WO2024076614A2 - Composés inhibiteurs d'irak et de flt3 multi-cycliques et leurs utilisations - Google Patents

Composés inhibiteurs d'irak et de flt3 multi-cycliques et leurs utilisations Download PDF

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Publication number
WO2024076614A2
WO2024076614A2 PCT/US2023/034438 US2023034438W WO2024076614A2 WO 2024076614 A2 WO2024076614 A2 WO 2024076614A2 US 2023034438 W US2023034438 W US 2023034438W WO 2024076614 A2 WO2024076614 A2 WO 2024076614A2
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Prior art keywords
cycloalkyl
inhibitor
alkyl
formula
alkoxy
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WO2024076614A3 (fr
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Scott Bryan HOYT
Daniel T. STARCZYNOWSKI
Craig Joseph THOMAS
Jan Susan Rosenbaum
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Cincinnati Childrens Hospital Medical Center
US Department of Health and Human Services
Kurome Therapeutics Inc
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Cincinnati Childrens Hospital Medical Center
US Department of Health and Human Services
Kurome Therapeutics Inc
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Priority to EP23875469.1A priority Critical patent/EP4598539A2/fr
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Publication of WO2024076614A3 publication Critical patent/WO2024076614A3/fr
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    • 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
    • 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

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).
  • MDS hematopoietic stem/progenitor cell
  • 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.
  • 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.
  • risk factors and chromosomal abnormalities have been identified, but the specific cause is not clear.
  • the prognosis for AML that arises from MDS is worse as compared to other types of AML.
  • compound of Formula (I) is a compound of Formula (IIa-2N): or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: A is N or CR 22a ; E is N or CR 23a ; G is N or CR 24a ; R 20a is selected from H, halogen, C 1 -C 6 alkyl, C 1 - C 6 alkoxy, C 3 -C 6 cycloalkyl, and -O-(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 -OH and halogen, and wherein C 3 -C 6 cycloalkyl and -O-(C 3 -C 6 cycloalkyl) are each optionally substituted with one or more substituents selected from C 1 -C 6 alkyl and
  • R 20a is selected from halogen, unsubstituted C 1 -C 6 alkoxy, C 1 -C 6 alkoxy substituted with one or more F, unsubstituted C 3 -C 6 cycloalkyl, and unsubstituted -O-(C 3 -C 6 cycloalkyl); and/or R 21a is selected from C 1 -C 6 alkyl substituted with one or more -OH; unsubstituted C 1 -C 6 alkoxy; C 1 -C 6 alkoxy substituted with one or more -OH and/or F; unsubstituted C 3 -C 6 cycloalkyl; C 3 -C 6 cycloalkyl substituted with one or more -CH 3 , -OH, and/or F; unsubstituted C 3 -C 5 heterocyclyl comprising one oxygen, one nitrogen, or one oxygen and one nitrogen; C 3 -C 5 heterocyclyl comprising one nitrogen
  • R 20a is H;
  • R 20a is selected from Cl, -OCH 3 , , , unsubstituted C 3 cycloalkyl, and
  • R 21a is H;
  • R 21a is selected from is -OCH 2 CH 3 , unsubstituted C 3 cycloalkyl, unsubstituted C 4 cycloalkyl, unsubstituted C 5 cycloalkyl, unsubstituted C 6 cycloalkyl,
  • R 25a , R 25a’ , R 26a , R 26a’ , R 27a , and R 27a’ are each H; or (vi) each of R 25a , R 26a , R 26a’ , R 27a , and R 27a’ is H and R 25a is F.
  • one of (i)-(iii) applies: (i) A is N, E is CR 23a , and G is CR 24a ; (ii) A is CR 22a , E is N, and G is CR 24a ; or (iii) A is CR 22a , E is CR 23a , and G is N.
  • one of (i)-(vi) applies: (i) A is N, E is CR 23a , and G is CR 24a , wherein R 23a and R 24a are each H; (ii) A is N, E is CR 23a , and G is CR 24a , wherein R 23a is H and R 24a is F or R 23a is F and R 24a is H; (iii) A is CR 22a , E is N, and G is CR 24a , wherein R 22a and R 24a are each H; (iv) A is CR 22a , E is N, and G is CR 24a , wherein R 22a is F and R 24a is H, R 22a is H and R 24a is F, or R 22a and R 24a are each F; (v) A is CR 22a , E is CR 23a , and G is N, wherein R 22a and R 23a are each H; or (vi) A is CR 22a , E is CR
  • the compound Formula (IIa-2N) is selected from: or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof.
  • the compound of Formula (I) is a compound of Formula (IIb-2N): or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof;
  • R 20b is selected from halogen, unsubstituted C 1 -C 6 alkoxy, C 1 -C 6 alkoxy substituted with one or more F, unsubstituted C 3 -C 6 cycloalkyl, and unsubstituted -O-(C 3 -C 6 cycloalkyl); and/or R 21b is selected from C 1 -C 6 alkyl substituted with one or more -OH; unsubstituted C 1 -C 6 alkoxy; C 1 -C 6 alkoxy substituted with one or more -OH and/or F; unsubstituted C 3 -C 6 cycloalkyl; C 3 -C 6 cycloalkyl substituted with one or more -CH 3 , -OH, and/or F; unsubstituted C 3 -C 5 heterocyclyl comprising one oxygen, one nitrogen, or one oxygen and one nitrogen; C 3 -C 5 heterocyclyl comprising one nitrogen
  • R 20b is H;
  • R 20b is selected from Cl, -OCH 3 , unsubstituted C 3 cycloalkyl, and R 21b is H;
  • R 21b is selected from is -OCH 2 CH 3 , unsubstituted C 3 cycloalkyl, unsubstituted C 4 cycloalkyl, unsubstituted C 5 cycloalkyl, unsubstituted C 6 cycloalkyl, and R 25b , R 25b’ , R 27b , R 27b’ , R 28b , R 28b’ , R 29b , and R 29b’ are each H; or (vi) and R 25b , R 25b’ , R 27b , R 27b’ , R 28b , R 29b , and R 29b’ are each H and R 28b , is F.
  • one of (i)-(iii) applies: (i) A is N, E is CR 23b , and G is CR 24b ; (ii) A is CR 22b , E is N, and G is CR 24b ; or (iii) A is CR 22b , E is CR 23b , and G is N.
  • one of (i)-(vi) applies: (i) A is N, E is CR 23b , and G is CR 24b , wherein R 23b and R 24b are each H; (ii) A is N, E is CR 23b , and G is CR 24b , wherein R 23b is H and R 24b is F or R 23b is F and R 24b is H; (iii) A is CR 22b , E is N, and G is CR 24b , wherein R 22b and R 24b are each H; (iv) A is CR 22b , E is N, and G is CR 24b , wherein R 22b is F and R 24b is H, R 22b is H and R 24b is F, or R 22b and R 24b are each F; (v) A is CR 22b , E is CR 23b , and G is N, wherein R 22b and R 23b are each H; or (vi) A is CR 22b , E is CR
  • the compound Formula (IIb-2N) is selected from: or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof.
  • the compound of Formula (I) is a compound of compound of Formula (IIa): or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R 20a is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and -O- (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 -OH and halogen, and wherein C 3 -C 6 cycloalkyl and -O- (C 3 -C 6 cycloalkyl) are each optionally substituted with one or more
  • R 20a is selected from halogen, unsubstituted C 1 -C 6 alkoxy, C 1 -C 6 alkoxy substituted with one or more F, unsubstituted C 3 -C 6 cycloalkyl, and unsubstituted -O-(C 3 -C 6 cycloalkyl); and/or R 21a is selected from C 1 -C 6 alkyl substituted with one or more -OH; unsubstituted C 1 -C 6 alkoxy; C 1 -C 6 alkoxy substituted with one or more -OH and/or F; unsubstituted C 3 -C 6 cycloalkyl; C 3 -C 6 cycloalkyl substituted with one or more -CH 3 , -OH, and/or F; unsubstituted C 3 -C 5 heterocyclyl comprising one oxygen, one nitrogen, or one oxygen and one nitrogen; C 3 -C 5 heterocyclyl comprising one nitrogen
  • R 20a is H;
  • R 20a is selected from Cl, -OCH 3 , unsubstituted C 3 cycloalkyl, and
  • R 21a is H;
  • R 21a is selected from is , -OCH 2 CH 3 , unsubstituted C 3 cycloalkyl, unsubstituted C 4 cycloalkyl, unsubstituted C 5 cycloalkyl, unsubstituted C 6 cycloalkyl, , , , , , , , (v) R 22a , R 23a , and R 24a are each H; (vi) R 22a is selected from F and CN, R 23a is H, and R 24a is H; R 22a is H, R 23a is H, and R 24a is selected from F and CN; or R 22a is selected from
  • the compound of Formula (I) is a compound of Formula (IIb): or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: is selected from R 20b is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and -O-(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 -OH and halogen, and wherein C 3 -C 6 cycloalkyl and -O-(C 3 -C 6 cycloalkyl) are each optionally substituted with one or more substituents selected from C 1 -C 6 al
  • R 20b is selected from halogen, unsubstituted C 1 -C 6 alkoxy, C 1 -C 6 alkoxy substituted with one or more F, unsubstituted C 3 -C 6 cycloalkyl, and unsubstituted -O-(C 3 - C 6 cycloalkyl); and/or R 21b is selected from C 1 -C 6 alkyl substituted with one or more -OH; unsubstituted C 1 -C 6 alkoxy; C 1 -C 6 alkoxy substituted with one or more -OH and/or F; unsubstituted C 3 -C 6 cycloalkyl; C 3 -C 6 cycloalkyl substituted with one or more -CH 3 , -OH, and/or F; unsubstituted C 3 -C 5 heterocyclyl comprising one oxygen, one nitrogen, or one oxygen and one nitrogen; C 3 -C 5 heterocyclyl comprising one nitrogen
  • R 20b is H;
  • R 20b is selected from Cl, -OCH 3 , , , unsubstituted C 3 cycloalkyl, and
  • R 21b is H;
  • R 21b is selected from , - OCH 2 CH 3 , unsubstituted C 3 cycloalkyl, unsubstituted C 4 cycloalkyl, unsubstituted C 5 cycloalkyl, unsubstituted C 6 cycloalkyl,
  • R 22b , R 23b , and R 24a are each H;
  • R 22b is selected from F and CN, R 23b is H, and R 24b is H;
  • R 22b is H, R 23b is H, and R 24b is selected from F and CN; or
  • 22b is selected from F and CN, R 23b is H, and R 24b is selected from
  • the compound of Formula (I) 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 (I) or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof including compounds of Formula (IIa), Formula (IIb), Formula (IIa-2N), Formula (IIb-2N), or salts, esters, solvates, optical isomers, geometric isomers, or salts of an isomer thereof, is an inhibitor of IRAK1 and IRAK4.
  • the compound of Formula (I) or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof including compounds of Formula (IIa), Formula (IIb), Formula (IIa-2N), Formula (IIb-2N), or salts, esters, solvates, optical isomers, geometric isomers, or salts of an isomer thereof, is an inhibitor of IRAK1, IRAK4, and FLT3.
  • the present disclosure provides a composition
  • a composition comprising a compound of any one of Formula (I) or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, including compounds of Formula (IIa), Formula (IIb), Formula (IIa-2N), Formula (IIb-2N), or salts, esters, solvates, optical isomers, geometric isomers, or salts of an isomer thereof, wherein the composition further comprises a formulary ingredient, an adjuvant, or a carrier.
  • the composition is administered to a subject in need thereof 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
  • the composition is administered to a subject in need thereof 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
  • 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 (I) or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, including compounds of Formula (IIa), Formula (IIb), Formula (IIa-2N), Formula (IIb-2N), or salts, esters, solvates, optical isomers, geometric isomers, or salts of an isomer thereof, or a composition comprising a compound of any one of Formula (I) or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, including compounds of Formula (IIa), Formula (IIb), Formula (IIa-2N), Formula (IIb- 2N), or salts, esters, solvates, optical isomers, geometric isomers, or salts 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.
  • the administration comprises parenteral administration, mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration.
  • 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.
  • the disease or disorder comprises a hematopoietic cancer.
  • the disease or disorder comprises: (i) at least one cancer selected from myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL with MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer
  • MDS myel
  • 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
  • additional therapies
  • 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 a BCL2 inhibitor resistant disease or disorder.
  • the disease or disorder is BCL2 inhibitor resistant acute myeloid leukemia (AML), venetoclax resistant AML, BCL2 inhibitor resistant refractory AML, venetoclax resistant refractory AML, BCL2 inhibitor resistant relapsed AML, or venetoclax resistant relapsed AML.
  • the disease or disorder is a FLT3 inhibitor resistant disease or disorder.
  • the disease or disorder is FLT3 inhibitor resistant acute myeloid leukemia (AML), FLT3 inhibitor resistant refractory AML, or FLT3 inhibitor resistant relapsed AML.
  • the compound of any one of Formula (I) or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof including compounds of Formula (IIa), Formula (IIb), Formula (IIa-2N), Formula (IIb-2N), or salts, esters, solvates, optical isomers, geometric isomers, or salts of an isomer thereof, or the composition comprising a compound of any one of Formula (I) or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, including compounds of Formula (IIa), Formula (IIb), Formula (IIa-2N), Formula (IIb-2N), or salts, esters, solvates, optical isomers, geometric isomers, or salts of an isomer thereof, and the one or more additional therapies are administered together in one administration or composition.
  • compound of any one of Formula (I) or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof including compounds of Formula (IIa), Formula (IIb), Formula (IIa-2N), Formula (IIb-2N), or salts, esters, solvates, optical isomers, geometric isomers, or salts of an isomer thereof, or the composition comprising a compound of any one of Formula (I) or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, including compounds of Formula (IIa), Formula (IIb), Formula (IIa-2N), Formula (IIb-2N), or salts, esters, solvates, optical isomers, geometric isomers, or salts 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 IRAK1, IRAK4, and FLT3 in the subject. In one embodiment, the disease or disorder is alleviated by inhibiting IRAK1 and IRAK4 in the subject. In one embodiment, the disease or disorder is alleviated by inhibiting IRAK1, IRAK4, and FLT3 in the subject.
  • the compound is a compound of any one of Formula (I), Formula (IIa), Formula (IIb), Formula (IIa-2N), Formula (IIb-2N), Formulas (IIIa)-(IIIp), Formulas (IIIa- 2N)-(IIIp-2N), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof.
  • WO 2018081738 TREATMENT OF DISEASES ASSOCIATED WITH ACTIVATED IRAK, filed October 30, 2017; U.S.
  • Patent No.11,254,667 Substituted imidazo[1,2-a]pyridines as IRAK 1/4 and FLT3 inhibitors, issued February 2, 2022; U.S. Publication No.2022/0213094, Substituted Imidazo[l,2-a]-pyridines as IRAK 1/4 and FLT3 Inhibitors, filed January 4, 2022; U.S. Publication No.2020/0199123, Substituted imidazo[1,2-a]pyridines as IRAK 1/4 and FLT3 inhibitors, filed February 28, 2020; U.S.
  • WO 2023009833 Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, filed July 29, 2022; International Patent Application No. PCT/US2023/068520, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, filed June 15, 2023, International Patent Application No. PCT/US2023/068897, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, filed June 22, 2023, and International Patent Application No. PCT/US2023/071435, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, filed August 1, 2023.
  • compositions comprising the disclosed compound.
  • compositions for treating for example, certain diseases using the disclosed compounds.
  • Some embodiments include methods of using the disclosed compound (e.g., in compositions or in pharmaceutical compositions) for administering and treating.
  • Further embodiments include methods for making the disclosed compound.
  • Yet further embodiments include methods for determining whether a particular patient is likely to be responsive to such treatment with the disclosed compounds and compositions.
  • terms are to be understood according to conventional usage by those of ordinary skill in the relevant art.
  • 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.
  • 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 -.
  • the term “attached” signifies a stable covalent bond, certain preferred points of attachment being apparent to those of ordinary skill in the art.
  • 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., C 1 -C 10 means one to ten carbons).
  • C 1 -C 7 alkyl or C 1 -C 4 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-septyl.
  • Examples of C 1 -C 4 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.
  • 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.
  • 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.
  • heteroalkyl 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 quaternized.
  • the heteroatom(s) O, N, P, S, and Si can be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule.
