fluoro-6-(6-(2-hydroxypropan-2-yl)imidazo[l,2- a]pyrazin-3-yl)pyridin-2-yl)amino)piperidine- 1 -carboxylate
Figure imgf000241_0001
[00637] AA mmiixxttuurree of 2-[3-(6-bromo-5-fluoro-2-pyridyl)imidazo[l,2-a]pyrazin-6- yl]propan-2-ol (0.050 g, 0.142 mmol), tert-butyl (3S,4S)-3-amino-4-fluoropiperidine-l- carboxylate (0.037 g, 0.171 mmol), methanesulfonato[2,2-bis(diphenylphosphino)-l,l- binaphthyl](2-amino-l,l-biphenyl-2-yl)palladium(II) (0.014 g, 0.014 mmol), (R)-(+)-2,2 - bis(diphenylphosphino)-l,l'-binaphthyl (0.013 g, 0.021 mmol), and cesium carbonate (0.139 g, 0.427 mmol) in 2-methylbutan-2-ol (2.0 mL) was degassed and purged with nitrogen, and was then heated at 80 °C for 2 hours under nitrogen atmosphere. The reaction mixture was then cooled to room temperature, filtered, and concentrated under reduced pressure to provide the title compound: LCMS m/z 489.2 [M+H]+.
Step F. 2-(3-(5-fluoro-6-(((3S,4S)-4-fluoropiperidin-3-yl)amino)pyridin-2-yl)imidazo[l,2- a]pyrazin-6-yl)propan-2-ol
Figure imgf000242_0001
[00638] To a solution of tert-butyl (3S,4S)-4-fluoro-3-[[3-fluoro-6-[6-(l-hydroxy-l- methyl-ethyl)imidazo[l ,2-a]pyrazin-3-yl]-2-pyridyl]amino]piperidine- 1 -carboxylate (0.050 g, 0.102 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.770 g, 6.75 mmol, 0.50 mL). The resulting reaction was stirred at room temperature for 1 hour, and was then concentrated under reduced pressure. The resulting crude product was purified by HPLC (Phenomenex Luna C18 column, 3 micron, 100 x 40 mm; 1 - 35% acetonitrile in water containing 0.05% hydrochloric acid) to provide the title compound: LCMS m/z 389.1 [M+H]+; 1H NMR (400 MHz, CD3OD) δ 10.14 - 10.09 (s, 1 H), 9.10 - 9.05 (s, 1 H), 8.41 (s, 1 H), 7.51 (dd, J= 8.3, 10.8 Hz, 1 H), 7.40 (dd, J= 3.0, 8.3 Hz, 1 H), 5.08 - 4.92 (m, 1 H), 4.70 (m, 1 H), 4.00 (m, 1 H), 3.67 - 3.58 (m, 1 H), 3.31 - 3.24 (m, 1 H), 3.12 (m, 1 H), 2.64 - 2.50 (m, 1 H), 2.29 - 2.14 (m, 1 H), 1.75 (s, 3 H), 1.67 (s, 3 H).
[00639] The compounds in Table 2 were all prepared using the synthetic procedures described in Example 2.
Table 2. Additional compounds prepared according to Example 2.
Figure imgf000242_0002
Figure imgf000243_0001
Example 3 Biological Data for Exemplary Compounds
[00640] Kinase inhibitory data were obtained for various exemplary compounds prepared in Examples 1 and 2 using the RBC HotSpot Kinase Assay Protocol (Anastassiadis T, et al. Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat Biotechnol. 2011 Oct 30; 29(11): 1039-45), as described below. This assay uses the isolated kinase enzyme. This assay is very useful for determining competition of the inhibitor for ATP and/or substrates and for measuring the kinetics of enzyme inhibition. It also allows for measuring the relative affinity of binding to the isolated enzyme protein, and hence determines selectivity. Unlike kinase binding assays that measure competition for ATP, the HotSpot Kinase Assay is a functional assay that measures catalytic activity; as such it measures relative functional potency regardless of the mechanism of enzyme inhibition. This assay uses the form of the various enzymes that are easiest to express, which may not necessarily be the form of the enzyme that exist in the cell. (Sometimes the carboxy terminus has been truncated to aid in expression, or, if it is a receptor kinase, the enzyme itself is isolated from the other parts of the receptor that are involved in regulating kinase activity.)
[00641] The reagent used was as follows: Base Reaction buffer; 20 mM Hepes (pH 7.5), 10 mM MgC12, 1 mM EGTA, 0.01% Brij35, 0.02 mg/ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO. Required cofactors were added individually to each kinase reaction. [00642] The reaction procedure was as follows:
1) Substrates were prepared in freshly prepared Reaction Buffer.
2) Any required cofactors were delivered to the substrate solution above.
3) Kinase was delivered into the substrate solution and gently mixed.
4) Compounds were delivered in 100% DMSO into the kinase reaction mixture by Acoustic technology (Echo550; nanoliter range), followed by incubation for 20 min at room temp.
5) 33P-ATP was delivered into the reaction mixture to initiate the reaction.
6) The mixture was incubated for 2 hours at room temperature.
7) Kinase activity was detected by P81 filter-binding method.
Table 3. Biological data obtained in accordance with the protocol described in Example 3.
Figure imgf000244_0001
Figure imgf000245_0001
Figure imgf000246_0001
Figure imgf000247_0001
Example 4 Biological Data for Exemplary Compounds
[00643] Kinase binding data were obtained for various exemplary compounds in Example
1 and 2 using the DiscoverX KINOME-sccm® active site-directed competition binding site- directed assay protocol described below. Unlike other kinase competitive binding site assays, KINOMEscaiz® assays do not require ATP. As a result, the data report thermodynamic interaction affinities (Kd values), rather than IC50 values that are dependent on ATP concentrations. The assay uses a DNA-tagged version of the protein kinase, and an immobilized ligand bound to a solid support. Compounds that directly or indirectly prevent kinase binding to the immobilized ligand reduce the amount of kinase captured on the solid support, which is detected using an ultra-sensitive qPCR method. Affinity constants reported from the assay have been reported to be independent of the immobilized ligand used that is coupled to the solid support (See supplemental information in Fabian, M.A. et. al., (2005) Nat. Biotechnol. 23, 329- 336; Wodicka, L.M. et. al., (2010) Chem. Biol. 17, 1241-1249.)
[00644] Kinase-tagged T7 phage strains were prepared in an E. colt host derived from the BL21 strain. E. colt were grown to log-phase and infected with T7 phage and incubated with shaking at 32 °C until lysis. The lysates were centrifuged and filtered to remove cell debris. The remaining kinases were produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays. The liganded beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and to reduce non- specific binding. Binding reactions were assembled by combining kinases, liganded affinity beads, and test compounds in lx binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT). Test compounds were prepared as 11 lx stocks in 100% DMSO. Kds were determined using an 11 -point 3 -fold compound dilution series with three DMSO control points. All compounds for Kd measurements are distributed by acoustic transfer (non-contact dispensing) in 100% DMSO. The compounds were then diluted directly into the assays such that the final concentration of DMSO was 0.9%. All reactions were performed in polypropylene 384- well plates. Each was a final volume of 0.02 mL. The assay plates were incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (lx PBS, 0.05% Tween 20). The beads were then re-suspended in elution buffer (lx PBS, 0.05% Tween 20, 0.5 μM nonbiotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the eluates was measured by qPCR.