  • 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 or “halo” means monovalent Cl, F, Br, or I. Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl 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.
  • aryl groups include, but are not limited to, phenyl, naphthyl, tolyl, and xylyl.
  • 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 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 quaternized.
  • 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.
  • 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, 1H-pyrazol-4-yl, 1-Me-pyrazol-4-yl, pyridin-3-yl, pyridin-4-yl, 3,5-dimethylisoxazolyl, 1H- pyrrol-3-yl, 3,5-di-Me-pyrazolyl, and 1H-pyrazol-4-yl.
  • arylene and a “heteroarylene,” alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively.
  • 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, arylC 1-16 alkyl, C 0-16 alkyloxyC 0-16 alkyl, arylC 0-16 alkyloxyC 0-16 alkyl, C 0-16 alkylthioC 0-16 alkyl, arylC 0-16 alkylthioC 0-16 alkyl, C 0- 16 alkylaminoC 0-16 alkyl, arylC 0-16 alkylaminoC 0-16 alkyl, di(arylC 1-16 alkyl)aminoC 0-16 alkyl, C 1 - 16 alkylcarbonylC 0-16 alkyl, arylC 1-16 alkylcarbonylC 0-16 alkyl, C 1-16 alkylcarboxyC 0-16 alkyl, arylC 1- 16 alkylcarboxyC 0-16 alky
  • Aryl includes but is not limited to pyrazolyl and triazolyl.
  • aryl when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above.
  • 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-(1-naphthyloxy)propyl, and the like), or a sulfur atom.
  • an oxygen atom e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like
  • sulfur atom e.g.
  • cycloalkyl (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.
  • 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.
  • cycloalkyl examples 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.
  • heterocycloalkyl a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
  • heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1- piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, tetrahydropyran, pyrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, or pyrrolidin- 4-yl), piperazinyl (e.g., piperazin-1-yl, piperazin-2-yl), piperaz
  • 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.
  • the term “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 as used herein, 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., “C 1 -C 4 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 n or -NHCO-R n ), thioamido (-CSNH-R n or -NHCS-R n ), carboxyl (-CO 2 -R n or -OCOR n ), carbonyl (-CO-R n ), urea (-NHCONH-R n ), thiourea (-NHCSNH-R n ), sulfonamido (-NHSO 2 -R n or -SO 2 NH-R n ), ether (-O-R n ), sulfonyl (-SO 2 -R n ), sulfoxyl (-SO-R n ), carbamoyl (-NHCO 2 -R n or -OCONH-R n ), or amino (-NHR n ) linking moieties.
  • 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.
  • 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) -NH 2 , -SH, -CN, -CF 3 , -NO 2 , halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO 2 H), nitro (-NO 2 ), -N(CH 3 ) 2 , ethynyl (-CCH), propynyl, sulfo (-SO 3 H), CONH 2 , - CON(CH 3 ) 2 , unsubstituted C 1 -C 7 alkyl, unsubstituted C 1 -C 7 heteroalkyl, unsubstituted C
  • a “size-limited substituent” or “ 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) 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.
  • 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.
  • 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.
  • 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.
  • outcome can refer to survival / mortality over a given time horizon.
  • outcome can refer to survival / mortality over 1 month, 3 months, 6 months, 1 year, 5 years, or 10 years or longer.
  • an increased risk for a poor outcome indicates that a therapy has had a poor efficacy
  • a reduced risk for a poor outcome indicates that a therapy has had a good efficacy.
  • 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. 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.
  • 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.
  • 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.
  • 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.
  • “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.
  • 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 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. 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.
  • 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 disclosed compounds (e.g., compounds of Formula (I), Formula (I-5013), or Formula (I-5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N)).
  • Other embodiments include compositions (e.g., pharmaceutical compositions) comprising the disclosed compound.
  • Still other embodiments of the disclosure include compositions (e.g., pharmaceutical compositions) for treating, for example, certain diseases using the disclosed compounds.
  • Some embodiments include methods of using the disclosed 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 disclosed compounds. Additional embodiments of the disclosure are also discussed herein.
  • 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 fuse
  • 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 is 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 is H.
  • 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), Formula (I-5013), or Formula (I-5013-2N).
  • the compound is not an ester, not a solvate, and not a prodrug of a compound of Formula (I), Formula (I-5013), or Formula (I-5013-2N).
  • A is N
  • E is CR 4
  • G is CR 5 .
  • A is CR 3
  • E is N
  • G is CR 5 .
  • A is CR 3
  • E is CR 4
  • G is N.
  • R 1 is H, halogen, C 1 -C 7 alkoxy, cycloalkyl, or -O-cycloalkyl, wherein C 1 -C 7 alkoxy is optionally substituted with one or more halogen, such as F.
  • R 1 is H, Cl, -OCH 3 , C 3 cycloalkyl, -O-(C 3 cycloalkyl), In some embodiments, R 1 is not H.
  • R 2 is H, C 1 -C 7 alkyl, C 1 -C 7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, or spiro-fused heterocyclyl, wherein C 1 -C 7 alkyl, C 1 -C 7 alkoxy, cycloalkyl, or heterocyclyl is optionally substituted with one or more of halogen, hydroxy, or C 1 -C 7 alkyl.
  • R 2 is H, substituted C 1 -C 7 alkyl, unsubstituted C 1 -C 7 alkoxy, substituted C 1 -C 7 alkoxy, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocyclyl, substituted heterocyclyl, unsubstituted spiro-fused cycloalkyl, or unsubstituted spiro-fused heterocyclyl.
  • R 2 is not H.
  • R 2 is C 3 cycloalkyl or .
  • R 3 is H, halogen, hydroxy, -CN, methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, or C 1 -C 7 alkoxy, wherein C 1 -C 7 alkyl, or C 1 -C 7 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 , -CON
  • R 3 is H, halogen, hydroxy, -CN, methyl, -CF 3 , or methoxy.
  • R 4 is H, halogen, hydroxy, -CN, methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, or C 1 -C 7 alkoxy, wherein C 1 -C 7 alkyl, or C 1 -C 7 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, piperidy
  • R 4 is H, halogen, hydroxy, -CN, methyl, -CF 3 , or methoxy.
  • R 5 is H, halogen, hydroxy, -CN, methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, or C 1 -C 7 alkoxy, wherein C 1 -C 7 alkyl, or C 1 -C 7 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, piperidy
  • R 5 is H, halogen, hydroxy, -CN, methyl, -CF 3 , or methoxy.
  • R 3 is F or CN
  • R 5 is F or CN
  • R 4 is H.
  • R 3 is H
  • R 4 is H
  • R 5 is F or CN.
  • R 3 is F or CN
  • R 4 is H
  • R 5 is H.
  • each of R 3 , R 4 , and R 5 are H.
  • A is N
  • E is CR 4
  • G is CR 5 , wherein R 4 and R 5 are each H.
  • A is N, E is CR 4 , and G is CR 5 , wherein R 4 is H and R 5 is F or R 4 is F and R 5 is H.
  • A is CR 3 , E is N, and G is CR 5 , wherein R 3 and R 5 are each H.
  • A is CR 3 , E is N, and G is CR 5 , wherein R 3 is F and R 5 is H, R 3 is H and R 5 is F, or R 3 and R 5 are each F.
  • A is CR 3 , E is CR 4 , and G is N, wherein R 3 and R 4 are each H.
  • A is CR 3 , E is CR 4 , and G is N, wherein R 3 is H and R 4 is F or R 3 is F and R 4 is H.
  • 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-f
  • each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 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 me
  • 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 are 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.
  • each of R 31 and R 32 is independently selected from H, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl, wherein C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl are each optionally substituted with one or more halogen.
  • 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. In certain embodiments, can be or 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 In some embodiments in Formula (I), Formula (I-5013), or Formula (I-5013-2N), R 6 is (Ia). In one embodiment, R 6 is (Ia), m is 0 or 1, n is 0 or 1, o is 0 or 1, and p is 0 or 1.
  • R 6 is (Ia), m is 0, n is 2, o is 1, and p is 1.
  • R 6 is (Ia) wherein 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 not H, and/or R 11 , R 12 , R 13 , and R 14 are H, and at least one of R 7 , R 8 , R 9 , and R 10 is not H.
  • R 6 is (Ia), m is 0, n is 2, o is 1, p is 1, and each of R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 is H.
  • R 6 is (Ia) wherein R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are independently selected from H, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-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.
  • R 6 is (Ia) wherein 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, 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 1 -C 7 alkoxy, or spiro-fused cycloalkyl is optionally substituted with one or more halogen.
  • R 6 is (Ia) wherein R 11 , R 12 , R 13 , and R 14 are H, and 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, or spiro-fused cycloalkyl, which methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C2-C 7 alkynyl, C 1 -C 7 alkoxy, or spiro-fused cycloalkyl is optionally substituted with one or more halogen.
  • R 6 is (Ia) 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, or spiro-fused cycloalkyl.
  • R 6 is (Ia) wherein at least one of R 7 , R 8 , R 9 , and R 10 is F, hydroxyl, methyl, methoxy, -CHF 2 , -CF 3 , 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, or spiro-fused cycloalkyl.
  • at least one of R 11 , R 12 , R 13 , and R 14 is F, hydroxyl, methyl, methoxy, -CHF2, -CF 3 , 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. In another embodiment, both of R 11 and R 12 or both of R 13 and R 14 are methyl. Further to any embodiment above wherein the compound comprises an R 6 of (Ia), the compound can have a structure of Formula (IIa), Formula (IIb), Formula (IIa-2N), or Formula (IIb-2N).
  • the compound of Formula (I) or Formula (I-5013) is a compound of Formula (IIa): or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R 20a is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and -O-(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 -OH and halogen, and wherein C 3 -C 6 cycloalkyl and -O-(C 3 -C 6 cycloalkyl) are each optionally substituted with one or more substituents selected from C 1 -C 6 alkyl and halogen; R 21a is selected from H, halogen, C 1 -C 6 alkyl, C
  • R 20a is H. In another embodiment, R 20a is not H. In an embodiment, R 20a is halogen. In one embodiment, R 20a is Cl. In another embodiment, R 20a is unsubstituted C 1 -C 6 alkoxy. In one embodiment, R 20a is -OCH 3 . In one embodiment, R 20a is . In another embodiment, R 20a is C 1 -C 6 alkoxy substituted with one or more fluorine atoms. In one embodiment, R 20a is In another embodiment, R 20a is C 3 -C 6 cycloalkyl. In one embodiment, R 20a is unsubstituted C 3 cycloalkyl.
  • R 20a is unsubstituted -O-(C 3 -C 6 cycloalkyl). In one embodiment, R 20a is . In an embodiment of Formula (IIa), R 21a is H. In another embodiment, R 21a is not H. In an embodiment, R 21a is C 1 -C 6 alkyl substituted with one or more -OH. In one embodiment, R 21a is . In another embodiment, R 21a is unsubstituted C 1 -C 6 alkoxy. In one embodiment, R 21a is ethoxy. In another embodiment, R 21a is C 1 -C 6 alkoxy substituted with one or more substituents selected from -OH and halogen.
  • R 21a is C 1 -C 6 alkoxy substituted with one or more F. In one embodiment, R 21a is In another embodiment of Formula (IIa), R 21a is unsubstituted C 3 -C 6 cycloalkyl. In one embodiment, R 21a is unsubstituted C 3 , C 4 , C 5 , or C 6 cycloalkyl. In another embodiment, R 21a is C 3 -C 6 cycloalkyl substituted with one or more C 1 -C 6 alkyl. In one embodiment, R 21a is C 3 , C 4 , C 5 , or C 6 cycloalkyl substituted with one or more -CH 3 .
  • R 21a is , In another embodiment, R 21a is C 3 -C 6 cycloalkyl substituted with one or more C 1 -C 6 alkyl and one or more -OH. In one embodiment, R 21a is C 3 , C 4 , C 5 , or C 6 cycloalkyl substituted with one or more -CH 3 and one or more -OH. In one embodiment, R 21a is . In another embodiment, R 21a is C 3 -C 6 cycloalkyl substituted with one or more halogen. In one embodiment, R 21a is C 3 , C 4 , C 5 , or C 6 cycloalkyl substituted with one or more F.
  • R 21a is In another embodiment, R 21a is unsubstituted C 3 -C 9 heterocyclyl. In one embodiment, R 21a is unsubstituted C 3 , C 4 , or C 5 heterocyclyl comprising one oxygen. In one embodiment, R 21a is . In one embodiment, R 21a is unsubstituted C 3 , C 4 , or C 5 heterocyclyl comprising one nitrogen. In one embodiment, R 21a is In one embodiment, R 21a is unsubstituted C 3 , C 4 , or C 5 heterocyclyl comprising one oxygen and one nitrogen.
  • R 21a is In another embodiment, R 21a is C 3 -C 9 heterocyclyl substituted with one or more substituents selected from C 1 -C 6 alkyl, halogen, and -OH. In one embodiment, R 21a is C 3 , C 4 , or C 5 heterocyclyl substituted with one or more C 1 -C 6 alkyl. In one embodiment, R 21a is C 3 , C 4 , or C 5 heterocyclyl substituted with one or more -CH 3 . In one embodiment, R 21a is C 3 , C 4 , or C 5 heterocyclyl comprising one nitrogen and substituted with one or more -CH 3 .
  • R 21a is C 6 -C 12 spiro-fused cycloalkyl. In one embodiment, R 21a is C 7 , C 8 , C 9, C 10 , or C 11 spiro-fused cycloalkyl. In one embodiment, R 21a is In another embodiment, R 21a is C 5 -C 10 spiro-fused heterocyclyl. In one embodiment, R 21a is C 5 , C 6 , C 7 , C 8 , C 9, or C 10 spiro-fused heterocyclyl. In one embodiment, R 21a is C 6 , C 7 , C 8 , C 9, or C 10 spiro-fused heterocyclyl comprising one oxygen.
  • R 21a is In one embodiment, R 21a is C 6 , C 7 , C 8 , C 9 , or C 10 spiro-fused heterocyclyl comprising one nitrogen. In one embodiment, R 21a is In one embodiment, R 21a is C 5 , C 6 , C 7 , C 8 , C 9 , or C 10 spiro-fused heterocyclyl comprising one oxygen and one nitrogen. In one embodiment, R 21a is In an embodiment of Formula (IIa), each of R 22a , R 23a , and R 24a is H. In an embodiment, R 22a and R 24a are each independently halogen and R 23a is H. In one embodiment, R 22a and R 24a are each F and R 23a is H.
  • R 22a and R 24a are each H and R 23a is halogen. In one embodiment, R 22a and R 24a are each H and R 23a is F. In another embodiment, R 23a and R 24a are each halogen and R 22a is H. In one embodiment, R 23a and R 24a are each F and R 22a is H. In another embodiment, R 22a and R 23a are each H and R 24a is halogen. In one embodiment, R 22a and R 23a are each H and R 24a is F. In an embodiment, R 22a and R 24a are each CN and R 23a is H. In an embodiment, R 22a and R 24a are each H and R 23a is CN.
  • R 23a and R 24a are each CN and R 22a is H. In another embodiment, R 22a and R 23a are each H and R 24a is CN.
  • each of R 25a , R 25a’ , R 26a , R 26a’ , R 27a , and R 27a’ is H. In an embodiment, each of R 26a , R 26a’ , R 27a , and R 27a’ is H and R 25a and/or R 25a’ is halogen. In one embodiment, each of R 25a , R 26a , R 26a’ , R 27a , and R 27a’ is H and R 25a’ is F.
  • each of R 26a , R 26a’ , R 27a , and R 27a’ is H and each of R 25a and R 25a’ is F.
  • R 26a , R 26a’ , R 27a , and R 27a’ are each H and R 25a and/or R 25a’ is C 1 -C 6 alkyl.
  • each of R 26a , R 26a’ , R 27a , and R 27a’ is H and each of R 25a and R 25a’ is -CH 3 .
  • each of R 25a , R 26a , R 26a’ , R 27a , and R 27a’ is H and R 25a’ is -CH 3 .
  • the compound of Formula (IIa) has one or more stereocenters. In one embodiment, the compound of Formula (IIa) comprises a stereocenter where the moiety connects to the remaining portion of Formula (IIa). In one embodiment, the compound of Formula (IIa) comprises a stereocenter at one or more of R 25a , R 25a’ , R 26a , R 26a’ , R 27a , and/or R 27a’ . In an embodiment, the compound of Formula (IIa) is selected from:
  • compound of Formula (IIa) is selected from:
  • the compound of Formula (I) or Formula (I-5013) is a compound of Formula (IIb): or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: is selected from R 20b is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and -O-(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 -OH and halogen, and wherein C 3 -C 6 cycloalkyl and -O-(C 3 -C 6 cycloalkyl) are each optionally substituted with one or more substituents selected from
  • R 20b is H. In another embodiment, R 20b is not H. In an embodiment, R 20b is halogen. In one embodiment, R 20b is Cl. In another embodiment, R 20b is unsubstituted C 1 -C 6 alkoxy. In one embodiment, R 20b is -OCH 3 . In one embodiment, R 20b is . In another embodiment, R 20b is C 1 -C 6 alkoxy substituted with one or more fluorine atoms. In one embodiment, R 20b is . In another embodiment, R 20b is C 3 -C 6 cycloalkyl. In one embodiment, R 20b is unsubstituted C 3 cycloalkyl.
  • R 20b is -O-(C 3 -C 6 cycloalkyl). In one embodiment, R 20b is . In an embodiment of Formula (IIb), R 21b is H. In another embodiment, R 21b is not H. In an embodiment, R 21b is C 1 -C 6 alkyl substituted with one or more -OH. In one embodiment, R 21b is . In another embodiment, R 21b is unsubstituted C 1 -C 6 alkoxy. In one embodiment, R 21b is ethoxy. In another embodiment, R 21b is C 1 -C 6 alkoxy substituted with one or more substituents selected from -OH and halogen.
  • R 21b is C 1 -C 6 alkoxy substituted with one or more F. In one embodiment, R 21b is In another embodiment of Formula (IIb), R 21b is unsubstituted C 3 -C 6 cycloalkyl. In one embodiment, R 21b is unsubstituted C 3 , C 4 , C 5 , or C 6 cycloalkyl. In another embodiment, R 21b is C 3 -C 6 cycloalkyl substituted with one or more C 1 -C 6 alkyl. In one embodiment, R 21b is C 3 , C 4 , C 5 , or C 6 cycloalkyl substituted with one or more -CH 3 .
  • R 21b is In another embodiment, R 21b is C 3 -C 6 cycloalkyl substituted with one or more C 1 -C 6 alkyl and one or more -OH. In one embodiment, R 21b is C 3 , C 4 , C 5 , or C 6 cycloalkyl substituted with one or more -CH 3 and one or more -OH. In one embodiment, R 21b is . In another embodiment, R 21b is C 3 -C 6 cycloalkyl substituted with one or more halogen. In one embodiment, R 21b is C 3 , C 4 , C 5 , or C 6 cycloalkyl substituted with one or more F.
  • R 21b is In another embodiment, R 21b is unsubstituted C 3 -C 9 heterocyclyl. In one embodiment, R 21b is unsubstituted C 3 , C 4 , or C 5 heterocyclyl comprising one oxygen. In one embodiment, R 21b is . In one embodiment, R 21b is unsubstituted C 3 , C 4 , or C 5 heterocyclyl comprising one nitrogen. In one embodiment, R 21b is . In one embodiment, R 21b is unsubstituted C 3 , C 4 , or C 5 heterocyclyl comprising one oxygen and one nitrogen. In one embodiment, R 21b is .
  • R 21b is C 3 -C 9 heterocyclyl substituted with one or more substituents selected from C 1 -C 6 alkyl, halogen, and -OH. In one embodiment, R 21b is C 3 , C 4 , or C 5 heterocyclyl substituted with one or more C 1 -C 6 alkyl. In one embodiment, R 21b is C 3 , C 4 , or C 5 heterocyclyl substituted with one or more -CH 3 . In one embodiment, R 21b is C 3 , C 4 , or C 5 heterocyclyl comprising one nitrogen and substituted with one or more -CH 3 .
  • R 21b is C 7 , C 8 , C 9 , C 10 , or C 11 spiro-fused cycloalkyl. In one embodiment, R 21b is In another embodiment, R 21b is C 5 -C 10 spiro-fused heterocyclyl. In one embodiment, R 21b is C 6 , C 7 , C 8 , C 9, or C 10 spiro-fused heterocyclyl. In one embodiment, R 21b is C 6 , C 7 , C 8 , C 9 , or C 10 spiro-fused heterocyclyl comprising one oxygen.
  • R 21b is In one embodiment, R 21b is C 6 , C 7 , C 8 , C 9, or C 10 spiro-fused heterocyclyl comprising one nitrogen. In one embodiment, R 21b is In one embodiment, R 21b is C 6 , C 7 , C 8 , C 9 , or C 10 spiro-fused heterocyclyl comprising one oxygen and one nitrogen. In one embodiment, R 21b In an embodiment of Formula (IIb), each of R 22b , R 23b , and R 24b is H. In an embodiment, R 22b and R 24b are each independently halogen and R 23b is H. In one embodiment, R 22b and R 24b are each F and R 23b is H.
  • R 22b and R 24b are each H and R 23b is halogen. In one embodiment, R 22b and R 24b are each H and R 23b is F. In another embodiment, R 23b and R 24b are each halogen and R 22b is H. In one embodiment, R 23b and R 24b are each F and R 22b is H. In another embodiment, R 22b and R 23b are each H and R 24b is halogen. In one embodiment, R 22b and R 23b are each H and R 24b is F. In an embodiment, R 22b and R 24b are each independently CN and R 23b is H. In an embodiment, R 22b and R 24b are each H and R 23b is CN.
  • R 23b and R 24b are each CN and R 22b is H. In another embodiment, R 22b and R 23b are each H and R 24b is CN. In an embodiment of Formula (IIb) wherein R 25b , R 25b’ , R 27b , R 27b’ , R 28b , R 28b ,, R 29b , and R 29b’ are each H. In another embodiment, each of R 25b , R 25b’ , R 27b , R 27b’ , R 29b , and R 29b’ is H and R 28b and/or R 28b’ is halogen.
  • each of R 25b , R 25b’ , R 27b , R 27b’ , R 28b , R 29b , and R 29b’ is H and R 28b , is F. In one embodiment, each of R 25b , R 25b’ , R 27b , R 27b’ , R 29b , and R 29b’ is H and each of R 28b and R 28b , is F. In an embodiment, R 25b , R 25b’ , R 27b , R 27b’ , R 29b , and R 29b’ is H and R 28b and/or R 28b , is C 1 -C 6 alkyl.
  • each of R 25b , R 25b’ , R 27b , R 27b’ , R 29b , and R 29b’ is H and each of R 28b and R 28b’ is -CH 3 .
  • each of R 25b , R 25b’ , R 27b , R 27b’ , R 28b , R 29b , and R 29b’ is H and R 28b , is -CH 3 .
  • the compound of Formula (IIb) has one or more stereocenters.
  • the compound of Formula (IIb) comprises a stereocenter where the moiety connects to the remaining portion of Formula (IIb).
  • the compound of Formula (IIb) comprises a stereocenter at one or more of R 25b , R 25b’ , R 26b , R 26b’ , R 27b , R 27b’ , R 28b , R 28b ,, R 29b , and R 29b’ .
  • the compound of Formula (IIb) is selected from: or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof.
  • the compound of Formula (llb) is selected from:
  • the compound is a compound of Formula (I) wherein A is CR 3 , E is CR 4 , G is CR 5 , and R 6 is (Ib) or a compound of Formula (I-5013) wherein R 6 is (Ib).
  • R 6 is (Ib) and q, r, s, t, u, v, w, and x are independently 0, 1, or 2.
  • 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, wherein methanoyl (- COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, 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 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 compound is a compound of Formula (I) wherein A is CR 3 , E is CR 4 , G is CR 5 , and R 6 is (Ib) or a compound of Formula (I-5013) wherein R 6 is (Ib) and the compound has a structure according to any of Formula (IIIa)-(IIIp), as follows:
  • the compound of Formula (I-5013-2N) or Formula (I) is a compound of Formula (IIa-2N): or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: A is N or CR 22a ; E is N or CR 23a ; G is N or CR 24a ; R 20a is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and -O-(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 -OH and halogen, and wherein C 3 -C 6 cycloalkyl and -O-(C
  • R 20a is H. In another embodiment, R 20a is not H. In an embodiment, R 20a is halogen. In one embodiment, R 20a is Cl. In another embodiment, R 20a is unsubstituted C 1 -C 6 alkoxy. In one embodiment, R 20a is -OCH 3 . In one embodiment, R 20a is . In another embodiment, R 20a is C 1 -C 6 alkoxy substituted with one or more fluorine atoms. In one embodiment, R 20a is In another embodiment, R 20a is C 3 -C 6 cycloalkyl. In one embodiment, R 20a is unsubstituted C 3 cycloalkyl.
  • R 20a is unsubstituted -O-(C 3 -C 6 cycloalkyl). In one embodiment, R 20a is In an embodiment in Formula (IIa-2N), R 21a is H. In another embodiment, R 21a is not H. In an embodiment, R 21a is C 1 -C 6 alkyl substituted with one or more -OH. In one embodiment, R 21a is . In another embodiment, R 21a is unsubstituted C 1 -C 6 alkoxy. In one embodiment, R 21a is ethoxy. In another embodiment, R 21a is C 1 -C 6 alkoxy substituted with one or more substituents selected from -OH and halogen.
  • R 21a is C 1 -C 6 alkoxy substituted with one or more F. In one embodiment, R 21a is . In another embodiment in Formula (IIa-2N), R 21a is unsubstituted C 3 -C 6 cycloalkyl. In one embodiment, R 21a is unsubstituted C 3 , C 4 , C 5 , or C 6 cycloalkyl. In another embodiment, R 21a is C 3 -C 6 cycloalkyl substituted with one or more C 1 -C 6 alkyl. In one embodiment, R 21a is C 3 , C 4 , C 5 , or C 6 cycloalkyl substituted with one or more -CH 3 .
  • R 21a is , In another embodiment, R 21a is C 3 -C 6 cycloalkyl substituted with one or more C 1 -C 6 alkyl and one or more -OH. In one embodiment, R 21a is C 3 , C 4 , C 5 , or C 6 cycloalkyl substituted with one or more -CH 3 and one or more -OH. In one embodiment, R 21a is . In another embodiment, R 21a is C 3 -C 6 cycloalkyl substituted with one or more halogen. In one embodiment, R 21a is C 3 , C 4 , C 5 , or C 6 cycloalkyl substituted with one or more F.
  • R 21a is In another embodiment, R 21a is unsubstituted C 3 -C 9 heterocyclyl. In one embodiment, R 21a is unsubstituted C 3 , C 4 , or C 5 heterocyclyl comprising one oxygen. In one embodiment, R 21a is . In one embodiment, R 21a is unsubstituted C 3 , C 4 , or C 5 heterocyclyl comprising one nitrogen. In one embodiment, R 21a is . In one embodiment, R 21a is unsubstituted C 3 , C 4 , or C 5 heterocyclyl comprising one oxygen and one nitrogen. In one embodiment, R 21a is .
  • R 21a is C 3 -C 9 heterocyclyl substituted with one or more substituents selected from C 1 -C 6 alkyl, halogen, and -OH. In one embodiment, R 21a is C 3 , C 4 , or C 5 heterocyclyl substituted with one or more C 1 -C 6 alkyl. In one embodiment, R 21a is C 3 , C 4 , or C 5 heterocyclyl substituted with one or more -CH 3 . In one embodiment, R 21a is C 3 , C 4 , or C 5 heterocyclyl comprising one nitrogen and substituted with one or more -CH 3 .
  • R 21a is C 7 , C 8 , C 9, C 10 , or C 11 spiro-fused cycloalkyl. In one embodiment, R 21a is In another embodiment, R 21a is C 5 -C 10 spiro-fused heterocyclyl. In one embodiment, R 21a is C 5 , C 6 , C 7 , C 8 , C 9 , or C 10 spiro-fused heterocyclyl. In one embodiment, R 21a is C 6 , C 7 , C 8 , C 9 , or C 10 spiro-fused heterocyclyl comprising one oxygen.
  • R 21a is In one embodiment, R 21a is C 6 , C 7 , C 8 , C 9, or C 10 spiro-fused heterocyclyl comprising one nitrogen. In one embodiment, R 21a is In one embodiment, R 21a is C 5 , C 6 , C 7 , C 8 , C 9 , or C 10 spiro-fused heterocyclyl comprising one oxygen and one nitrogen. In one embodiment, R 21a is In one embodiment in Formula (IIa-2N), A is N, E is CR 23a , and G is CR 24a . In one embodiment, A is N, R 23a is H, and R 24a is H. In one embodiment, A is N, R 23a is halogen, and R 24a is H.
  • A is N, R 23a is F, and R 24a is H. In one embodiment, A is N, R 23a is H, and R 24a is halogen. In one embodiment, A is N, R 23a is H, and R 24a is F. In one embodiment, A is N, R 23a is CN, and R 24a is H. In one embodiment, A is N, R 23a is H, and R 24a is CN. In one embodiment in Formula (IIa-2N), A is CR 22a , E is N, and G is CR 24a . In one embodiment, E is N, R 22a is H, and R 24a is H. In one embodiment, E is N, R 22a is halogen, and R 24a is H.
  • E is N, R 22a is F, and R 24a is H. In one embodiment, E is N, R 22a is H, and R 24a is halogen. In one embodiment, E is N, R 22a is H, and R 24a is F. In one embodiment, E is N, R 22a is halogen, and R 24a is halogen. In one embodiment, E is N, R 22a is F, and R 24a is F. In one embodiment, E is N, R 22a is CN, and R 24a is H. In one embodiment, E is N, R 22a is H, and R 24a is CN. In one embodiment, E is N, R 22a is CN, and R 24a is CN. In one embodiment, E is N, R 22a is CN, and R 24a is CN.
  • A is CR 22a
  • E is CR 23a
  • G is N.
  • G is N, R 22a is H, and R 23a is H.
  • R 22a is halogen
  • R 23a is H.
  • G is N, R 22a is F
  • R 23a is H.
  • G is N, R 22a is H, and R 23a is halogen.
  • G is N, R 22a is H, and R 23a is F.
  • G is N, R 22a is CN, and R 23a is H.
  • G is N, R 22a is H, and R 23a is CN.
  • each of R 25a , R 25a’ , R 26a , R 26a’ , R 27a , and R 27a’ is H.
  • each of R 26a , R 26a’ , R 27a , and R 27a’ is H and R 25a and/or R 25a’ is halogen.
  • each of R 25a , R 26a , R 26a’ , R 27a , and R 27a’ is H and R 25a’ is F.
  • each of R 26a , R 26a’ , R 27a , and R 27a’ is H and each of R 25a and R 25a’ is F.
  • R 26a , R 26a’ , R 27a , and R 27a’ are each H and R 25a and/or R 25a’ is C 1 -C 6 alkyl. In one embodiment, each of R 26a , R 26a’ , R 27a , and R 27a’ is H and each of R 25a and R 25a’ is -CH 3 . In one embodiment, each of R 25a , R 26a , R 26a’ , R 27a , and R 27a’ is H and R 25a’ is -CH 3 . In an embodiment, the compound of Formula (IIa-2N) has one or more stereocenters.
  • the compound of Formula (IIa-2N) comprises a stereocenter where the moiety connects to the remaining portion of Formula (IIa-2N). In one embodiment, the compound of Formula (IIa-2N) comprises a stereocenter at one or more of R 25a , R 25a’ , R 26a , R 26a’ , R 27a , and/or R 27a’ . In an embodiment, the compound of Formula (IIa-2N) is selected from: or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. In an embodiment, the compound of Formula (IIa-2N) is selected from:
  • the compound of Formula (I) is a compound of Formula (IIb-2N): Formula (IIb-2N), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: A is N or CR 22b ; E is N or CR 23b ; G is N or CR 24b ; is selected from R 20b is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and -O-(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 -OH and halogen, and wherein C 3 -C 6 cycloalkyl and
  • R 20b is H. In another embodiment, R 20b is not H. In an embodiment, R 20b is halogen. In one embodiment, R 20b is Cl. In another embodiment, R 20b is unsubstituted C 1 -C 6 alkoxy. In one embodiment, R 20b is -OCH 3 . In one embodiment, R 20b is . In another embodiment, R 20b is C 1 -C 6 alkoxy substituted with one or more fluorine atoms. In one embodiment, R 20b is In another embodiment, R 20b is C 3 -C 6 cycloalkyl. In one embodiment, R 20b is unsubstituted C 3 cycloalkyl.