[00645] Binding constants (Kds) were calculated with a standard dose-response curve using the Hill equation. The Hill Slope was set to -1. Curves were fitted using a non-linear least square fit with the Levenberg-Marquardt algorithm.
Table 4. Biological data obtained in accordance with the protocol described in Example 4.
Figure imgf000248_0001
Table 5. Biological data obtained in accordance with the protocol described in Example 4.
Figure imgf000248_0002
Figure imgf000249_0001
Example 5
Biological Data for Exemplary Compounds
[00646] Kinase cellular potency data were obtained for various exemplary compounds in Examples 1 and 2, using the Reaction Biology NanoBRET assay protocol described below. The NanoBRET assay measures kinase engagement in real time in the context of the intact cell. Unlike the previously described biochemical kinase assay methodologies in Examples 3 and 4, the NanoBRET assay measures the binding and activity characteristics under equilibrium conditions using full-length kinases in the presence of cellular concentrations of ATP in live, uncompromised cells. As such, the assay provides a more relevant assessment of kinase potency and selectivity that would be expected to be observed in the native cellular environment, where potency is often considerably lower than that observed in the isolated biochemical assays (Vasta, J.D. et al., (2018) Cell Chem. Biol. 25, 206-214). The assay uses a Kinase-NanoLuc® fusion vector expressing a kinase protein to which a luciferase tag has been added, a cell-permeant fluorescent NanoBRET™ tracer, a NanoLuc® substrate, and an extracellular NanoLuc® inhibitor. Upon expression of the luciferase-tagged kinase, cells will produce a strong BRET signal only in the presence of the NanoBRET™ tracer. The extracellular NanoLuc® inhibitor ensures that the BRET signal observed emanates only from live cells. Because the BRET signal has tight distance constraints, addition of the test compound will decrease the BRET signal if the compound competes with the NanoBRET™ tracer for binding to the kinase domain. Under the appropriate tracer conditions established by the manufacturer, quantitative intracellular affinity and relative potency can then be determined using Mass Action model equations.
[00647] HEK-293 cells were purchased from ATCC. FuGENEHD Transfection Reagent,
Kinase-NanoLucfusion plasmids, Transfection Carrier DNA, NanoBRETTracers and dilution buffer, NanoBRETNano-Glo Substrate, Extracellular NanoLucInhibitor were obtained from Promega. [00648] Assays were conducted following Promega assay protocol with some modifications. HEK-293 Cells were transiently transfected with Kinase-NanoLucFusion Vector DNA by FuGENEHD Transfection Reagent. Testing compounds were delivered into 384 well assay plate by Echo 550 (Labcytelnc, Sunnyvale, CA). Transfected cells were harvested and mixed with NanoBRETTracer Reagent and dispensed into 384 well plates and incubated at 37 °C in 5% CO2 cell culture incubator for 1 hour. The NanoBRETNano-Glo Substrate plus Extracellular NanoLucInhibitor Solution were added into the wells of the assay plate and incubated for 2 - 3 minutes at room temperature. The donor emission wavelength (460 nm) and acceptor emission wavelength (600 nm) were measured in the En Visionplate reader. The BRET Ratios were calculated. BRET Ratio = [(Acceptor sample Donor sample) - (Acceptor no-tracer control + Donor no-tracer control)]. The IC50 values of compounds were calculated with Prism GraphPad program.
NanoBRET™ Target Engagement Assay Protocol
1. Transient Transfection of HEK-293 Cells NanoLuc® Fusion Vector DNA
1). Cultivate HEK-293 cells (70-80% confluence) appropriately prior to assay. Trypsinize and collect HEK-293 cells.
2). Prepare lipid: DNA complexes as follows: a. Prepare a 10 μg/ml solution of DNA in Opti-MEM without serum that consists of the following ratios of carrier DNA and DNA encoding NanoLuc® fusion. 9.0 μg/mL of Transfection Carrier DNA, 1.0 μg/mL of NanoLuc fusion vector DNA and 1 mL of Opti-MEM without phenol red. Mix thoroughly. b. Add 30 pl of FuGENE HD Transfection Reagent into each milliliter of DNA mixture to form lipid: DNA complex. c. Mix by inversion 10 times. d. Incubate at ambient temperature for 20 minutes to allow complexes to form.
3). In a sterile, conical tube, mix 1 part of lipid: DNA complex with 20 parts of HEK-293 cells in suspension. Mix gently by inversion 5 times.
4). Dispense cells + lipid: DNA complex into a sterile tissue culture dish and incubate for 22-24 hours.
2. Addition of Test Compounds (dry plate shooting) Each test compound is delivered from the compound source plate to the wells of 384-well white NBS plate by Echo 550.
3. Preparation of Cells with NanoBRET™ Tracer Reagent
1). Remove medium from dish with transfected HEK-293 cells via aspiration, trypsinize and allow cells to dissociate from the dish.
2). Neutralize trypsin using medium containing serum and centrifuge at 200 x g for 5 minutes to pellet the cells. Adjust the cell density to 2 x 105 cells/mL in Opti-MEM without phenol red.
3). Prepare Complete 20X NanoBRET™ Tracer Reagent with Tracer Dilution Buffer.
4). Dispense one part of Complete 20X NanoBRET™ Tracer Reagent to 20 parts of cells in the tube. Mix gently by inversion 10 times.
5). Dispense cell suspension into white, 384-well NBS plates. Incubate the plate at 37 °C, 5% CO2 for 1 hour.
Note: Prepare a separate set of samples without tracer for background correction steps.
4. NanoBRET™ Assay
1). Remove plate from incubator and equilibrate to room temperature for 15 minutes.
2). Prepare 3X Complete Substrate plus Inhibitor Solution in Assay Medium (Opti-MEMR I Reduced Serum Medium, no phenol red) just before measuring BRET.
3). Add 3X Complete Substrate plus Inhibitor Solution to each well of the 384-well plate. Incubate for 2-3 minutes at room temperature.
4). Measure donor emission wavelength (460 nm) and acceptor emission wavelength (600 nm) using the Envision 2104 plate reader.
5. Determination of BRET Ratio
To generate raw BRET ratio values, divide the acceptor emission value (600 nm) by the donor emission value (460 nm) for each sample. To correct for background, subtract the BRET ratio in the absence of tracer (average of no-tracer control samples) from the BRET ratio of each sample. NanoBRET™ ratio equation:
BRET Ratio = (Acceptor sample Donor sample)
NanoBRET™ ratio equation, including optional background correction: BRET Ratio [(Acceptor sample Donor sample) - (Acceptor no-tracer control Donor no- tracer control)]
Normalized Bret Response equation (%):
(BRET Ratio of Compound Treated Sample/BRET Ratio of DMSO Control Sample) *100%
6. Determination of IC50 Values
IC50 curves are plotted and IC50 values are calculated using the GraphPad Prism program based on a sigmoidal dose-response equation.