  • R 20b is -O-(C 3 -C 6 cycloalkyl). In one embodiment, R 20b is . In an embodiment of Formula (IIb-2N), R 21b is H. In another embodiment, R 21b is not H. In an embodiment, R 21b is C 1 -C 6 alkyl substituted with one or more -OH. In one embodiment, R 21b is . In another embodiment, R 21b is unsubstituted C 1 -C 6 alkoxy. In one embodiment, R 21b is ethoxy. In another embodiment, R 21b is C 1 -C 6 alkoxy substituted with one or more substituents selected from -OH and halogen.
  • R 21b is C 1 -C 6 alkoxy substituted with one or more F. In one embodiment, R 21b is . In another embodiment of Formula (IIb-2N), R 21b is unsubstituted C 3 -C 6 cycloalkyl. In one embodiment, R 21b is unsubstituted C 3 , C 4 , C 5 , or C 6 cycloalkyl. In another embodiment, R 21b is C 3 -C 6 cycloalkyl substituted with one or more C 1 -C 6 alkyl. In one embodiment, R 21b is C 3 , C 4 , C 5 , or C 6 cycloalkyl substituted with one or more -CH 3 .
  • R 21b is , In another embodiment, R 21b is C 3 -C 6 cycloalkyl substituted with one or more C 1 -C 6 alkyl and one or more -OH. In one embodiment, R 21b is C 3 , C 4 , C 5 , or C 6 cycloalkyl substituted with one or more -CH 3 and one or more -OH. In one embodiment, R 21b is . In another embodiment, R 21b is C 3 -C 6 cycloalkyl substituted with one or more halogen. In one embodiment, R 21b is C 3 , C 4 , C 5 , or C 6 cycloalkyl substituted with one or more F.
  • R 21b is In another embodiment, R 21b is unsubstituted C 3 -C 9 heterocyclyl. In one embodiment, R 21b is unsubstituted C 3 , C 4 , or C 5 heterocyclyl comprising one oxygen. In one embodiment, R 21b is , , or . In one embodiment, R 21b is unsubstituted C 3 , C 4 , or C 5 heterocyclyl comprising one nitrogen. In one embodiment, R 21b is . In one embodiment, R 21b is unsubstituted C 3 , C 4 , or C 5 heterocyclyl comprising one oxygen and one nitrogen. In one embodiment, R 21b is .
  • R 21b is C 3 -C 9 heterocyclyl substituted with one or more substituents selected from C 1 -C 6 alkyl, halogen, and -OH. In one embodiment, R 21b is C 3 , C 4 , or C 5 heterocyclyl substituted with one or more C 1 -C 6 alkyl. In one embodiment, R 21b is C 3 , C 4 , or C 5 heterocyclyl substituted with one or more -CH 3 . In one embodiment, R 21b is C 3 , C 4 , or C 5 heterocyclyl comprising one nitrogen and substituted with one or more -CH 3 .
  • R 21b is C 7 , C 8 , C 9 , C 10 , or C 11 spiro-fused cycloalkyl. In one embodiment, R 21b is In another embodiment, R 21b is C 5 -C 10 spiro-fused heterocyclyl. In one embodiment, R 21b is C 6 , C 7 , C 8 , C 9, or C 10 spiro-fused heterocyclyl. In one embodiment, R 21b is C 6 , C 7 , C 8 , C 9, or C 10 spiro-fused heterocyclyl comprising one oxygen.
  • R 21b is In one embodiment, R 21b is C 6 , C 7 , C 8 , C 9, or C 10 spiro-fused heterocyclyl comprising one nitrogen. In one embodiment, R 21b is In one embodiment, R 21b is C 6 , C 7 , C 8 , C 9 , or C 10 spiro-fused heterocyclyl comprising one oxygen and one nitrogen. In one embodiment, R 21b In one embodiment in Formula (IIb-2N), A is N, E is CR 23b , and G is CR 24b . In one embodiment, A is N, R 23b is H, and R 24b is H. In one embodiment, A is N, R 23b is halogen, and R 24b is H.
  • A is N, R 23b is F, and R 24b is H. In one embodiment, A is N, R 23b is H, and R 24b is halogen. In one embodiment, A is N, R 23b is H, and R 24b is F. In one embodiment, A is N, R 23b is CN, and R 24b is H. In one embodiment, A is N, R 23b is H, and R 24b is CN. In one embodiment in Formula (IIb-2N), A is CR 22b , E is N, and G is CR 24b . In one embodiment, E is N, R 22b is H, and R 24b is H. In one embodiment, E is N, R 22b is halogen, and R 24b is H.
  • E is N, R 22b is F, and R 24b is H. In one embodiment, E is N, R 22b is H, and R 24b is halogen. In one embodiment, E is N, R 22b is H, and R 24b is F. In one embodiment, E is N, R 22b is halogen, and R 24b is halogen. In one embodiment, E is N, R 22b is F, and R 24b is F. In one embodiment, E is N, R 22b is CN, and R 24b is H. In one embodiment, E is N, R 22b is H, and R 24b is CN. In one embodiment, E is N, R 22b is CN, and R 24b is CN. In one embodiment, E is N, R 22b is CN, and R 24b is CN.
  • A is CR 22b
  • E is CR 23b
  • G is N.
  • G is N, R 22b is H, and R 23b is H.
  • G is N, R 22b is halogen, and R 23b is H.
  • G is N, R 22b is F, and R 23b is H.
  • G is N, R 22b is H, and R 23b is halogen.
  • G is N, R 22b is H, and R 23b is F.
  • G is N, R 22b is CN, and R 23b is H.
  • G is N, R 22b is H, and R 23b is CN.
  • R 25b , R 25b’ , R 27b , R 27b’ , R 28b , R 28b ,, R 29b , and R 29b’ are each H.
  • each of R 25b , R 25b’ , R 27b , R 27b’ , R 29b , and R 29b’ is H and R 28b and/or R 28b , is halogen.
  • each of R 25b , R 25b’ , R 27b , R 27b’ , R 28b , R 29b , and R 29b’ is H and R 28b’ is F.
  • each of R 25b , R 25b’ , R 27b , R 27b’ , R 29b , and R 29b’ is H and each of R 28b and R 28b , is F.
  • R 25b , R 25b’ , R 27b , R 27b’ , R 29b , and R 29b’ is H and R 28b and/or R 28b , is C 1 -C 6 alkyl.
  • each of R 25b , R 25b’ , R 27b , R 27b’ , R 29b , and R 29b’ is H and each of R 28b and R 28b’ is -CH 3 .
  • each of R 25b , R 25b’ , R 27b , R 27b’ , R 28b, R 29b , and R 29b’ is H and R 28b’ is -CH 3 .
  • the compound of Formula (IIb-2N) has one or more stereocenters. In one embodiment, the compound of Formula (IIb-2N) comprises a stereocenter where the moiety connects to the remaining portion of Formula (IIb-2N).
  • the compound of Formula (IIb-2N) comprises a stereocenter at one or more of R 25b , R 25b’ , R 26b , R 26b’ , R 27b , R 27b’ , R 28b , R 28b’ , R 29b , and R 29b’ .
  • the compound of Formula (IIb-2N) is selected from:
  • the compound of Formula (IIb-2N) is selected from:
  • R 6 of Formula (I) or Formula (I-5013-2N) is (Ib).
  • R 6 is (Ib) and 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 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 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, wherein 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.
  • 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 compound is a compound of Formula (I) wherein one of A, E, or G is N and the compound comprises an R 6 of (Ib) or the compound is a compound Formula (I- 5013-2N) comprising an R 6 of (Ib) and the compound has a structure according to any of Formula (IIIa-2N)-(IIIp-2N), as follows:
  • the compounds of Formula (I), Formula (I-5013), or Formula (I- 5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N) are IRAK inhibitors.
  • the compounds of Formula (I), Formula (I-5013), or Formula (I-5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N), are IRAK1, IRAK4, IRAK1/4, and/or FLT3 inhibitors.
  • the compounds of Formula (I), Formula (I-5013), or Formula (I- 5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N), are IRAK1/4, panFLT3 inhibitors.
  • the compounds of Formula (I), Formula (I-5013), or Formula (I- 5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N), can be any of those specified in Tables 1-10 herein, such as Compounds 1-24 and Compounds 1a-15a, as described in Examples 1-12.
  • one or more of R 3 , R 4 , R 5 is not H and is a substituent as defined elsewhere herein.
  • one or more small substituents on the pyridine ring decreases the activity of the compound of Formula (I), Formula (I-5013), or Formula (I-5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N) at off target kinases, increases the permeability of the compound of Formula (I), Formula (I-5013), or Formula (I-5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)- (IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N) into cells, and/or results in improved pharmacokinetic data of the compound of Formula (I), Formula (I-5013), or Formula (I-5013-2N), such as compounds of Formula (IIa
  • the “small substituent” comprises a halogen atom.
  • the halogen atom is fluorine.
  • the compound of Formula (I), Formula (I-5013), or Formula (I-5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N) shows decreased on target potency.
  • alkyl substituents such as -CH 3
  • alkoxy substituents such as -OCH 3
  • the compound of Formula (I), Formula (I-5013), or Formula (I-5013- 2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa- 2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N) comprises a stereocenter where the amine NH bonds to R 6 .
  • the compound of Formula (I), Formula (I-5013), or Formula (I-5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N) comprises one substituent on R 6 .
  • the amine NH is trans to the one R 6 substituent.
  • the amine NH is cis to the one R 6 substituent.
  • the compound of Formula (I), Formula (I-5013), or Formula (I-5013-2N such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa- 2N)-(IIIp-2N) wherein the amine NH is trans to the one R 6 substituent is a more potent inhibitor of interleukin-1 receptor-associated kinase (IRAK) and/or fms-like tyrosine kinase 3 (FLT3) compared to the same compound of Formula (I) wherein the amine NH is cis to the one R 6 substituent.
  • IRAK interleukin-1 receptor-associated kinase
  • FLT3 fms-like tyrosine kinase 3
  • the compounds of Formula (I), Formula (I-5013), or Formula (I- 5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N), 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).
  • 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.
  • the compounds of the disclosure having a chiral center and can exist in and be isolated in optically active and racemic forms.
  • 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.
  • 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.
  • 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.
  • 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.
  • compounds 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 compounds disclosed herein can exist in unsolvated forms as well as solvated forms, including hydrated forms.
  • 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
  • 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.
  • Some embodiments of the present disclosure include methods for the preparation of compounds of Formula (I), Formula (I-5013), or Formula (I-5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N).
  • a compound of Formula (I), Formula (I- 5013), or Formula (I-5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N) can be prepared comprising one or more of the steps set forth in Examples 1-12 herein.
  • the synthetic routes shown and described in Examples 1-12 can, for example, be used to prepare Compounds 1-24, Compounds 1a-15a as set forth in Tables 1-12 and structurally related compounds.
  • compositions and Formulations in one embodiment, further relates to a composition comprising a compound of Formula (I), Formula (I-5013), or Formula (I-5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N), and a composition comprising a therapeutic agent.
  • a composition comprising a compound of Formula (I), Formula (I-5013), or Formula (I-5013-2N
  • compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N a composition comprising a therapeutic agent.
  • exemplary therapeutic agents are described elsewhere herein.
  • the compound of Formula (I), Formula (I-5013), or Formula (I-5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa- 2N)-(IIIp-2N), and the therapeutic agent are co-formulated into a single composition.
  • the compound of Formula (I), Formula (I-5013), or Formula (I-5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N), and the therapeutic agent are administered together in one administration or composition.
  • the compound of Formula (I), Formula (I-5013), or Formula (I-5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N), 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), Formula (I-5013), or Formula (I-5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N), and the composition comprising the therapeutic agent are administered to a subject at the same time.
  • composition comprising the compound of Formula (I), Formula (I- 5013), or Formula (I-5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N), and the composition comprising the therapeutic agent are administered to a subject sequentially.
  • the composition comprising the compound of Formula (I), Formula (I-5013), or Formula (I-5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N), 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.
  • compositions comprising one or more compounds of the disclosure (e.g., Formula (I), Formula (I-5013), or Formula (I-5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N)).
  • 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.).
  • 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 Formula (I), Formula (I- 5013), or Formula (I-5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N), as disclosed herein, a compound as set forth in Tables 1-12, 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 1-12 herein.
  • 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.
  • salts examples 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.
  • 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 -NHSO 3 H, -COOH and -P(O)(OH) 2
  • Basic groups such as amino or basic heteroaryl radicals, or pyridyl and acidic salts, such as hydrochloride, hydrobromide, acetate, maleate, pamoate, 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
  • 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, a 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.
  • compositions 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 corn 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.
  • inert diluents such as calcium carbonate, lactose, calcium phosphate, carboxymethylcellulose, or sodium phosphate
  • granulating and disintegrating agents such as corn starch or alginic acid
  • binding agents such as starch, gelatin or acacia
  • 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.
  • 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.
  • 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.
  • 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.
  • Preservatives include antimicrobial, anti-oxidants, chelating agents and inert gases.
  • compositions 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 a 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 monoole
  • 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.
  • 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.
  • 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 (e.g.,
  • compositions can be formulated to release the active ingredient (e.g., one or more compounds of the disclosure such as Formula (I), Formula (I- 5013), or Formula (I-5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N)) 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), Formula (I- 5013), or Formula (I-5013-2N
  • 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.
  • 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.
  • various pharmaceutical compositions useful for ameliorating certain diseases and disorders are provided.
  • 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.
  • 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. Methods of Treating and Preventing Disease In addition to their ability to inhibit IRAK, IRAK inhibitors have been demonstrated to have selectivity for multiple kinases.
  • compounds described herein according to Formula (I), Formula (I-5013), or Formula (I-5013-2N such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N), such as Compounds 1-24 or Compounds 1a-15a as listed in Tables 1-12, exhibit have inhibitory action against one or more kinase, such as interleukin-1 receptor- associated kinase (IRAK) and FMS-like tyrosine kinase 3 (FLT3).
  • 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), Formula (I-5013), or Formula (I-5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N)) 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 (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, IRAK1 (interleukin-1 receptor associated kinase 1), isoforms of IRAK1, and/or mutations of IRAK1.
  • FLT3, mutations of FLT3 e.g., mutations in the juxtamembrane region of FLT3, mutations in the kinase domain of FLT3, FLT3 point
  • 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, IRAK1, isoforms of IRAK1, or mutations of IRAK1.
  • 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 IRAK1, or an isoform or mutation thereof.
  • 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 F
  • the compounds of the disclosure can inhibit FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1.
  • 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), Formula (I-5013), or Formula (I-5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N))) 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.
  • hematopoietic cancers that can be treated include, but are not limited to, MDS, AML, lymphoma, leukemia, 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 e.g., bone marrow cancer
  • non-Hodgkin lymphoma Waldenstrom’s macroglobulinemia
  • B cell lymphoma e.g. ABC DLBCL with MYD88 mutation (e.g., L265P)
  • follicular lymphoma e.g., or marginal zone lymphoma, or combinations thereof.
  • 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 over active IRAK1 and/or IRAK4.
  • compounds of the present disclosure can be used to inhibit over active IRAK1 and/or IRAK4 in conditions such as inflammatory diseases and autoimmune disease, wherein said inflammatory diseases and autoimmune diseases are characterized by over active IRAK1 and/or IRAK4.
  • inflammatory and autoimmune diseases characterized by dysregulated (e.g., hyperactive) IRAK expression (IRAK1 and/or IRAK4) and/or IRAK-mediated intracellular signaling can be treated, and include, but are not limited to, chronic inflammation (i.e., associated with viral and bacterial infection), sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’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
  • systemic lupus erythematosus inflammatory bowel disease
  • multiple sclerosis psoriasis
  • Sjögren’s syndrome Ankylosing spondylitis
  • systemic 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), Formula (I-5013), or Formula (I- 5013-2N)
  • MDS with a splicing factor mutation MDS with a mutation in isocitrate dehydrogenase 1
  • refractory cytopenia with unilineage dysplasia e.g., refractory anemia, refractory neutropenia
  • unilineage 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 dehydrogen
  • 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. In some instances, the subject is in need of the treatment (e.g., by showing signs of disease or MDS, 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), Formula (I-5013), or Formula (I- 5013-2N
  • 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 IRAK1 (or its mutations), or MDS that can be treated by inhibiting IRAK4 (or its mutations) and IRAK1 (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, IRAK1, or both IRAK4 and IRAK1.
  • inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1 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.
  • 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), Formula (I-5013), or Formula (I- 5013-2N)
  • MLL chromosome 9 and 11
  • 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), IRAK1 (e.g., using IRAK 1 inhibitors), and/or mutations of IRAK1 (e.g., using inhibitors of IRAK1 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
  • IRAK1 e.g., using IRAK 1 inhibitors
  • IRAK1 e.
  • 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 IRAK1 (or its mutations), or AML that can be treated by inhibiting IRAK4 (or its mutations) and IRAK1 (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, IRAK1, or both IRAK4 and IRAK1.
  • inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1 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.
  • 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
  • hematopoietic cancers that can be treated include, but are not limited to cancers that can be treated by inhibiting (e.g., reducing the activity or expression of) FLT3 (or its mutations) and IRAK4 (or its mutations), hematopoietic cancers that can be treated by inhibiting (e.g., reducing the activity or expression of) FLT3 (or its mutations) and IRAK1 (or its mutations), or hematopoietic cancers that can be treated by inhibiting (e.g., reducing the activity or expression of) FLT3 (or its mutations), IRAK4 (or its isoforms or mutations), and IRAK1 (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, IRAK1, or both IRAK4 and IRAK1.
  • inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1 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, IRAK1, or both IRAK4 and IRAK1.
  • inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1 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.
  • inflammatory and autoimmune diseases characterized by dysregulated (e.g., hyperactive) IRAK expression (IRAK1 and/or IRAK4) and/or IRAK- mediated intracellular signaling that can be treated include, but are not limited to, chronic inflammation (i.e., associated with viral and bacterial infection), sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’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, IRAK1, or both IRAK4 and IRAK1.
  • chronic inflammation i.e., associated with viral and bacterial infection
  • sepsis rheumatoid arthritis
  • systemic lupus erythematosus inflammatory bowel disease
  • multiple sclerosis
  • inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1 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.
  • 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.
  • 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
  • treating does not include prophylactic treatment of MDS (e.g., preventing or ameliorating future MDS).
  • MDS e.g., preventing or ameliorating future MDS.
  • hematopoietic cancer e.g., acute myeloid leukemia, lymphoma, leukemia, 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.
  • hematopoietic cancer e.g., acute myeloid leukemia, lymphoma, leukemia, bone marrow cancer, non-Hodgkin lymphoma, or Waldenstrom’s
  • treatment can include, but is not limited to: preventing cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, 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, 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
  • 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), Formula (I-5013), or Formula (I-5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp- 2N)).
  • methods of treatment comprise treating an animal 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).
  • 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 for a hematopoietic cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, bone marrow 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, bone marrow 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,
  • 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), Formula (I-5013), or Formula (I-5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N)) (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 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), Formula (I-5013), or Formula (I-5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N)).
  • a composition comprising a compound of the disclosure (e.g., Formula (I), Formula (I-5013), or Formula (I-5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N)).
  • 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, 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.
  • MDS such as but not limited to MDS (e.g., MDS with a splicing factor mutation,
  • 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), Formula (I-5013), or Formula (I-5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N), such as but not limited to Compounds 1-24 or Compounds 1a-15a as listed in Tables 1-12) (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
  • 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), Formula (I-5013), or Formula (I- 5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N), such as but not limited to Compounds 1-24 or Compounds 1a-15a as listed in Tables 1-12) (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/
  • an effective amount of at least one compound of the disclosure e.g., Formula (I), Formula (I-5013), or Formula (I-5013-2N
  • compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N) 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/
  • 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), Formula (I-5013), or Formula (I-5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N), such as but not limited to Compounds 1-24 or Compounds 1a-15a as listed in Tables 1-12) (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
  • 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), Formula (I-5013), or Formula (I- 5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N)
  • a compound of the disclosure e.g., Formula (I), Formula (I-5013), or Formula (I-5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N)
  • 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 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.
  • the compounds of Formula (I), Formula (I-5013), or Formula (I-5013- 2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa- 2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N), 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.
  • 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 (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, a steroid or glucocorticoid, a glucocorticoid receptor modulator, or EZH2 inhibitor, and the like, or
  • 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.
  • 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.
  • 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.
  • the ribonucleotide reductase inhibitor is gemcitabine.
  • the therapeutic agent comprises an adenosine deaminase inhibitor.
  • the adenosine deaminase inhibitor is cladribine.
  • the therapeutic agent comprises a Mek 1/2 inhibitor. In one embodiment, the Mek 1/2 inhibitor is trametinib.
  • 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.
  • 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, WO
  • the CDK inhibitor comprises an inhibitor described in: Alsfouk, A., Journal of Enzyme Inhibition and Medicinal Chemistry, 2021, 36(1):693-706; Goel, B. et al., Curr. Top. Med. Chem., 2020, 20(17):1535-1563; Heptinstall, A. B. et al., Future Med. Chem., 2018, 10(11):1369-1388; Sánchez-Mart ⁇ nez, 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.
  • 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; wherein R1 is wherein R is H or -CH 3 ; wherein R is -CH 3 and X is F, R is H and X is F, or R is -CH 3 and X is Cl; wherein 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; wherein R is t-butyl carboxyl and n is 1 or R is H and n is 2;
  • X is NH or O; wherein R is H and R’ is F, R is F and R’ is F, or R is H and 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-1yl and R’ is F or R is phenyl and R’ is -CH 3 ; wherein R is H or F and Alkyl is -CH 3 or -CH 2 CH 3 ; wherein R is 3-fluorophenyl or morpholin-4yl; wherein R is cyclopropan-1-ol-1-yl, X is Cl, and n is 1 or R is t
  • 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.
  • 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.
  • a concentration of an exemplary IRAK inhibitor was combined with venetoclax, the potency of venetoclax was increased by an unexpectedly high ⁇ 50-fold.
  • 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.
  • 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 IC 50 .
  • 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, S1, 2-methoxy antimycin A3, gossypol, AT-101, apogossypol, WEHI- 539, A-1155463, BXI-61, BXI-72, TW37, MIM1, UMI-77, and the like, and combinations thereof.
  • BCL2 inhibitor selected from ABT-263 (Navitoclax), ABT-737, ABT-199 (venetoclax), GDC-0199, GX15-070 (Obatoclax) (all available from Abbott Laboratories), HA14-1, S1, 2-methoxy antimycin A3, gossypol, AT-101, apogossypol, WEHI- 539, A-1155463,
  • 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.
  • 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 6-29, 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 inhibitors, 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, azacytidine, decitabine, cytarabine (ara- C; cytosine arabinoside), 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 (HDAC) inhibitor, such as, for example, vorinostat, panobinostat, valproic acid, and/or pracinostat, and the like; a purine nucleoside analogue (antimetabolite), such as, for example, fluor flu
  • Anti-CD70 e.g. ARGX-110, cusatuzumab
  • a bispecific antibody e.g. floteuzumab (CD123 x CD3)
  • Anti-CTLA4 e.g. ipilimumab
  • Anti-PD1/PDL1 e.g.
  • nivolumab nivolumab, pembrolizumab, atezolizumab, avelumab, PDR001, MBG453), and/or Anti-CD47 (e.g.5F9 (Magrolimab, for more information see Sallman, D. A.
  • 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 CDK inhibitor such as Alvociclib, Atuveciclib, Palbociclib, Ribociclib, and/or Zotiraciclib
  • a CDK9 inhibitor such as, for example, alvocidib, Bay 1143572, Dinaciclib (SCH 727965), SNS-032 (BMS-387032), TG02, CDKI-73 (LS-007), LY2857785, and/or voruciclib, and the like (for more information on CDK9 inhibitors, see Boffo, S.
  • 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 RAR ⁇ agonist), Tamibarotene, Adapalene, Bexarotene, and the like
  • a TP53 activator including a nonfunctional mutant TP53 reactivator
  • APR-246 Eprenetapopt; for more information, see Ceder, S. et al., EMBO Mol.
  • a CELMoD such as Lenalidomide, Pomalidomide, CC-92480, CC-90009, Avadomide, and/or Iberdomide
  • 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 (for more information, see Sullivan, R. J.
  • a PI3K inhibitor such as, for example, copanlisib, gedatolisib, pictilisib, fimepinostat (CUDC-907), alpelisib, leniolisib (CDZ-173), pilaralisib (XL147, SAR245408), and/or bimiralisib (PQR-309), and the like; an mTOR inhibitor, such as, for example, onatasertib, sirolimus, temsirolimus, bimiralisib (PQR-309), sapanisertib (TAK- 228, INK-128), ridaforolimus (MK-8669, AP-23573), everolimus, and
  • compounds and pharmaceutical compositions including the same can be used in prevention of secondary malignancies when used in combination with an EZH2 inhibitor.
  • the compounds and/or compositions described herein can be used together with, or in combination with, a hedgehog (Hh) inhibitor, such as Daurismo (glasdegib maleate, for more information see Wolska-Washer, A.
  • Hh hedgehog
  • Topoisomerase I inhibitor such as Topotecan and/or Irinotecan
  • Topoisomerase II inhibitor such as Mitoxantrone, Doxorubicin, and/or Daunorubicin
  • aminopeptidase/Leukotriene A4 hydrolase inhibitor such as Bestatin (Ubenimex, for more information, see Hitzerd, S. M.
  • a FLT3/Axl/ALK inhibitor such as Xospata (Gilteritinib, for more information, see Dhillon, S., Drugs, 2019, 79:331-339, which is incorporated herein by reference) and/or ASP2215
  • a FLT3/KIT/PDGFR, PKC, and/or KDR inhibitor such as Rydapt (Midostaurin, for more information, see Sheridan, C., Nature Biotechnology, 2017, 35:696-698, which is incorporated herein by reference)
  • a Syk inhibitor such as fostamatinib (R788), entospletinib (GS-9973, for more information, see Walker, A.
  • cerdulatinib PRT062070
  • TAK-659 an E-selectin inhibitor such as Uproleselan (for more information, see Barbier, V. et al., Nature Commun., 2020, 11:2042); an NEDD8-activator such as Pevonedistat (for more information, see Swords, R. T. et al., British J. Haematology, 2015, 169: 534-543, which is incorporated by reference herein); an MDM2 inhibitor such as idasanutlin (for more information, see Lehmann, C.
  • MLN8054 MLN8054, TAS-119, and/or erbumine (LY3295668)
  • aurora kinase inhibitor such as Alisertib, Danusertib, Barasertib, and/or Ilorasertib
  • EGFR inhibitor such as Erlotinib, Dacomitinib, and/or Varlitinib
  • AuroraB/C/VEGFR1/2/3/FLT3/CSF- 1R/Kit/PDGFRA/B inhibitor such as Ilorasertib (ABT-348; for more information, see Garcia- Manero, G.
  • AKT 1, 2, and/or 3 inhibitor such as Uprosertib (for more information, see Darici, S. et al., J. Clin.
  • Afuresertib (GSK2110183), CCT128930, Miransertib (ARQ 092), Capivasertib (AZD5363), GSK690693, Ipatasertib (GDC-0068), BAY1125976, and/or Oridonin (NSC-250682); a ABL1/2/SRC/EPHA2/LCK/YES1/KIT/PDGFRB/FYN inhibitor such as Dasatinib; a farnesyltransferase inhibitor such as tipifarnib (for more information, see Epling-Burnette, P. K.
  • the compounds and/or compositions described herein are used in one or more administrations, together with or in combination with Lenalidomide which is a highly effective treatment for myelodysplastic syndrome (MDS) with deletion of chromosome 5q (del(5q)).
  • MDS myelodysplastic syndrome
  • Lenalidomide induces the ubiquitination of casein kinase 1A1 (CK1 ⁇ ) by the E3 ubiquitin ligase CUL4–RBX1–DDB1–CRBN (known as CRL4CRBN), resulting in CK1 ⁇ degradation.
  • CK1 ⁇ is encoded by a gene within the common deleted region for del(5q) MDS and haploinsufficient expression sensitizes cells to lenalidomide therapy, providing a mechanistic basis for the therapeutic window of lenalidomide in del(5q) MDS.
  • the compounds and/or compositions described herein are used in one or more administrations, together with or in combination with Cytarabine (ara-C, cytosine arabinoside), which has been used for the treatment of acute myeloid leukemia (AML) for more than three decades. It was initially used in remission-induction therapy at a dose of 100 to 200 mg per square meter of body-surface area. From about 1975 to 1985, investigators began evaluating the use of high-dose cytarabine therapy, given in a dose of 3000 mg per square meter twice daily for 6 days. In single-group studies, high response rates were noted among patients with relapse and promising results were reported for those with a new diagnosis of AML.
  • Cytarabine ara-C, cytosine arabinoside
  • the compounds and/or compositions described herein are used in one or more administrations, together with or in combination with a hypomethylating agent such as Azacitidine, Decitabine and/or Venclexta.
  • a hypomethylating agent such as Azacitidine, Decitabine and/or Venclexta.
  • DNA methylation is the modification of DNA nucleotides by addition of a methyl group.
  • a hypomethylating agent or demethylating agent is a drug that inhibits DNA methylation.
  • hypomethylating agents are considered a type of epigenetic therapy.
  • Currently available hypomethylating agents block the activity of DNA methyltransferase (DNA methyltransferase inhibitors / DNMT inhibitors).
  • Two members of the class, azacitidine and decitabine are FDA-approved for use in the United States in myelodysplastic syndrome.
  • Azacitidine marketed as Vidaza, is used mainly in the treatment of myelodysplastic syndrome, for which it received approval by the U.S. Food and Drug Administration (FDA) on May 19, 2004.
  • Venclexta is a selective small- molecule inhibitor of BCL-2, an antiapoptotic protein.
  • BCL-2 inhibitors such as Venclexta facilitate apoptosis by binding directly to the BCL-2 protein, displacing proapoptotic proteins, and triggering mitochondrial outer-membrane permeabilization and caspase activation.
  • the compounds and/or compositions described herein are used in one or more administrations, together with or in combination with an anti- CD47 Monoclonal Antibody such as Magrolimab.
  • Magrolimab is a first-in-class investigational monoclonal antibody against CD47 and macrophage checkpoint inhibitor which is being developed in several hematologic and solid tumor malignancies, including MDS. Magrolimab has been granted Fast Track Designation by the FDA for the treatment of MDS, AML, diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma.
  • the compounds and/or compositions described herein are used in one or more administrations, together with or in combination with an SYK inhibitor such as Entospletinib.
  • Spleen tyrosine kinase is a nonreceptor cytoplasmic tyrosine kinase primarily expressed in cells of hematopoietic lineage.
  • Constitutive activation of SYK in AML has been reported and targeted inhibition of SYK induced differentiation in vitro and demonstrated anti-leukemia activity in AML mouse models.
  • SYK has also been shown to directly phosphorylate the FLT3 receptor, modulating its activation and possibly promoting its role in leukemogenesis.
  • Entospletinib is an orally bioavailable, selective inhibitor of SYK shown to be clinically active in B-cell malignancies.
  • the compounds and/or compositions described herein are used in one or more administrations, together with or in combination with an E-selectin inhibitor such as Uproleselan.
  • E-selectin directly triggers signaling pathways that promote malignant cell survival and regeneration.
  • AML blasts release inflammatory mediators that upregulate endothelial niche E-selectin expression. Alterations in cell-surface glycosylation associated with oncogenesis enhances AML blast binding to E-selectin and enable promotion of pro-survival signaling through AKT/NF- ⁇ B pathways.
  • CDK9 inhibitors are nonselective, predictive biomarkers that may help identify patients most likely to respond to CDK9 inhibitors are now being utilized, with the goal of improving efficacy and safety.
  • Alvocidib is a multi-serine threonine cyclin-dependent kinase inhibitor with demonstrable in vitro and clinical activity in AML when combined in a timed sequential chemotherapy regimen.
  • the compounds and/or compositions described herein are used in one or more administrations, together with or in combination with a Menin-KMT2A (MLL) inhibitor such as Ko-539 and/or SNDX-5613.