Table 6. Biological data obtained in accordance with the protocol described in Example 5.
Figure imgf000252_0001
Example 7
Biological Data for Exemplary Compounds
[00649] Cellular potency data were obtained for various exemplary compounds in Examples 1 and 2 using the NF-kB assay protocol described below. Activation of NF-kB gene transcription is a downstream signal in the IRAK signaling pathway (Balka, K.R. and DeNardo, D., J. Leukoc. Biol. (2019) 105, 339-351. Because THP-1 cells do not contain activated FLT3 receptors, measurement of the ability of a FLT3/IRAK1/IRAK4 inhibitor compound to inhibit the NF-kB production reflects the ability to inhibit signaling downstream of blocking signaling through the IRAK 1/4 complex and is not a composite measurement of activity that includes FLT3 kinase inhibition.
[00650] THP-1 -Blue NF-KB cells (InvivoGen) carrying a stable integrated NF-KB- inducible secreted embryonic alkaline phosphatase (SEAP) reporter construct were plated at a concentration of 1 x 105 cells per well. The cells were stimulated with Pam3CSK4 (1 ng/mL) or hILIB (1 ng/mL). After 10 - 20 minutes, the cells were then treated with vehicle (DMSO) or serial dilutions of the test compounds (10 doses tested for each test compound, with a 1 :10 dilution series starting at 1 μM or 3 μM) with a final volume of 200 μL for 24 hours at 37 °C. After 24 hours, the cells were centrifuged and 20 μL supernatant was incubated with 180 μL QUANTI-Blue reagent at 37 °C for 30 - 60 minutes. The levels of NF-KB-induced was measured in a microplate reader at 620 nm.
Table 7. Biological data obtained in accordance with the protocol described in Example 7.
Figure imgf000253_0001
Figure imgf000254_0001
Example 8
Biological Data for Exemplary Compounds
[00651] Cellular potency data were obtained for various exemplary compounds in Examples 1 and 2, using the M0LM14 D835Y and MOLM14 F691L cell viability assay protocols described below. Both cell lines have activated FLT3 receptors, each of which carry additional resistance mutations in the kinase domain (D835Y and F691L, respectively). Leukemias from patients harboring these kinase domain resistance mutations are resistant to FLT3 inhibitors that do not inhibit the mutant kinase. Because the activated FLT3 receptor drives a mitogenic response, and because there can be a discrepancy between activity in the biochemical kinase assay and in the context of a whole cell (Vasta, J.D. et al., (2018) Cell Chem. Biol. 25, 206-214), demonstration of antiproliferative activity in these cell lines with compounds known to inhibit the D835Y or F691L kinases in biochemical assays provides a more relevant cellular context for demonstration of activity.
[00652] M0LM14 D835Y and M0LM14 F691L cells were grown in RPMI-1640 media supplemented with 20% fetal bovine serum (FBS). For viability/cytotoxicity assessments, cells were seeded into 1536-well white polystyrene tissue culture-treated Greiner plates using a Multidrop Combi dispenser (ThermoFisher), in final volume 5 μL of growth media per well, at a density of 1000 cells per well. After cell addition, 23 nL of test compound were transferred into individual wells (22 doses tested for each test compound, with a 1 :2 dilution series starting at 10 μM) via a 1536 pin-tool. Bortezomib (final concentration 2.3 μM) was used as a positive control for cell cytotoxicity. Plates were incubated for 48 hours at standard incubator conditions covered by a stainless steel gasketed lid to prevent evaporation. 48 hours post compound addition, 3 μL of Cell Titer Gio (Promega) were added to each well and plates were incubated at room temperature for 15 minutes with the stainless-steel lid in place. Luminescence readings were taken using a Viewlux imager (PerkinElmer) with a 2 second exposure time per plate.
Table 8. Biological data obtained in accordance with the protocol described in Example 8.
Figure imgf000255_0001
Figure imgf000256_0001
Figure imgf000257_0001
N.D. = experiment not performed
Example 9
Combination Drug Screening for Exemplary Compounds
[00653] Combination drug therapy has the potential to produce enhanced effects with lower side effects not obtained using either agent alone, or beyond the additive effect of the different concentrations of the two different agents. To determine whether enhanced effects are observed in different drug combinations in the setting of FLT3 resistance, combination drug screening was performed as previously described (Mathews-Griner, L. A. et al., Proc. Nat. Acad. Sci., 2014, 111:2439-2454; Lin, G. L. et al., Sci. Trans. Med., 2019, l l:eaaw0064). Briefly, 10 nL of compounds were acoustically dispensed into 1536-well white polystyrene tissue culture- treated plates with an Echo 550 acoustic liquid handler (Labcyte). M0LM14 (D835Y) Cells were then added to compound-containing plates at a density of 500-cells/well in 5 μL of medium. A 10-point custom concentration range was used for all listed drugs. Plates were incubated for 48 hours at standard incubator conditions covered by a stainless steel gasketed lid to prevent evaporation. 48h post compound addition, 3 μL of Cell Titer Gio (Promega) were added to each well and plates were incubated at room temperature for 15 minutes with the stainless- steel lid in place. Luminescence readings were taken using a Viewlux imager (PerkinElmer) with a 2 second exposure time per plate. The results can be seen in Table 9.
Table 9. Sum excess HSA scores for a combination therapy of Compounds 25, 31, 35, 50, 51, 80, 82, 97, 118, and 119 with Venetoclax (0-20,000 nM) obtained in MOLM14 (D835Y) cells in a 10 x 10 dataset.
Figure imgf000257_0002
Figure imgf000258_0001
[00654] The sum excess HSA scores for Compounds 25, 31, 35, 50, 51, 80, 82, 97, 118, and 119 in Table 9 are used herein to quantitate drug interactions for enhanced pharmacological effects in the MOLM14 (D835Y) cell line. This is a FLT3-ITD cell line that harbors a FLT3 resistance mutation in the tyrosine kinase domain at position 835 (D835Y). More information on excess HSA scores can be found in Vlot, Anna H. C. et al., Drug Discovery Today, 2019, 24(12):2286-2298. While there are other methods of quantitating drug interactions, excess HSA method is preferred because it does not require making assumptions about similarities in the mechanism of action of the drugs involved or the shape of the dose-response curves being compared and does not place arbitrary requirements on the computational algorithm that the two drugs produce similar efficacy in the given system. However, different methodologies may yield different numerical scores, and different definitions of what constitutes a deviation from mere additivity vs true drug synergy. Table 9 summarizes the combination results of Compounds 25, 31, 35, 50, 51, 80, 82, 97, 118, and 119 with Venetoclax. In Table 9, Compounds 35 and 82 were studied over a concentration range of 0-500 nM and 0-200 nM, respectively, and Venetoclax was studied over a concentration range of 0-2,000 nM. A large negative sum excess HSA score indicates profound synergism with Venetoclax, whereas a positive sum excess HSA score indicates antagonism with Venetoclax in certain drug combinations.