  • MLL Menin-KMT2A
  • MN1 Meningioma-1
  • KMT2A-r KMT2A-rearranged leukemia
  • Menin (Men1) is also critical for the self-renewal of MN1-driven AML through the maintenance of a distinct gene expression program.
  • Men1 led to a decrease in the number of functional leukemia-initiating cells.
  • Pharmacologic inhibition of the KMT2A–Menin interaction has been shown to decrease colony-forming activity, induce differentiation programs in MN1-driven murine leukemia, and decrease leukemic burden in a human AML xenograft.
  • Menin inhibition as a promising therapeutic strategy in MN1-driven leukemia.
  • a phase 2 clinical trial of SNDX-5613 will recruit patients according to disease and molecular genetics (MLLr AML, NPM1c AML, or MLLr acute lymphoid leukemia) while KO-539 is recruiting patients for a phase 1 study for relapsed/refractory AML.
  • the compounds and/or compositions described herein are used in one or more administrations, together with or in combination with a nonfunctional mutant TP53 reactivator such as Eprenetapopt (APR-246).
  • TP53 gene mutations are detected in approximately 10%-20% of patients with de novo myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) and 30%-40% of patients with therapy-related disease. Treatment outcomes for patients with TP53 mutations are poor with available therapies.
  • Hypomethylating agents such as azacitidine and decitabine, yield statistically similar complete remission (CR) rates of approximately 15%-20% in patients with either TP53-mutant or wild-type MDS.
  • OS median overall survival
  • Eprenetapopt APR-246 is converted to methylene quinuclidinone (MQ) that targets mutant p53 protein and perturbs cellular antioxidant balance.
  • MQ methylene quinuclidinone
  • 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
  • the therapeutic agent has a chiral center and can exist in and be isolated in optically active and racemic forms.
  • 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.
  • 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).
  • 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 therapeutic agent disclosed herein can exist in unsolvated forms as well as solvated forms, including hydrated forms.
  • 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.
  • Further therapies are described below and are contemplated in combination therapies in the context of the present disclosure. Chemotherapy / Targeted Therapy / Alternative Therapy 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)), Antiitor (Everolimus), Adjustitor Disperz (Everolimus), alimta (PEMETREXED), alkeran Injection (Melphalan Injection), alkeran Tablets (Melphalan), aredia (Pamidronate), arimidex (Anastrozole), aromasin (Exemestane), arranon (Nelarabine), ar
  • approved targeted therapies include ado-trastuzumab emtansine (Kadcyla), afatinib (Gilotrif), aldesleukin (Proleukin), alectinib (Alecensa), alemtuzumab (Campath), axitinib (Inlyta), bosutinib (Bosulif), brentuximab vedotin (Adcetris), cabozantinib (Cabometyx [tablet], Cometriq [capsule]), canakinumab (Ilaris), carfilzomib (Kyprolis), ceritinib (Zykadia), cetuximab (Erbitux), cobimetinib (Cotellic), crizotinib (Xalkori), dabrafenib (Tafinlar), daratumumab (Darzalex), dasatinib
  • the approved chemotherapy is an anthracycline, such as Doxorubicen, Daunarubicin, Epirubicin, and/or Idarubicin.
  • the approved chemotherapy is selected from Azacitidine (for more information, see Keating, G. M., Drugs, 2012, 72:1111–1136, which is incorporated herein by reference), Venclexta (for more information, see Raedler, L. A., Journal of Hematology Oncology Pharmacy, 2017, 7:53-55, which is incorporated herein by reference)
  • Azacitidine for more information, see Keating, G. M., Drugs, 2012, 72:1111–1136, which is incorporated herein by reference
  • Venclexta for more information, see Raedler, L. A., Journal of Hematology Oncology Pharmacy, 2017, 7:53-55, which is incorporated herein by reference
  • 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
  • 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.
  • 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.
  • 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
  • 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 In addition to chemotherapies, targeted therapies, alternative therapies, and immunotherapies, cancer can additionally be treated by other strategies.
  • compositions of the disclosure can include methods of administering or treating an animal, which can involve treatment with an amount of at least one compound of the disclosure (e.g., Formula (I), Formula (I-5013), or Formula (I-5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N)) 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.
  • a compound of the disclosure e.g., Formula (I), Formula (I-5013), or Formula (I-5013-2N
  • the composition or pharmaceutical composition comprises at least one compound of the disclosure (e.g., Formula (I), Formula (I-5013), or Formula (I-5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N)) 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
  • an animal
  • 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., 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, preferably about 1-10 nM, 10-100 nM, or 0.1-1 ⁇ M.
  • the compounds and/or pharmaceutical compounds of the disclosure e.g., compounds of Formula (I), Formula (I-5013), or Formula (I-5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N), and pharmaceutical compositions including the same
  • compounds of Formula (I), Formula (I-5013), or Formula (I-5013-2N such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N)
  • pharmaceutical compositions including the same 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. 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.
  • 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.
  • 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.
  • animal models can be used to determine effective dosages for treatment of particular disorders.
  • 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.
  • the parenteral dosage in mg/mL times 1.8 the corresponding oral dosage in milligrams (“mg”).
  • 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, 5th Ed., (W. B. Saunders Co.), pp.1708 and 1651.
  • 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.
  • 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), Formula (I-5013), or Formula (I-5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N), 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.
  • composition can, if desired, also contain other compatible therapeutic agents.
  • the compounds of the disclosure e.g., compounds according to Formula (I), Formula (I- 5013), or Formula (I-5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N)
  • the compounds of the disclosure e.g., Formula (I), Formula (I-5013), or Formula (I-5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N)) 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 e.g., Formula (I), Formula (I-5013), or Formula (I-5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N)
  • 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.
  • 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, the particular disease (e.g., cancer or MDS), and the severity of the disease (e.g., stage or severity of cancer or MDS).
  • diseases e.g., cancer or MDS
  • the severity of the disease e.g., stage or severity of cancer or MDS
  • 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), Formula (I- 5013), or Formula (I-5013-2N), such as compounds of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N)) 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 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.
  • Toxicity The ratio between toxicity and therapeutic effect for a particular compound is its therapeutic index and can be expressed as the ratio between LD 50 (the amount of compound lethal in 50% of the population) and ED50 (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.
  • Clause 2 The compound of clause 1, wherein the compound of Formula (I) is a compound of Formula (IIa): or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: A is N or CR 22a ; E is N or CR 23a ; G is N or CR 24a ; R 20a is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and -O-(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 -OH and halogen, and wherein C 3 -C 6 cycloalkyl and -O-(C 3 -C 6 cycloalkyl) are each optionally substituted with one or more substituents selected from C 1 -
  • Clause 3 The compound of clause 2, wherein R 20a is H.
  • Clause 4 The compound of clause 2, wherein R 20a is selected from halogen, unsubstituted C 1 -C 6 alkoxy, C 1 -C 6 alkoxy substituted with one or more F, unsubstituted C 3 -C 6 cycloalkyl, and unsubstituted -O-(C 3 -C 6 cycloalkyl).
  • Clause 5 The compound of clause 4, wherein R 20a is selected from Cl, -OCH 3 , , unsubstituted C cycloalkyl, and 3 .
  • Clause 6. The compound of any one of clauses 2-5, wherein R 21a is H.
  • Clause 8 The compound of clause 7, wherein R 21a is selected from is , -OCH 2 CH 3 , , unsubstituted C 3 cycloalkyl, unsubstituted C 4 cycloalkyl, unsubstituted C 5 cycloalkyl, unsubstituted C 6 cycloalkyl, and Clause 9.
  • A is N
  • E is CR 23a
  • G is CR 24a .
  • Clause 10 The compound of clause 9, wherein R 23a and R 24a are each H.
  • Clause 11 The compound of clause 9, wherein R 23a is H and R 24a is F; or R 23a is F and R 24a is H.
  • Clause 22 The compound of clause 21, wherein R 20b is H.
  • Clause 23 The compound of clause 21, wherein R 20b is selected from halogen, unsubstituted C 1 - C 6 alkoxy, C 1 -C 6 alkoxy substituted with one or more F, unsubstituted C 3 -C 6 cycloalkyl, and unsubstituted -O-(C 3 -C 6 cycloalkyl).
  • Clause 24 The compound of clause 23, wherein R 20b is selected from Cl, -OCH 3 , , unsubstituted C 3 cycloalkyl, and .
  • Clause 25 The compound of any one of clauses 21-24, wherein R 21b is H.
  • Clause 27 The compound of clause 26, wherein R 21b is selected from is , -OCH 2 CH 3 , unsubstituted C 3 cycloalkyl, unsubstituted C 4 cycloalkyl, unsubstituted C 5 cycloalkyl, unsubstituted C 6 cycloalkyl, and Clause 28.
  • Clause 30 The compound of clause 28, wherein R 23b is H and R 24b is F; or R 23b is F and R 24b is H. Clause 31.
  • Clause 41 The compound of any one of clauses 1-40, wherein the compound is an inhibitor of at least one of IRAK1, IRAK4, and FLT3.
  • Clause 42 The compound of any one of clauses 1-41, wherein the compound is an inhibitor of at least two of IRAK1, IRAK4, and FLT3.
  • Clause 43 The compound of any one of clauses 1-42, wherein the compound is an inhibitor of IRAK1 and IRAK4.
  • Clause 44. The compound of any one of clauses 1-42, wherein the compound is an inhibitor of IRAK1, IRAK4, and FLT3.
  • Clause 45 The compound of any one of clauses 41, 42, or 44, wherein FLT3 is selected from WT FLT3, activated FLT3, and mutated FLT3.
  • Clause 46 The compound of clause 45, wherein the mutated FLT3 is D835Y mutated FLT3 or F691L mutated FLT3.
  • Clause 47 A composition comprising a compound of any one of clauses 1-46, wherein the composition further comprises a formulary ingredient, an adjuvant, or a carrier.
  • composition of clause 47 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 sterol
  • Clause 49 The composition of clause 48, 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.
  • 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.
  • composition of clause 49 wherein the CDK inhibitor is a CDK4 inhibitor, a CDK6 inhibitor, a CDK7 inhibitor, and/or a CDK9 inhibitor.
  • 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.
  • a method of treating a disease or disorder in a subject comprising administering to the subject a therapeutically effective amount of a compound of any one of clauses 1-46 or a composition of any one of clauses 47-55.
  • Clause 57 The method of clause 56, wherein the method comprises administering to the subject a composition comprising the therapeutically effective amount of the compound of clause 1 and a formulary ingredient, an adjuvant, or a carrier.
  • Clause 58. The method of clause 56 or 57, wherein 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
  • any one of clauses 56-58 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 60 The method of any one of clauses 56-59, 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 61 The method of any one of clauses 56-60, wherein the disease or disorder comprises a hematopoietic cancer. Clause 62.
  • the disease or disorder comprises myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML).
  • MDS myelodysplastic syndrome
  • AML acute myeloid leukemia
  • Clause 63 The method of any one of clauses 56-60, 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.
  • 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 IRAK1 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, thyroid cancer, squamous cell carcinoma, neuroblastoma
  • Clause 65 The method of any one of clauses 56-60, wherein the disease or disorder comprises one or more inflammatory diseases or autoimmune disease selected from chronic inflammation, sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, or combinations thereof.
  • inflammatory diseases or autoimmune disease selected from chronic inflammation, sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, or combinations thereof.
  • 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. Clause 67.
  • the MDS with a splicing factor mutation comprises MDS with a splicing factor mutation in U2AF1 or SF3B1 and the AML splicing factor mutation comprises AML with a splicing factor mutation in U2AF1 or SF3B1.
  • 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.
  • any one of clauses 56-68 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 m
  • Clause 70 The method of any one of clauses 56-69, 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 71. The method of clause 70, 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.
  • Clause 72 The method of clause 71, wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof.
  • Clause 78 The method of any one of clauses 56-72, wherein the disease or disorder is venetoclax resistant refractory acute myeloid leukemia (AML).
  • Clause 79 The method of any one of clauses 56-72, wherein the disease or disorder is BCL2 inhibitor resistant relapsed acute myeloid leukemia (AML).
  • Clause 80 The method of any one of clauses 56-72 wherein the disease or disorder is venetoclax resistant relapsed acute myeloid leukemia (AML).
  • Clause 81 The method of clause 71, wherein the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof, wherein: R 1 is 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, -C( O)NR 31a R 31b , cycloalkyl, spiro-fused cycloalkyl, -O-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
  • Clause 202 The compound of clause 201, wherein the compound of Formula (I) is a compound of compound of Formula (IIa): or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R 20a is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and -O-(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 -OH and halogen, and wherein C 3 -C 6 cycloalkyl and -O-(C 3 -C 6 cycloalkyl) are each optionally substituted with one or more substituents selected from C 1 -C 6 alkyl and halogen; R 21a is selected from H, halogen, C 1
  • Clause 203 The compound of clause 202, wherein R 20a is H.
  • Clause 204 The compound of clause 202, wherein R 20a is selected from halogen, unsubstituted C 1 -C 6 alkoxy, C 1 -C 6 alkoxy substituted with one or more F, unsubstituted C 3 -C 6 cycloalkyl, and unsubstituted -O-(C 3 -C 6 cycloalkyl).
  • Clause 205 The compound of clause 204, wherein R 20a is selected from Cl, -OCH 3 , , unsubstituted C 3 cycloalkyl, and .
  • R 21a is H.
  • Clause 208 The compound of clause 207, wherein R 21a is selected from is , - OCH 2 CH 3 , unsubstituted C 3 cycloalkyl, unsubstituted C 4 cycloalkyl, unsubstituted C 5 cycloalkyl, unsubstituted C 6 cycloalkyl, , Clause 209.
  • R 22a , R 23a , and R 24a are each H.
  • R 22b , R 23b , and R 24b are each independently selected from H and halogen;
  • R 25b , R 25b ' , R 26b , R 26b ’ , R 27b , R 27b ' , R 28b , R 28b ' , R 29b , and R 29b’ 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 216 The compound of clause 214, wherein R 20b is selected from halogen, unsubstituted C 1 -C 6 alkoxy, C 1 -C 6 alkoxy substituted with one or more F, unsubstituted C 3 -C 6 cycloalkyl, and unsubstituted -O-(C 3 -C 6 cycloalkyl).
  • Clause 220 The compound of clause 219, wherein R 21b is selected from is , - OCH 2 CH 3 , unsubstituted C 3 cycloalkyl, unsubstituted C 4 cycloalkyl, unsubstituted C 5 cycloalkyl, unsubstituted C 6 cycloalkyl, , , , Clause 221.
  • R 22b , R 23b , and R 24a are each H. Clause 222.
  • each of R 25b , R 25b’ , R 27b , R 27b’ , R 28b , R 29b , and R 29b’ is H and R 28b , is F.
  • Clause 226 The compound of any one of clauses 216, 217, or 219-225, wherein the compound is selected from: , , Clause 227.
  • Clause 228 The compound of any one of clauses 201-227, wherein the compound is an inhibitor of at least two of IRAK1, IRAK4, and FLT3.
  • a composition comprising a compound of any one of clauses 201-232, wherein the composition further comprises a formulary ingredient, an adjuvant, or a carrier.
  • Clause 234. The composition of clause 233, 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
  • Clause 235 The composition of clause 234, 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 236 The composition of clause 235, wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof.
  • Clause 237 The composition of clause 235, wherein the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof.
  • composition of clause 235 wherein the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone or a pharmaceutically acceptable salt of any one thereof.
  • the CDK inhibitor is a CDK4 inhibitor, a CDK6 inhibitor, a CDK7 inhibitor, and/or a CDK9 inhibitor.
  • the composition of clause 239, wherein 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. Clause 241.
  • composition of clause 235 wherein the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof.
  • a method of treating a disease or disorder in a subject comprising administering to the subject a therapeutically effective amount of a compound of any one of clauses 201-232 or a composition of any one of clauses 233-241.
  • Clause 243 The method of clause 242, 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 242 or 243 wherein 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
  • Clause 245. The method of any one of clauses 242-244, 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 246 The method of any one of clauses 242-245, 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 247 The method of any one of clauses 242-246, wherein the disease or disorder comprises a hematopoietic cancer.
  • Clause 248 The method of any one of clauses 242-246, 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
  • follicular 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 one or more inflammatory diseases or autoimmune disease characterized by overactive IRAK1 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, thyroid cancer, squamous cell carcinoma, neuroblastoma
  • Clause 251 The method of any one of clauses 242-246, wherein the disease or disorder comprises one or more inflammatory diseases or autoimmune disease selected from chronic inflammation, sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, or combinations thereof.
  • inflammatory diseases or autoimmune disease selected from chronic inflammation, sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, or combinations thereof.
  • 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. Clause 253.
  • the MDS with a splicing factor mutation comprises MDS with a splicing factor mutation in U2AF1 or SF3B1 and the AML splicing factor mutation comprises AML with a splicing factor mutation in U2AF1 or SF3B1.
  • 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.
  • any one of clauses 242-254 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 m
  • Clause 256 The method of any one of clauses 242-255, 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 257 The method of clause 255, 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.
  • Clause 258 The method of clause 257, wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof. Clause 259.
  • 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 fuse
  • Clause 302. The compound of clause 301, wherein the compound of Formula (I) is a compound of Formula (IIa-2N): or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: A is N or CR 22a ; E is N or CR 23a ; G is N or CR 24a ; R 20a is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and -O-(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 -OH and halogen, and wherein C 3 -C 6 cycloalkyl and -O-(C 3 -C 6 cycloalkyl) are each optionally substituted with one or more substituents selected
  • Clause 303 The compound of clause 302, wherein R 20a is H.
  • Clause 304 The compound of clause 302, wherein R 20a is selected from halogen, unsubstituted C 1 -C 6 alkoxy, C 1 -C 6 alkoxy substituted with one or more F, unsubstituted C 3 -C 6 cycloalkyl, and unsubstituted -O-(C 3 -C 6 cycloalkyl).
  • Clause 305 The compound of clause 304, wherein R 20a is selected from Cl, -OCH 3 , , unsubst ituted C 3 cycloalkyl, and .
  • Clause 308 The compound of clause 307, wherein R 21a is selected from is , - OCH 2 CH 3 , unsubstituted C 3 cycloalkyl, unsubstituted C 4 cycloalkyl, unsubstituted C 5 cycloalkyl, unsubstituted C 6 cycloalkyl, Clause 309.
  • the compound of clause 309, wherein R 23a and R 24a are each H. Clause 311.
  • Clause 322 The compound of clause 321, wherein R 20b is H.
  • Clause 323. The compound of clause 321, wherein R 20b is selected from halogen, unsubstituted C 1 -C 6 alkoxy, C 1 -C 6 alkoxy substituted with one or more F, unsubstituted C 3 -C 6 cycloalkyl, and unsubstituted -O-(C 3 -C 6 cycloalkyl).
  • Clause 324 The compound of clause 323, wherein R 20b is selected from Cl, -OCH 3 , , , unsubstituted C 3 cycloalkyl, and .
  • Clause 325 The compound of any one of clauses 321-324, wherein R 21b is H.
  • Clause 327 The compound of clause 326, wherein R 21b is selected from is , - OCH 2 CH 3 , unsubstituted C 3 cycloalkyl, unsubstituted C 4 cycloalkyl, unsubstituted C 5 cycloalkyl, unsubstituted C 6 cycloalkyl, , Clause 328.
  • Clause 329 The compound of clause 328, wherein R 23b and R 24b are each H. Clause 330.
  • each of R 25b , R 25b’ , R 27b , R 27b’ , R 28b , R 29b , and R 29b’ is H and R 28b , is F.
  • Clause 340 The compound of any one of clauses 323, 324, 326, 327, 331, 332, or 334-339, wherein the compound is selected from:
  • Clause 342 The compound of clause 341, wherein R 20a is H.
  • Clause 343. The compound of clause 341, wherein R 20a is selected from halogen, unsubstituted C 1 -C 6 alkoxy, C 1 -C 6 alkoxy substituted with one or more F, unsubstituted C 3 -C 6 cycloalkyl, and unsubstituted -O-(C 3 -C 6 cycloalkyl).
  • Clause 344 The compound of clause 343, wherein R 20a is selected from Cl, -OCH 3 , , unsubstituted C 3 cycloalkyl, and .
  • Clause 345 The compound of any one of clauses 341-344, wherein R 21a is H.
  • Clause 347 The compound of clause 346, wherein R 21a is selected from is , - OCH 2 CH 3 , unsubstituted C 3 cycloalkyl, unsubstituted C 4 cycloalkyl, unsubstituted C 5 cycloalkyl, unsubstituted C 6 cycloalkyl, , Clause 348.
  • R 22a , R 23a , and R 24a are each H. Clause 349.
  • Clause 354 The compound of clause 353, wherein R 20b is H.
  • Clause 355. The compound of clause 353, wherein R 20b is selected from halogen, unsubstituted C 1 -C 6 alkoxy, C 1 -C 6 alkoxy substituted with one or more F, unsubstituted C 3 -C 6 cycloalkyl, and unsubstituted -O-(C 3 -C 6 cycloalkyl).
  • Clause 356 The compound of clause 355, wherein R 20b is selected from Cl, -OCH 3 , , unsubstituted C 3 cycloalkyl, and .
  • Clause 357 The compound of any one of clauses 353-356, wherein R 21b is H.
  • Clause 366 The compound of any one of clauses 301-365, wherein the compound is an inhibitor of at least one of IRAK1, IRAK4, and FLT3.
  • Clause 367 The compound of any one of clauses 301-366, wherein the compound is an inhibitor of at least two of IRAK1, IRAK4, and FLT3.
  • Clause 368 The compound of any one of clauses 301-367, wherein the compound is an inhibitor of IRAK1 and IRAK4.
  • Clause 369 The compound of any one of clauses 301-367, wherein the compound is an inhibitor of IRAK1, IRAK4, and FLT3.
  • Clause 370 The compound of any one of clauses 366, 367, or 369, wherein FLT3 is selected from WT FLT3, activated FLT3, and mutated FLT3. Clause 371. The compound of clause 370, wherein the mutated FLT3 is D835Y mutated FLT3 or F691L mutated FLT3. Clause 372. A composition comprising a compound of any one of clauses 301-371, wherein the composition further comprises a formulary ingredient, an adjuvant, or a carrier. Clause 373.
  • composition of clause 372 wherein the composition is administered to a subject in need thereof 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 m
  • Clause 374 The composition of clause 373, wherein the composition is administered to a subject in need thereof in combination with at least one of a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor.
  • Clause 375 The composition of clause 374, wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof.
  • Clause 376 The composition of clause 374, wherein the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof.
  • composition of clause 374 wherein the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone or a pharmaceutically acceptable salt of any one thereof.
  • the CDK inhibitor is a CDK4 inhibitor, a CDK6 inhibitor, a CDK7 inhibitor, and/or a CDK9 inhibitor.
  • Clause 379. The composition of clause 378, wherein 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.
  • Clause 380 The composition of clause 374, wherein the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone or a pharmaceutically acceptable salt of any one thereof.
  • composition of clause 374 wherein the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof.
  • a method of treating a disease or disorder in a subject comprising administering to the subject a therapeutically effective amount of a compound of any one of clauses 301-371 or a composition of clause 372.
  • Clause 382. The method of clause 381, 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.
  • 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.
  • 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.
  • 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, rhabdomyo
  • the disease or disorder comprises one or more inflammatory diseases or autoimmune disease selected from chronic inflammation, sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, Crohn’s disease, colitis, or combinations thereof.
  • inflammatory diseases or autoimmune disease selected from chronic inflammation, sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, Crohn’s disease, colitis, or combinations thereof.
  • 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. Clause 392.
  • the MDS with a splicing factor mutation comprises MDS with a splicing factor mutation in U2AF1 or SF3B1 and the AML splicing factor mutation comprises AML with a splicing factor mutation in U2AF1 or SF3B1.
  • the disease or disorder comprises diffuse large B-cell lymphoma (DLBCL)
  • the DLBCL comprises a L265P MYD88 mutant (ABC) subtype of DLBCL or a S219C MYD88 mutant (GCB) subtype of DLBCL.
  • any one of clauses 381-393 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 m
  • Clause 395 The method of any one of clauses 381-394, 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 396 The method of clause 395, wherein the additional therapy is a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, or a DNA methyltransferase inhibitor.
  • Clause 397 The method of clause 396, wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof.
  • Clause 427 The method of any one of clauses 381-426, wherein the disease or disorder is alleviated by inhibiting at least one of IRAK1, IRAK4, and FLT3 in the subject.
  • Clause 428 The method of any one of clauses 381-427, wherein the disease or disorder is alleviated by inhibiting at least two of IRAK1, IRAK4, and FLT3 in the subject.
  • Clause 429 The method of any one of clauses 381-428, wherein the disease or disorder is alleviated by inhibiting IRAK1 and IRAK4 in the subject.
  • Clause 430 The method of any one of clauses 381-428, wherein the disease or disorder is alleviated by inhibiting IRAK1, IRAK4, and FLT3 in the subject.
  • Clause 431 The method of any one of clauses 427, 428, or 430, wherein FLT3 is selected from WT FLT3, activated FLT3, and mutated FLT3.
  • Clause 432 The method of clause 431, wherein the mutated FLT3 is D835Y mutated FLT3 or F691L mutated FLT3. Clause 433.
  • c-Bu cyclobutyl
  • c-Pr cyclopropyl
  • Cy cyclohexyl
  • DAST (diethylamino)sulfur trifluoride
  • dba dibenzylideneacetone
  • DCM dichloromethane
  • DIAD diisopropylazodicarboxylate
  • DIBAL, DIBAL-H diisobutylaluminum hydride
  • DIEA diisopropylethylamine
  • DME 1,2-dimethoxyethane
  • DMEM Dulbecco’s modified eagle medium
  • DMAP 4-dimethylaminopyridine
  • DMF N,N- dimethylformamide
  • DMSO dimethylsulfoxide; eq.
  • 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)-1H-1,2,3-triazolo[4,5-b]pyridin-1- ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide
  • HOAc acetic acid
  • HOAt 3H-[1,2,3]-triazolo[4,5-b]pyridin-3-ol
  • HOBt 1H-benzotriazol-1-ol
  • HPLC High pressure liquid chromatography
  • HTRF homogenous time resolved fluor
  • TBAF tetrabutylammonium fluoride
  • TBAI tetrabutylammonium iodide
  • t-Bu tert-butyl
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran
  • TLC thin layer chromatography
  • prep TLC preparative thin layer chromatography
  • Tosyl toluenesulfonyl
  • 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’
  • Example 1 Exemplary Synthetic Procedure #1 (Compounds 1 – 6) Compound 1, 6-(5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidin-3-yl)-5-fluoro-N-((3S,4S)- 4-fluoropyrrolidin-3-yl)pyridin-2-amine Step A.
  • Step B 5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidin-7-ol
  • acetic acid 100 mL
  • 1H-pyrazol-5-amine 4.58 g, 55.2 mmol
  • Step C.7-chloro-5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidine A mixture of 5-cyclopropyl-6-methoxy-pyrazolo[1,5-a]pyrimidin-7-ol (7.00 g, 34.1 mmol) and phosphorus oxychloride (70 mL) was cooled to 0 °C. N-Ethyl-N-isopropyl-propan-2-amine (22.04 g, 170.6 mmol, 29.71 mL) was then added in a dropwise fashion. The resulting reaction was heated at 60 °C for 16 hours, and was then cooled to room temperature, filtered, and concentrated under reduced pressure.
  • Step D 5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidine
  • methanol 10 mL
  • dichloromethane 10 mL
  • triethylamine 0.98 g, 4.92 mmol, 0.685 mL
  • 10% palladium on carbon 1.10 g
  • Step E.5-cyclopropyl-6-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5- a]pyrimidine A mixture of 5-cyclopropyl-6-methoxy-pyrazolo[1,5-a]pyrimidine (0.870 g, 4.60 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (5.84 g, 23.0 mmol), (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (0.183 g, 0.276 mmol), and 4-tert- butyl-2-(4-tert-butyl-2-pyridyl)pyridine (0.086 g, 0.322 mmol) in hexane (10 mL) was degassed
  • a mixture of 5-cyclopropyl-6-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrazolo[1,5-a]pyrimidine (0.500 g, 1.59 mmol), 2,6-dibromo-3-fluoro-pyridine (0.809 g, 3.17 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.116 g, 0.159 mmol), and potassium phosphate (0.674 g, 3.17 mmol) in dio
  • the reaction was then cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (3 x 10 mL). The organic extracts were combined, washed with saturated aqueous sodium chloride solution (3 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was triturated with methanol (3 x 3 mL) and filtered.
  • Step G (3S,4S)-tert-butyl 3-((6-(5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidin-3-yl)-5- fluoropyridin-2-yl)amino)-4-fluoropyrrolidine-1-carboxylate
  • 3-(6-bromo-3-fluoro-2-pyridyl)-5-cyclopropyl-6-methoxy-pyrazolo[1,5- a]pyrimidine (0.015 g, 0.041 mmol)
  • tert-butyl (3S,4S)-3-amino-4-fluoro-pyrrolidine-1- carboxylate (0.013 g, 0.062 mmol)
  • [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium [1- (2-diphenylphosphanyl-1-naphthyl)-2-naphthyl
  • Step H 6-(5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidin-3-yl)-5-fluoro-N-((3S,4S)-4- fluoropyrrolidin-3-yl)pyridin-2-amine
  • a solution of tert-butyl (3S,4S)-3-[[6-(5-cyclopropyl-6-methoxy-pyrazolo[1,5- a]pyrimidin-3-yl)-5-fluoro-2-pyridyl]amino]-4-fluoro-pyrrolidine-1-carboxylate (0.050 g, 0.103 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.770 g, 6.75 mmol, 0.500 mL).
  • Example 2 Exemplary Synthetic Procedure #2 (Compounds 7 – 8) Compound 7, 6-(5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidin-3-yl)-5-fluoro-2-(((3S,4S)- 4-fluoropiperidin-3-yl)amino)nicotinonitrile Step A.2-chloro-6-(5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidin-3-yl)-5- fluoronicotinonitrile A mixture of 5-cyclopropyl-6-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrazolo[1,5-a]pyrimidine (0.380 g, 1.21 mmol), 2,6-dichloro-5-fluoronicotinonitrile (0.230 ).
  • reaction was then cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (3 x 10 mL). The organic extracts were combined, washed with saturated aqueous sodium chloride solution (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure.
  • Step B 5,7-dichloro-6-methoxypyrazolo[1,5-a]pyrimidine
  • 7-hydroxy-6-methoxypyrazolo[1,5-a]pyrimidin-5(4H)-one (25.00 g, 138.0 mmol)
  • phosphorus oxychloride 250 mL
  • the reaction was cooled to 0 °C, and N,N-diethylaniline (3.09 g, 20.7 mmol, 3.31 mL) was then added in a dropwise fashion.
  • Step C 5-chloro-6-methoxypyrazolo[1,5-a]pyrimidine
  • 5.00 g, 27.5 mmol 5,7-dichloro-6-methoxypyrazolo[1,5-a]pyrimidine
  • ethanol 120 mL
  • tetrahydrofuran 120 mL
  • ammonium chloride 7.36 g, 137.6 mmol
  • Zinc dust (9.00 g, 137.59 mmol) was then added in portions, and the resulting mixture was stirred for 16 hours while warming to room temperature. The reaction was then quenched by addition of 2 N hydrochloric acid (55 mL), diluted with water (200 mL), and extracted with ethyl acetate (3 x 200 mL).
  • Step D.6-methoxy-5-(prop-1-en-2-yl)pyrazolo[1,5-a]pyrimidine A mixture of potassium isopropenyltrifluoroborate (3.39 g, 22.9 mmol), 5-chloro-6- methoxypyrazolo[1,5-a]pyrimidine (4.20 g, 22.9 mmol), [1,1- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.67 g, 2.29 mmol), and cesium carbonate (22.36 g, 68.63 mmol) in toluene (180 mL), tetrahydrofuran (60 mL), and water (60 mL) was degassed and purged with nitrogen, and was then heated at 100 °C for 16 hours under nitrogen atmosphere.
  • reaction was then cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (3 x 25 mL). The organic extracts were combined, washed with saturated aqueous sodium chloride solution (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure.