[00655] The degree to which combination therapy has to potential to produce enhanced effects with lower side effects not obtained using either agent alone, or beyond the additive effect of the different concentrations of the two different agents depends on the nature of the drugs used in the combination, and the specific doses/concentrations at which they are ultimately used in the therapeutic regimen. A negative sum excess HSA score illustrates that the drug combination is better than either drug alone (at the concentrations being studied), and the sum excess HSA score is a measurement of the overall deviation from additivity that is observed across the entire matrix of concentrations studied. Hence, the drug combinations that are noteworthy as having more profound synergistic effects are those with greater negative excess sum HSA scores. However, the utility in certain drug combinations vs others should not be distinguished based on cutoffs between excess sum HSA scores, because the score itself is only a relative indicator that is completely dependent on experimental design and is not an absolute number. Furthermore, the concept of what constitutes clinically meaningful drug synergy is something that is still being debated, not only between pharmacologists and physicians, but amongst pharmacologists themselves. The data in Table 28 illustrate that the nature of the combined effect is dependent on the characteristics of each individual compound, as not every compound produced a synergistic interaction in combination with Venetoclax over the illustrated concentration range.
Example 10
Combination Drug Screening for Exemplary Compounds
THP1 Cells
Table 10. Sum excess HSA scores for a combination therapy of Compound 35 (0-20,000 nM concentration) obtained in THP1 cells in a 10 x 10 dataset.
Figure imgf000259_0001
Table 11. Sum excess HSA scores for a combination therapy of Compound 82 (0-10,000 nM concentration) obtained in THP1 cells in a 10 x 10 dataset.
Figure imgf000260_0001
Table 12. Sum excess HSA scores for a combination therapy of emavusertib (CA-4948) (an IRAK4/FLT3 inhibitor, 0-20,000 nM concentration) obtained in THP1 cells in a 10 x 10 dataset.
Figure imgf000260_0002
Table 13. Sum excess HSA scores for a combination therapy of CG-806 (a FLT3/BTK inhibitor 0-20 000 nM concentration) obtained in THP1 cells in a 10 x 10 dataset
Figure imgf000261_0001
Table 14. Sum excess HSA scores for a combination therapy of Gilteritinib (a FLT3/Axl inhibitor, 0-20,000 nM concentration) obtained in THP1 cells in a 10 x 10 dataset.
Figure imgf000261_0002
Table 15. Sum excess HSA scores for a combination therapy of PF-06650833 (an IRAK4 inhibitor, 0-20,000 nM concentration) obtained in THP1 cells in a 10 x 10 dataset.
Figure imgf000262_0001
Table 16. Sum excess HSA scores for a combination therapy of Quizartinib (a FLT3/Kit/PDGFRa inhibitor, 0-20,000 nM concentration) obtained in THP1 cells in a 10 x 10 dataset.
Figure imgf000262_0002
Figure imgf000263_0001
Table 17. Sum excess HSA scores for a combination therapy of Compound 82 (0-10,000 nM concentration) obtained in THP1 cells in a 10 x 10 dataset.
Figure imgf000263_0002
Table 18. Sum excess HSA scores for a combination therapy of CG-806 (a FLT3/BTK inhibitor, 0-10,000 nM concentration) obtained in THP1 cells in a 10 x 10 dataset.
Figure imgf000263_0003
Figure imgf000264_0001
Table 19. Sum excess HSA scores for a combination therapy of Gilteritinib (a FLT3/AXL inhibitor, 0-10,000 nM concentration) obtained in THP1 cells in a 10 x 10 dataset.
Figure imgf000264_0002
Table 20. Sum excess HSA scores for a combination therapy of emavusertib (CA-4948) (an IRAK4/FLT3 inhibitor, 0-10,000 nM concentration) obtained in THP1 cells in a 10 x 10 dataset.
Figure imgf000265_0001
MOLM14(D835Y) Cells
Table 21. Sum excess HSA scores for a combination therapy of Compound 35 (0-2,000 nM concentration) obtained in MOLM14(D835Y) cells in a 10 x 10 dataset.
Figure imgf000265_0002
Figure imgf000266_0001
Table 22. Sum excess HSA scores for a combination therapy of Compound 82 (0-500 nM concentration) obtained in MOLM14(D835Y) cells in a 10 x 10 dataset.
Figure imgf000266_0002
Table 23. Sum excess HSA scores for a combination therapy of emavusertib (CA-4948) (an IRAK4/FLT3 inhibitor, 0-2,000 nM concentration) obtained in MOLM14(D835Y) cells in a 10 x 10 dataset.
Figure imgf000266_0003
Figure imgf000267_0001
Table 24. Sum excess HSA scores for a combination therapy of CG-806 (a FLT3/BTK inhibitor, 0-200 nM concentration) obtained in MOLM14(D835Y) cells in a 10 x 10 dataset.
Figure imgf000267_0002
Table 25. Sum excess HSA scores for a combination therapy of Gilteritinib (a FLT3/Axl inhibitor 0-500 nM concentration) obtained in MOLM14(D835Y) cells in a 10 x 10 dataset
Figure imgf000267_0003
Figure imgf000268_0001
Table 26. Sum excess HSA scores for a combination therapy of PF-06650833 (a IRAK4 inhibitor, 0-10,000 nM concentration) obtained in MOLM14(D835Y) cells in a 0 x 10 dataset.
Figure imgf000268_0002
Table 27. Sum excess HSA scores for a combination therapy of Quizartinib (a FLT3/Kit/PDGFRa inhibitor, 0-2,000 nM concentration) obtained in MOLM14(D835Y) cells in a 10 x 10 dataset
Figure imgf000268_0003
Figure imgf000269_0001
[00656] The data in Tables 10-27 illustrate that the potential for drug synergy varies with the agents being studied as well as the concentration range and the cell background in which the drug combination is investigated. The illustrated representative compounds (Tables 10, 11, 17, 21, and 22) synergize with multiple therapeutic agents/mechanisms with a relative potency that differs from that of FLT3 inhibitors that do not also inhibit both IRAK4 and IRAKI, as illustrated by the Sum Excess HSA scores obtained with comparative compounds shown in Tables 12-16, 18-20, and 23-27.
[00657] Table 17 demonstrates that Compound 82 shows synergy with a number of different CDK inhibitors, and a DNMT inhibitor that is used in the clinic in FLT3 WT cells (THP1 cells) but is different from Azacitidine (Decitabine). Tables 10 and 11 demonstrate that Compounds 35 and 82, respectively, show strong synergy with Venetoclax in a FLT3 WT setting, whereas Tables 21 and 22 demonstrate that Compounds 35 and 82, respectively, show strong synergy with Venetoclax and a number of other drugs in the FLT3 mutant cell background.
[00658] Although not wishing to be limited by theory, the exact concentration range studied influences the size of the area available for synergy to be present. The Sum Excess HSA score computes the score over the entire area studied so the size of the concentration range (“synergy area”) will affect the Sum Excess HSA score. In Table 9, Compound 35 was run at a concentration range of 0-500 nM. When tested over that concentration range, the combination with 0-2000 nM Venetoclax has an Excess HSA score that signifies an antagonistic interaction. However, in Tables 10 and 21, Compound 35 was run over a different concentration range - Table 10 (THP1 cells): 0-20,000 nM Compound 35 vs 0-20,000 nM venetoclax; Table 21 : (M0LM14 (D835Y) cells) 0-2,000 nM Compound 35 vs 0-2,000 venetoclax), demonstrating synergy between Compound 35 and venetoclax. These concentration ranges were used for the M0LM14 D835Y cells because the compounds of the disclosure are more potent in this cell line than in the THP1 cells.
Example 11
Combination Drug Screening for Exemplary Compounds
[00659] FIG. 1 depicts the combination outcomes for representative compounds with Venetoclax in the Cell Titer Gio assay in THP1 cells at 48 hours. Panel A depicts the relative Excess HSA values for Compounds 35 and 82 in comparison to representative FLT3 inhibitors. A negative Excess HSA score illustrates that the drug combination is better than either drug alone, wherein greater synergy is observed at larger negative values of the Excess HSA score. Panel B depicts the relative concentration (nM) of CG-806, Compound 82, Compound 35, Gilteritinib hemifumerate, or emavusertib (CA-4948), respectively, to potentiate (<30%) of the 1250 nM Venetoclax Cell Titer Gio response at 48 hours. A smaller concentration indicates higher potency to synergize with Venetoclax. Panels C and D illustrate the concentration ranges over which the combination of Venetoclax and either Compound 82 (Panel C) or Compound 35 (Panel D) are studied in a 10 x 10 combination matrix. The numbers in each cell represent the % response (left) or the Delta Bliss score (right) at each given concentration combination. The number contained within the circle represents the resultant response at which the indicated concentrations of each agent reduce the activity of 1250 nM of Venetoclax to <30%.
[00660] FIG. 2 depicts the combination outcomes for representative compounds with Venetoclax in the Cell Titer Gio assay in MOLM 14 FLT3 ITD (D835Y) cells at 48 hours. Panel A depicts the relative Excess HSA values for Compounds 35 and 82 in comparison to representative FLT3 inhibitors. A negative Excess HSA score illustrates that the drug combination is better than either drug alone, wherein greater synergy is observed at larger negative values of the Excess HSA score. Panel B depicts the relative concentration (nM) of Compound 82, CG-806, Compound 35, Gilteritinib hemifumerate, or emavusertib (CA-4948), respectively, to potentiate (<10%) of the 125 nM Venetoclax Cell Titer Gio response at 48 hours. A smaller concentration indicates higher potency to synergize with Venetoclax. Panels C and D illustrate the concentration ranges over which the combination of Venetoclax and either Compound 82 (Panel C) or Compound 35 (Panel D) are studied in a 10 x 10 combination matrix. The numbers in each cell represent the % response (left) or the Delta Bliss score (right) at each given concentration combination. The number contained within the circle represents the resultant response at which the indicated concentrations of each agent reduce the activity of 125 nM of Venetoclax to <10%.
[00661] FIGS. 1 and 2 demonstrate that synergy is seen in both the FLT3 mutant setting (MOLM14 (D835Y) cells) and the FLT3 WT (THP1 cells) setting. Furthermore, in the FLT3 ITD mutant setting, the synergy is seen in a cell line that carries a FLT3 resistant mutation. This is a cell line that has the FLT3 ITD mutation but also the FLT3 D835Y kinase domain mutation.
Synergy is observed over different concentration ranges in the two different settings. Although not wishing to be limited by theory, this could be the case in the clinic as well. Different drugs require different concentrations for efficacy depending on the cell background, as well as the tumor microenvironment. Excess HSA is a measure of synergy vs. additivity or antagonism, wherein a negative Excess HSA value is indicative of synergy. If just the Excess HSA values are examined, it can be seen that the illustrated drug combinations are synergistic. The Excess HSA values presented in FIGS. 1-2 as well as in Tables 30, 31, and 37 (THP1 cells) and Tables 41 and 42 (M0LM14 (D835Y cells)) illustrate that Compounds 35 and 82 synergize with venetoclax and do so to seemingly equivalent or better degrees than competitor compounds. FIGS. 1-2 also illustrate that Compound 82 is more potent in synergizing with venetoclax than are either Compound 35 or competitor compounds in both the FLT3 WT (THP1) and FLT3 mutant (MOLM14 (D835Y)) cells.
Example 12
Combination Drug Screening for Exemplary Compounds
[00662] Combination drug therapy has the potential to produce enhanced effects with lower side effects not obtained using either agent alone, or beyond the additive effect of the different concentrations of the two different agents. To determine whether enhanced effects are observed in different drug combinations, combination drug screening was performed as previously described (Mathews-Griner, L. A. et al., Proc. Nat. Acad. Sci., 2014, 111 : 2349-2354; Lin, G. L. et al., Sci. Trans. Med., 2019, 11 :eaaw0064). Briefly, 10 nL of compounds were acoustically dispensed into 1536-well white polystyrene tissue culture-treated plates with an Echo 550 acoustic liquid handler (Labcyte). Cells were then added to compound-containing plates at a density of 500-cells/well in 5 pL of medium. A 6-point or 10-point custom concentration range was used for all listed drugs. Plates were incubated for 48 hours at standard incubator conditions covered by a stainless steel gasketed lid to prevent evaporation. 48h post compound addition, 3 μL of Cell Titer Gio (Promega) were added to each well and plates were incubated at room temperature for 15 minutes with the stainless-steel lid in place. Luminescence readings were taken using a Viewlux imager (PerkinElmer) with a 2 second exposure time per plate. The results can be seen in Table 28.
Table 28. Excess HSA scores for a combination therapy of select compounds of the disclosure and CDK inhibitor palbociclib obtained M0LM14 (D835Y) cells in a 10 x 10 dataset.
Figure imgf000272_0001
Figure imgf000273_0001
[00663] The excess HSA scores in Table 28 are used herein to quantitate drug interactions for enhanced pharmacological effects. More information on excess HSA scores can be found in Vlot, Anna H. C. et al., Drug Discovery Today, 2019, 24(12):2286-2298. While there are other methods of quantitating drug interactions, excess HSA method is preferred because it does not require making assumptions about similarities in the mechanism of action of the drugs involved or the shape of the dose-response curves being compared and does not place arbitrary requirements on the computational algorithm that the two drugs produce similar efficacy in the given system. However, different methodologies may yield different numerical scores, and different definitions of what constitutes a deviation from mere additivity vs true drug synergy.
[00664] A negative excess HSA score illustrates that the drug combination is better than either drug alone (at the concentrations being studied), and the excess HSA score is a measurement of the overall deviation from additivity that is observed across the entire matrix of concentrations studied. Hence, the drug combinations that are noteworthy as having more profound synergistic effects are those with greater negative excess HSA scores. However, the utility in certain drug combinations vs others should not be distinguished based on defined cutoffs between HSA scores, because the score itself is only a relative indicator that is completely dependent on experimental design and is not an absolute number. Furthermore, the concept of what constitutes clinically meaningful drug synergy is something that is still being debated, not only between pharmacologists and physicians, but amongst pharmacologists themselves.
Example 13
AML Efficacy Studies in Mice
Methods
[00665] Female, NSG-SGM3 (NOD.Cg-Prkdcscid I12rgtmlwjl Tg(CMV-
IL3,CSF2,KITLG)lEav/MloySzJ) mice were intravascularly engrafted with MOLM14-FLT3- ITD (D835Y) acute myeloid leukemia cells. Injection of leukemia cells was performed on 3/21/2022. Mice were randomized and dosing began three weeks following engraftment. Animals were administered vehicle control article or test article daily, Monday through Friday, wherein the comparative compounds used in these studies are depicted in FIG. 3. Mice experiencing clinical signs prior to scheduled end-date, including weight loss, lethargy, hunched posture, ruffled coat, or hind limb paralysis were humanely euthanized.
[00666] Bone marrow aspirates were performed when the initial vehicle control mice became clinical, 9 days following initiation of treatment. Aspirates were centrifuged, treated with RBC lysis buffer, resuspended in 250 μL PBS, and two cytospin chamber slides were loaded with 125 μL. Cytospins were used to create two cytology slides per mouse: one for Wright-Giemsa staining and the other for huCD45 immunocytochemistry, if needed. Cytology slides were graded according to the number of leukemic cells identified per 400x field as follows: 0, none; 1, 1-5 CD45+ cells; 2, 6-10 CD45+ cells; 3, 11-15 CD45+ cells; 4, 16-30 CD45+ cells; 5, >30 CD45+ cells.
[00667] At necropsy, sections of femur, tibia, vertebra, and sternum were evaluated for the presence of leukemic cells using H&E and CD45 immunohistochemistry, if needed. Grades for long bones, vertebrae, and sternum were recorded as follows: 0, no leukemic cells; 1, <1% of cells; 2, 1-10% of cells; 3, 10-50% of bone marrow; 4, >50% of bone marrow. Sums of the individual grades were taken for each mouse (range 0 to 12).
Results and Discussion
Survival
[00668] Survival analyses were performed for all groups. One mouse treated with Compound 82 was censored due to procedural related deaths, and 35 mice were censored due to end of study. FIG. 4 provides survival data for 80 days of mice xenografted with M0LM14 FLT3-ITD (D835Y) and treated with gilteritinib (30 mg/kg), CA-4948 (emavusertib) (30 mg/kg), and Compound 82 (10 mg/kg) versus vehicle control. Significant differences in survival were observed for Compound 82 compared to vehicle control mice (p-value = 0.0004 using a Log-rank test) and for Compound 82 compared to emavusertib (CA-4948) (p-value = 0.0348 using a Log-rank test).
Bone marrow cytology and hematology for model verification and leukemic burden quantification [00669] Leukemic burden was measured in NSGS mice xenografted with M0LM14 FLT3-ITD (D835Y) and quantified using bone marrow (BM) aspirates. An initial BM aspirate, accompanied by peripheral CBC evaluation (submandibular samples), was collected at the time that clinical signs first appeared in control mice to verify AML engraftment prior to the start of drug dosing. Cytospin chambers were used to create two cytology slides per bone marrow sample. Aspirate samples were of high quality for 85% of samples. A semi-quantitative grading system was applied to each bone marrow aspirate according to the number of leukemic cells identified per 400x field as follows:
Bone Marrow Cytospin Grade
□ 1: 1-5 leukemic cells (per HPF)
□ 2: 6-10 leukemic cells
□ 3: 11-15 leukemic cells
□ 4: 16-30 leukemic cells
□ 5: >30 leukemic cells
[00670] All mice had evidence of leukemia within the bone marrow aspirate.
Histopathology scores we re-taken for long bones (femur and tibia), vertebrae, and sternum as follows: 0, no leukemic cells; 1, <1% of cells; 2, 1-10% of cells; 3, 10-50% of bone marrow; 4, >50% of bone marrow. Scores were totaled (range: 0 to 12) and plotted by group at necropsy (FIG. 5 A). To incorporate survival, the bone marrow grade was divided by the time on test (FIG. 5B). When adjusting for survival, all treated animals show significant improvement compared to untreated controls.
[00671] The headings used in the disclosure are not meant to suggest that all disclosure relating to the heading is found within the section that starts with that heading. Disclosure for any subject may be found throughout the specification.
[00672] It is noted that terms like “preferably,” “commonly,” and “typically” are not used herein to limit the scope of the claimed disclosure or to imply that certain features are critical, essential, or even important to the structure or function of the claimed disclosure. Rather, these terms are merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment of the present disclosure.
[00673] The various methods and techniques described above provide a number of ways to carry out the disclosure. Of course, it is to be understood that not necessarily all objectives or advantages described can be achieved in accordance with any particular embodiment described herein. Thus, for example, those skilled in the art will recognize that the methods can be performed in a manner that achieves or optimizes one advantage or group of advantages as taught herein without necessarily achieving other objectives or advantages as taught or suggested herein. A variety of alternatives are mentioned herein. It is to be understood that some preferred embodiments specifically include one, another, or several features, while others specifically exclude one, another, or several features, while still others mitigate a particular feature by inclusion of one, another, or several advantageous features.
[00674] Furthermore, the skilled artisan will recognize the applicability of various features from different embodiments. Similarly, the various elements, features and steps discussed above, as well as other known equivalents for each such element, feature, or step, can be employed in various combinations by one of ordinary skill in this art to perform methods in accordance with the principles described herein. Among the various elements, features, and steps some will be specifically included, and others specifically excluded in diverse embodiments.
[00675] Although the application has been disclosed in the context of certain embodiments and examples, it will be understood by those skilled in the art that the embodiments of the disclosure extend beyond the specifically disclosed embodiments to other alternative embodiments and/or uses and modifications and equivalents thereof.
[00676] In some embodiments, the numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth, used to describe and claim certain embodiments of the application are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the application are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable.
[00677] In some embodiments, the terms “a” and “an” and “the” and similar references used in the context of describing a particular embodiment of the application (especially in the context of certain of the following claims) can be construed to cover both the singular and the plural. The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (for example, “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the application and does not pose a limitation on the scope of the application otherwise claimed. As used in the disclosure or claims, “another” means at least a second or more, unless otherwise specified. As used in the disclosure, the phrases “such as”, “for example”, and “e.g.” mean “for example, but not limited to” in that the list following the term (“such as”, “for example”, or “e.g.”) provides some examples but the list is not necessarily a fully inclusive list. The word “comprising” means that the items following the word “comprising” may include additional unrecited elements or steps; that is, “comprising” does not exclude additional unrecited steps or elements. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the application.
[00678] In certain instances, sequences disclosed herein are included in publicly available databases, such as GENBANK® and SWISSPROT. Unless otherwise indicated or apparent the references to such publicly available databases are references to the most recent version of the database as of the filing date of this Application.
[00679] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about”. Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and claims are approximations that can vary depending upon the desired properties sought to be obtained by the presently disclosed subject matter. As used herein, the term “about,” when referring to a value or to an amount of mass, weight, time, volume, concentration or percentage is meant to encompass variations of in some embodiments ±20%, in some embodiments ±10%, in some embodiments ±5%, in some embodiments ±1%, in some embodiments ±0.5%, and in some embodiments ±0.1% from the specified amount, as such variations are appropriate to perform the disclosed method. [00680] Preferred embodiments of this application are described herein. Variations on those preferred embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. It is contemplated that skilled artisans can employ such variations as appropriate, and the application can be practiced otherwise than specifically described herein. Accordingly, many embodiments of this application include all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the application unless otherwise indicated herein or otherwise clearly contradicted by context.
[00681] All patents, patent applications, publications of patent applications, and other material, such as articles, books, specifications, publications, documents, things, and/or the like, referenced herein are hereby incorporated herein by this reference in their entirety for all purposes, excepting any prosecution file history associated with same, any of same that is inconsistent with or in conflict with the present document, or any of same that may have a limiting affect as to the broadest scope of the claims now or later associated with the present document. By way of example, should there be any inconsistency or conflict between the description, definition, and/or the use of a term associated with any of the incorporated material and that associated with the present document, the description, definition, and/or the use of the term in the present document shall prevail.
[00682] In closing, it is to be understood that the embodiments of the application disclosed herein are illustrative of the principles of the embodiments of the disclosure. Other modifications that can be employed can be within the scope of the application. Thus, by way of example, but not of limitation, alternative configurations of the embodiments of the application can be utilized in accordance with the teachings herein. Accordingly, embodiments of the present application are not limited to that precisely as shown and described.

Claims

CLAIMS What is claimed is:
1. A compound of Formula (I):
Figure imgf000279_0001
or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof, wherein:
R2, R3, R4, and R5 are each independently selected from H, halogen, hydroxy, oxo (=O), - CN, amino, amido, -O-aryl, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 heteroalkyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, wherein amino, amido, -O-aryl, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro- fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), - NH2, -NHCH3, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, - CONHCH3, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl which is substituted with cycloalkyl, wherein two adjacent optional substituents can bond or fuse to form a ring;
R6 is selected from
Figure imgf000280_0001
R7, R8, R9, R10, R11, R12, R13, and R14 are each independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, wherein methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more halogen and/or C1-C6 alkyl;
R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R29, R29, and R30 are each independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (- CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, wherein methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro- fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more halogen and/or C1-C6 alkyl; and m, n, 0, p, q, r, s, t, u, v, w, and x are each independently selected from 0, 1, 2, 3, 4, or 5; where q+r+s+t is at least 1, and where u+v+w+x is at least 1.
2. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (IIi):
Figure imgf000280_0002
or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R20i is selected from C1-C6 alkyl and C1-C6 alkoxy, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen; R21i, R22i, and R23i are each independently selected from H and halogen; and
R24ia, R24ib, R25ia, R25ib, R26ia, and R26ib are each independently selected from H, halogen, - OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more halogen atoms.
3. The compound of claim 2, with the proviso that when R20i is
Figure imgf000281_0003
R21i is halogen and Rz2i and R23i are each H; or R23i is halogen and R21i and R22i are each H.
4. The compound of claim 2, wherein R21i is halogen, R22i and R23i are each H; or R23i is halogen, R21i and R22i are each H.
5. The compound of any one of claims 2-4, wherein one or more of R24ia, R24ib, R25ia, Risib, R26ia, and R2&b is halogen.
6. The compound of any one of claims 2-5, wherein at least one of (i)-(iv) applies:
(i) R20iis
Figure imgf000281_0002
(ii) R21i is F, R22i and R23i are each H;
(iii) R23i is F, R21i and R22i are each H;
(iv) R24ia, R25ia, R25ib, R26ia, R26ib are each H and R24ib is F.
7. The compound of any one of claims 2-6, wherein the compound is selected from:
Figure imgf000281_0001
8. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (Ilj):
Figure imgf000282_0001
or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein:
Figure imgf000282_0002
R20j is selected from C1-C6 alkyl and C1-C6 alkoxy, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen;
R21j, R22j, and R23j are each independently selected from H and halogen; and
R24ja, R24jb, R25ja, R25jb, R26ja, R26jb, R27ja, R27jb, R28ja, and R28jb are each independently selected from H, halogen, -OH, and C1-C6 alkyl.
9. The compound of claim 8, with the proviso that when R20j is
Figure imgf000282_0003
R21j is halogen and R22j and R23j are each H; or R23j is halogen and R21j and R22j are each H.
10. The compound of claim 8, wherein R21j is halogen, R22j and R23j are each H; or R23j is halogen, R21j and R22j are each H.
11. The compound of any one of claims 8-10, wherein one or more of R24ja, R24jb, R25ja, R25jb, R26ja, R26jb, R27ja, R27jb, R28ja, and R28jb is halogen.
12. The compound of any one of claims 8-11, wherein at least one of (i)-(v) applies:
(i) R20j is
Figure imgf000282_0004
(ii) R21j is F, R22j and R23j are each H;
(iii) R23j is F, R2ij and R22j are each H;
Figure imgf000283_0003
R28ja, and R28jb is H;
Figure imgf000283_0002
and R28jb is H and R27jb is F.
13. The compound of any one of claims 8-12, wherein the compound is selected from:
Figure imgf000283_0001
14. The compound of any one of claims 1-13, wherein the compound is an inhibitor of at least one of IRAKI, IRAK4, and FLT3.
15. The compound of any one of claims 1-14, wherein the compound is an inhibitor of IRAKI and IRAK4.
16. The compound of any one of claims 1-14, wherein the compound is an inhibitor of IRAKI, IRAK4, and FLT3.
17. A composition comprising a compound of any one of claims 1-16, wherein the composition further comprises a formulary ingredient, an adjuvant, or a carrier.
18. The composition of claim 17, wherein the composition is used in combination with one or more of: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, a BTK inhibitor, a DNA methyltransferase inhibitor/hypomethylating agent, an anthracycline, a histone deacetylase (HD AC) inhibitor, a purine nucleoside analogue (antimetabolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor, an antibody-drug conjugate, an mAbs/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, 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, an NEDD 8 -activator, an MDM2 inhibitor, a PLK1 inhibitor, an Aura A inhibitor, an aurora kinase inhibitor, an EGFR inhibitor, an AuroraB/C/VEGFRl/2/3/FLT3/CSF-lR/Kit/PDGFRA/B inhibitor, an AKT 1, 2, and/or 3 inhibitor, a ABL1/2/SRC/EPHA2/LCK/YES1/KIT/PDGFRB/FYN inhibitor, a famesyltransferase inhibitor, a BRAF/MAP2K1/MAP2K2 inhibitor, a Menin-KMT2A/MLL inhibitor, and a multikinase inhibitor.
19. The composition of claim 18, wherein the composition is used in combination with at least one of a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor.
20. The composition of claim 19, wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof, the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof, the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone or a pharmaceutically acceptable salt of any one thereof, the CDK inhibitor is selected from CDK4/6 inhibitor Palbociclib, CDK7 inhibitor THZ1, and/or CDK9 inhibitors BAY 1251152 and Atuveciclib, or a pharmaceutically acceptable salt of any one thereof, or the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof.
21. A method of treating a disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-13 or a composition of any one of claims 14-20.
22. The method of claim 21, wherein the method comprises administering to the subject a composition comprising the therapeutically effective amount of the compound of claim 1 and a formulary ingredient, an adjuvant, or a carrier.
23. The method of claim 21 or 22, wherein the disease or disorder is responsive to at least one of interleukin- 1 receptor-associated kinase (IRAK) inhibition and fins-like tyrosine kinase 3 (FLT3) inhibition.
24. The method of any one of claims 21-23, wherein the disease or disorder comprises a hematopoietic cancer.
25. The method of any one of claims 21-23, wherein the disease or disorder comprises myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML).
26. The method of any one of claims 21-23, wherein the disease or disorder comprises lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL with MYD88 mutation, follicular lymphoma, or marginal zone lymphoma.
27. The method of any one of claims 21-23, wherein the disease or disorder comprises at least one cancer selected from glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, Glioma, oral cancer, nasopharyngeal carcinoma, rectal cancer, stomach cancer, and uterine cancer, or combinations thereof.
28. The method of any one of claims 21-23, wherein the disease or disorder comprises one or more inflammatory diseases or autoimmune disease 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 mellitus, Crohn’s disease, colitis, or combinations thereof.
29. The method of any one of claims 21-28, further comprising administering to the subject one or more additional therapies selected from: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, a BTK inhibitor, a DNA methyltransferase inhibitor/hypomethylating agent, an anthracycline, a histone deacetylase (HD AC) inhibitor, a purine nucleoside analogue (antimetabolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor, an antibody- drug conjugate, an mAbs/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, 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, an NEDD 8 -activator, an MDM2 inhibitor, a PLK1 inhibitor, an Aura A inhibitor, an aurora kinase inhibitor, an EGFR inhibitor, an AuroraB/C/VEGFRl/2/3/FLT3/CSF-lR/Kit/PDGFRA/B inhibitor, an AKT 1, 2, and/or 3 inhibitor, a ABL1/2/SRC/EPHA2/LCK/YES1/KIT/PDGFRB/FYN inhibitor, a famesyltransferase inhibitor, a BRAF/MAP2K1/MAP2K2 inhibitor, a Menin-KMT2A/MLL inhibitor, and a multikinase inhibitor.
30. The method of claim 29, wherein the additional therapy is at least one of a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor.
31. The method of claim 30, wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof, the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof, the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone, or a pharmaceutically acceptable salt of any one thereof, the CDK inhibitor is selected from CDK4/6 inhibitor palbociclib, CDK7 inhibitor THZ1, and/or CDK9 inhibitors BAY1251152 and atuveciclib, or a pharmaceutically acceptable salt of any one thereof, and the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof.
32. The method of any one of claims 21-31, wherein the disease or disorder is BCL2 inhibitor resistant acute myeloid leukemia (AML) and/or FLT3 inhibitor resistant AML.
33. The method of claim 29, wherein the compound of any one of claims 1-13 or the composition of any one of claims 14-20 and the one or more additional therapies are administered together in one administration or composition.
34. The method of claim 29, wherein the compound of any one of claims 1-13 or the composition of any one of claims 14-20 and the one or more additional therapies are administered separately in more than one administration or more than one composition.
35. The method of any one of claims 21-34, wherein the disease or disorder is alleviated by inhibiting at least one of IRAKI, IRAK4, and FLT3 in the subject.
36. The method of any one of claims 21-35, wherein the disease or disorder is alleviated by inhibiting IRAKI and IRAK4 in the subject.
37. The method of any one of claims 21-35, wherein the disease or disorder is alleviated by inhibiting IRAKI, IRAK4, and FLT3 in the subject.
38. A method of increasing survivability in a subject diagnosed with acute myeloid leukemia (AML) or suspected of having AML, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-13 or a composition of any one of claims 14-20.
39. The method of claim 38, wherein the survivability of the subject is increased compared to a subject treated with a therapeutically effective amount of the standard of care for AML.
40. The method of claim 39, wherein the standard of care for AML comprises gilteritinib or a pharmaceutically acceptable salt thereof.
41. The method of any one of claims 38-40, wherein the subject is a human.
42. The method of claim 41, wherein the survivability of the subject is increased by about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, about 11 years, about 12 years, about 13 years, about 14 years, about 15 years, about 16 years, about 17 years, about 18 years, about 19 years, or about 20 years compared to a subject treated with a therapeutically effective amount of the standard of care for AML.
43. The method of any one of claims 38-42, comprising administering to the subject the therapeutically effective amount of a compound of any one of claims 1-13 or the composition of any one of claims 14-20 about every 6 hours, every 12 hours, every 18 hours, once a day, every other day, every 3 days, every 4 days, every 5 days, every 6 days, or once a week.
44. The method of any one of claims 38-43, further comprising administering to the subject one or more additional therapies selected from: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, a BTK inhibitor, a DNA methyltransferase inhibitor/hypomethylating agent, an anthracycline, a histone deacetylase (HD AC) inhibitor, a purine nucleoside analogue (antimetabolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor, an antibody- drug conjugate, an mAbs/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, 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, an NEDD 8 -activator, an MDM2 inhibitor, a PLK1 inhibitor, an Aura A inhibitor, an aurora kinase inhibitor, an EGFR inhibitor, an AuroraB/C/VEGFRl/2/3/FLT3/CSF-lR/Kit/PDGFRA/B inhibitor, an AKT 1, 2, and/or 3 inhibitor, a ABL1/2/SRC/EPHA2/LCK/YES1/KIT/PDGFRB/FYN inhibitor, a famesyltransferase inhibitor, a BRAF/MAP2K1/MAP2K2 inhibitor, a Menin-KMT2A/MLL inhibitor, and a multikinase inhibitor.
45. The method of claim 44, wherein the additional therapy is at least one of a BCL2 inhibitor, a BTK inhibitor, a gluococorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor.
46. The method of claim 45, wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof, the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof, the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone, or a pharmaceutically acceptable salt of any one thereof, the CDK inhibitor is selected from CDK4/6 inhibitor palbociclib, CDK7 inhibitor THZ 1 , and/or CDK9 inhibitors BAY1251152 and atuveciclib, or a pharmaceutically acceptable salt of any one thereof, and the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof.
47. The method of any one of claims 38-46, wherein the AML is BCL2 inhibitor resistant and/or FLT3 inhibitor resistant.
48. The method of claim 44, wherein the compound of any one of claims 1-13 or the composition of any one of claims 14-20 and the one or more additional therapies are administered together in one administration or composition.
49. The method of claim 44, wherein the compound of any one of claims 1-13 or the composition any one of claims 14-20 and the one or more additional therapies are administered separately in more than one administration or more than one composition.
50. The method of any one of claims 38-49, wherein the survivability is increased by inhibiting at least one of IRAKI, IRAK4, and FLT3 in the subject.
51. The method of any one of claims 38-50, wherein the survivability is increased by inhibiting IRAKI and IRAK4 in the subject.
52. The method of any one of claims 38-50, wherein the survivability is increased by inhibiting IRAKI, IRAK4, and FLT3 in the subject.
53. The method of any one of claims 38-52, wherein the compound is a compound of any one of Formula (Ila)-(IIj), Formula (Illa)-(IIIp), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof.
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