  • 6-methoxy-5-(prop-1-en-2-yl)pyrazolo[1,5-a]pyrimidine 2.10 g, 11.1 mmol
  • propan-2-ol 60 mL
  • phenylsilane 3.60 g, 33.3 mmol, 4.11 mL
  • Step F 2-(3-bromo-6-methoxypyrazolo[1,5-a]pyrimidin-5-yl)propan-2-ol
  • 2-(6-methoxypyrazolo[1,5-a]pyrimidin-5-yl)propan-2-ol (0.240 g, 1.16 mmol) in acetonitrile (5 mL) was cooled to 0 °C.
  • 1-Bromopyrrolidine-2,5-dione 0.227 g, 1.27 mmol
  • reaction was then basified to pH ⁇ 10 by addition of aqueous 2 N sodium hydroxide solution, diluted with water (5 mL), and extracted with ethyl acetate (3 x 5 mL). The organic extracts were combined, washed with saturated aqueous sodium chloride solution, (5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide the title compound: LCMS m/z 286.1 [M+H] + .
  • Step G 2-(6-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidin- 5-yl)propan-2-ol
  • 2-(3-bromo-6-methoxy-pyrazolo[1,5-a]pyrimidin-5-yl)propan-2-ol (0.100 g, 0.350 mmol)
  • 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) 0.444 g, 1.75 mmol
  • methanesulfonate[2-[2-(methylamino)phenyl]phenyl]palladium tri-tert-butylphosphane 0.020 g, 0.035 mmol
  • potassium acetate 0.069 g, 0.699 mmol
  • Step H 2-chloro-5-fluoro-6-(5-(2-hydroxypropan-2-yl)-6-methoxypyrazolo[1,5-a]pyrimidin-3- yl)nicotinonitrile
  • 2-[6-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5- a]pyrimidin-5-yl]propan-2-ol (0.950 g, 2.85 mmol)
  • 2,6-dibromo-3,5-difluoro-pyridine (1.09 g, 5.70 mmol
  • [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) 0.209 g, 0.285 mmol
  • aqueous potassium phosphate solution 2.5 M, 2.28 mL) in dioxane (10 mL) was degassed and purged with nitrogen, and was then
  • Example 4 Exemplary Synthetic Procedure #4 (Compound 14) Compound 14, 6-(6-chloropyrazolo[1,5-a]pyrimidin-3-yl)-N-((3S,4S)-4-fluoropyrrolidin-3- yl)pyridin-2-amine Step A.6-chloropyrazolo[1,5-a]pyrimidine To a cooled 0° C solution of 2-chloropropanedial (2.00 g, 18.8 mmol) and 1H-pyrazol-5- amine (1.72 g, 20.7 mmol) in ethanol (80 mL) was added hydrochloric acid (12 M, 9.33 mL).
  • Step B 6-chloro-3-iodopyrazolo[1,5-a]pyrimidine
  • dichloromethane 10 mL
  • 1-iodopyrrolidine-2,5-dione 1.84 g, 8.17 mmol
  • Step C.3-(6-bromopyridin-2-yl)-6-chloropyrazolo[1,5-a]pyrimidine A mixture of 6-chloro-3-iodo-pyrazolo[1,5-a]pyrimidine (1.20 g, 4.29 mmol), (6-bromo-2- pyridyl)-tributylstannane (2.30 g, 5.15 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.496 g, 0.429 mmol) in toluene (2.0 mL) was degassed and purged with nitrogen, and was then heated at 100 °C for 10 hours under nitrogen atmosphere.
  • Step E 6-(6-chloropyrazolo[1,5-a]pyrimidin-3-yl)-N-((3S,4S)-4-fluoropyrrolidin-3-yl)pyridin-2- amine
  • a solution of tert-butyl (3S,4S)-3-[[6-(6-chloropyrazolo[1,5-a]pyrimidin-3-yl)-2- pyridyl]amino]-4-fluoro-pyrrolidine-1-carboxylate (0.030 g, 0.069 mmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (0.30 mL, 0.462 g, 4.05 mmol).
  • reaction was then cooled to room temperature, acidified to pH ⁇ 6 by addition of 2 N hydrochloric acid, and extracted with ethyl acetate (3 x 30 mL). The organic extracts were combined, washed with saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure.
  • Step B 6-(2,2-difluoroethoxy)pyrazolo[1,5-a]pyrimidine
  • pyrazolo[1,5-a]pyrimidin-6-ol (0.500 g, 3.70 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (1.58 g, 7.40 mmol) in acetonitrile (5.0 mL) was added potassium carbonate (0.767 g, 5.55 mmol).
  • the resulting reaction mixture was heated at 40 °C for 2 hours.
  • the reaction was then cooled to room temperature, diluted with water (5 mL), and extracted with ethyl acetate (3 x 10 mL).
  • Step C 6-(2,2-difluoroethoxy)-3-iodopyrazolo[1,5-a]pyrimidine
  • 6-(2,2-difluoroethoxy)pyrazolo[1,5-a]pyrimidine (0.500 g, 2.51 mmol) in dichloromethane (3.0 mL) was added 1-iodopyrrolidine-2,5-dione (0.565 g, 2.51 mmol).
  • the resulting reaction was stirred at room temperature for 16 hours, and was then filtered and concentrated under reduced pressure.
  • Step D.3-(6-bromopyridin-2-yl)-6-(2,2-difluoroethoxy)pyrazolo[1,5-a]pyrimidine A mixture of 6-(2,2-difluoroethoxy)-3-iodo-pyrazolo[1,5-a]pyrimidine (0.200 g, 0.615 mmol), (6-bromo-2-pyridyl)-tributylstannane (0.330 g, 0.738 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.071 g, 0.062 mmol) in toluene (3.0 mL) was degassed and purged with nitrogen, and was then heated at 100 °C for 10 hours under nitrogen atmosphere.
  • Step F 6-(6-(2,2-difluoroethoxy)pyrazolo[1,5-a]pyrimidin-3-yl)-N-((3S,4S)-4-fluoropyrrolidin- 3-yl)pyridin-2-amine
  • a solution of tert-butyl (3S,4S)-3-[[6-[6-(2,2-difluoroethoxy)pyrazolo[1,5-a]pyrimidin- 3-yl]-2-pyridyl]amino]-4-fluoro-pyrrolidine-1-carboxylate (0.050 g, 0.105 mmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (0.50 mL, 0.770 g, 6.75 mmol).
  • Example 4 The compounds in Table 4 were all prepared using the synthetic procedures described in Example 6. Table 4. Additional compounds prepared according to Example 6.
  • Example 7 Exemplary Synthetic Procedure #7 Compound 19, 6-(5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidin-3-yl)-N-((3S,4S)-4- fluoropyrrolidin-3-yl)pyridin-2-amine Step A.
  • Step B 5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidin-7-ol
  • a solution of methyl 3-cyclopropyl-2-methoxy-3-oxo-propanoate (9.50 g, 55.2 mmol) in acetic acid (100 mL) was added 1H-pyrazol-5-amine (4.58 g, 55.2 mmol).
  • Step C.7-chloro-5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidine Diisopropylethylamine (12.6 g, 97.5 mmol, 17.0 mL) was added dropwise to a solution of 5-cyclopropyl-6-methoxy-pyrazolo[1,5-a]pyrimidin-7-ol (4.00 g, 19.5 mmol) in phosphorus oxychloride (60 mL). The resulting reaction was heated at 60 °C for 1 hour under nitrogen, and was then cooled to room temperature and concentrated under reduced pressure.
  • Step D The crude product thus obtained was purified by flash chromatography on silica gel (0 – 30 % ethyl acetate in petroleum ether) to provide the title compound: LCMS m/z 224.1 [M+H] + .
  • Step D 5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidine
  • 7-chloro-5-cyclopropyl-6-methoxy-pyrazolo[1,5-a]pyrimidine (6.70 g, 30.0 mmol) and 10% palladium on carbon (2.80 g) in methanol (40 mL), dichloromethane (40 mL) and triethylamine (8 mL) was stirred at room temperature under 15 psi of hydrogen for 6 hours.
  • Step E 5-cyclopropyl-3-iodo-6-methoxypyrazolo[1,5-a]pyrimidine
  • acetonitrile 15.0 mL
  • 1-iodopyrrolidine-2,5-dione 1.19 g, 5.29 mmol
  • 5-cyclopropyl-3-iodo-6-methoxy-pyrazolo[1,5-a]pyrimidine (0.500 g, 1.59 mmol) in toluene (15.0 mL) were added (6-bromo-2-pyridyl)-tributylstannane (1.42 g, 3.17 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.183 g, 0.159 mmol).
  • the resulting reaction was heated at 100 °C for 16 hours.
  • Step H 6-(5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidin-3-yl)-N-((3S,4S)-4- fluoropyrrolidin-3-yl)pyridin-2-amine
  • a solution of tert-butyl (3S,4S)-3-[[6-(5-cyclopropyl-6-methoxy-pyrazolo[1,5- a]pyrimidin-3-yl)-2-pyridyl]amino]-4-fluoro-pyrrolidine-1-carboxylate (0.040 g, 0.085 mmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (0.50 mL, 0.778 g, 6.82 mmol).
  • Example 8 Exemplary Synthetic Procedure #8 (Compounds 22 – 24) Compound 22, 6-(5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidin-3-yl)-3,5-difluoro-N- ((3S,4S)-4-fluoropiperidin-3-yl)pyridin-2-amine Step A.3-bromo-5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidine To a cooled 0 °C solution of 5-cyclopropyl-6-methoxy-pyrazolo[1,5-a]pyrimidine (0.700 g, 3.70 mmol) in acetonitrile (15.0 mL) was added 1-bromopyrrolidine-2,5-dione (0.658 g, 3.70 mmol).
  • Step B 5-cyclopropyl-6-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5- a]pyrimidine
  • 3-bromo-5-cyclopropyl-6-methoxy-pyrazolo[1,5-a]pyrimidine 0.050 g, 0.186 mmol
  • 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane 0.237 g, 0.932 mmol
  • methanesulfonate[2-[2- (methylamino)phenyl]phenyl]palladium tri-tert-butylphosphane 0.011 g, 0.019 mmol
  • potassium acetate 0.037 g, 0.373 mmol
  • Step C.3-(6-bromo-3,5-difluoropyridin-2-yl)-5-cyclopropyl-6-methoxypyrazolo[1,5- a]pyrimidine A mixture of 5-cyclopropyl-6-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrazolo[1,5-a]pyrimidine (2.30 g, 7.30 mmol), 2,6-dibromo-3,5-difluoro-pyridine (2.99 g, 11.0 mmol), potassium phosphate (3.10 g, 14.6 mmol), and [1,1-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (0.534 g, 0.730 mmol) in dioxane (20.0 mL) and water (16.0 mL) was degassed and purged with nitrogen, and was then heated at 90 °
  • Step B 5,7-dichloro-6-methoxypyrazolo[1,5-a]pyrimidine
  • 7-hydroxy-6-methoxypyrazolo[1,5-a]pyrimidin-5(4H)-one (25.00 g, 138.0 mmol)
  • phosphorus oxychloride 250 mL
  • the reaction was cooled to 0 °C, and N,N-diethylaniline (3.09 g, 20.7 mmol, 3.31 mL) was then added in a dropwise fashion.
  • Step C 5-chloro-6-methoxypyrazolo[1,5-a]pyrimidine
  • 5.00 g, 27.5 mmol 5,7-dichloro-6-methoxypyrazolo[1,5-a]pyrimidine
  • ethanol 120 mL
  • tetrahydrofuran 120 mL
  • ammonium chloride 7.36 g, 137.6 mmol
  • Zinc dust (9.00 g, 137.59 mmol) was then added in portions, and the resulting mixture was stirred for 16 hours while warming to room temperature. The reaction was then quenched by addition of 2 N hydrochloric acid (55 mL), diluted with water (200 mL), and extracted with ethyl acetate (3 x 200 mL).
  • Step D.6-methoxy-5-(prop-1-en-2-yl)pyrazolo[1,5-a]pyrimidine A mixture of potassium isopropenyltrifluoroborate (3.39 g, 22.9 mmol), 5-chloro-6- methoxypyrazolo[1,5-a]pyrimidine (4.20 g, 22.9 mmol), [1,1- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.67 g, 2.29 mmol), and cesium carbonate (22.36 g, 68.63 mmol) in toluene (180 mL), tetrahydrofuran (60 mL), and water (60 mL) was degassed and purged with nitrogen, and was then heated at 100 °C for 16 hours under nitrogen atmosphere.
  • reaction was then cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (3 x 25 mL). The organic extracts were combined, washed with saturated aqueous sodium chloride solution (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure.
  • 6-methoxy-5-(prop-1-en-2-yl)pyrazolo[1,5-a]pyrimidine 2.10 g, 11.1 mmol
  • propan-2-ol 60 mL
  • phenylsilane 3.60 g, 33.3 mmol, 4.11 mL
  • Step F 2-(3-iodo-6-methoxypyrazolo[1,5-a]pyrimidin-5-yl)propan-2-ol
  • 2-(6-methoxypyrazolo[1,5-a]pyrimidin-5-yl)propan-2-ol (0.150 g, 0.724 mmol) in acetonitrile (1.5 mL) was cooled to 0 °C.
  • N-Iodosuccinimide 0.163 g, 0.724 mmol
  • Step G 2-(3-(2-chloropyrimidin-4-yl)-6-methoxypyrazolo[1,5-a]pyrimidin-5-yl)propan-2-ol
  • 2-chloro-4-(tributylstannyl)pyrimidine 0.170 g, 0.420 mmol
  • 2-(3-iodo-6- methoxypyrazolo[1,5-a]pyrimidin-5-yl)propan-2-ol 0.070 mg, 0.210 mmol
  • palladium tri- tert-butylphosphane 0.011 g, 0.021 mmol
  • Example 10 Exemplary Synthetic Procedure #10 (Compounds 4a – 6a) Compound 4a, (R)-2-(3-(5-fluoro-2-(piperidin-3-ylamino)pyrimidin-4-yl)-6- methoxypyrazolo[1,5-a]pyrimidin-5-yl)propan-2-ol Step A.2-(3-bromo-6-methoxypyrazolo[1,5-a]pyrimidin-5-yl)propan-2-ol A solution of 2-(6-methoxypyrazolo[1,5-a]pyrimidin-5-yl)propan-2-ol (0.240 g, 1.16 mmol) in acetonitrile (5 mL) was cooled to 0 °C.
  • Step B 2-(6-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidin- 5-yl)propan-2-ol
  • 2-(3-bromo-6-methoxy-pyrazolo[1,5-a]pyrimidin-5-yl)propan-2-ol (0.100 g, 0.350 mmol)
  • 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) 0.444 g, 1.75 mmol
  • methanesulfonate[2-[2-(methylamino)phenyl]phenyl]palladium tri-tert-butylphosphane 0.020 g, 0.035 mmol
  • potassium acetate 0.069 g, 0.699 mmol
  • 2-(6-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5- a]pyrimidin-5-yl)propan-2-ol (0.300 g, 0.900 mmol)
  • 2,4-dibromo-5-fluoropyrimidine 0.461 g, 1.80 mmol
  • [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) 0.066 g, 0.090 mmol
  • aqueous potassium phosphate solution 2.5 M, 0.720 mL) in dioxane (10 mL) was degassed and purged with nitrogen, and was then heated at 90 °C for
  • Example 7 The compounds in Table 7 were all prepared using the synthetic procedures described in Example 9. Table 7. Additional compounds prepared according to Example 9.
  • Example 10 Exemplary Synthetic Procedure #10 Compounds 7a – 9a) Compound 7a, 4-(5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidin-3-yl)-N-((3S,4S)-4- fluoropiperidin-3-yl)pyrimidin-2-amine Step A.
  • Step B 5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidin-7-ol
  • a solution of methyl 3-cyclopropyl-2-methoxy-3-oxo-propanoate (9.50 g, 55.2 mmol) in acetic acid (100 mL) was added 1H-pyrazol-5-amine (4.58 g, 55.2 mmol).
  • Step C.7-chloro-5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidine Diisopropylethylamine (12.6 g, 97.5 mmol, 17.0 mL) was added dropwise to a solution of 5-cyclopropyl-6-methoxy-pyrazolo[1,5-a]pyrimidin-7-ol (4.00 g, 19.5 mmol) in phosphorus oxychloride (60 mL). The resulting reaction was heated at 60 °C for 1 hour under nitrogen, and was then cooled to room temperature and concentrated under reduced pressure.
  • Step D The crude product thus obtained was purified by flash chromatography on silica gel (0 – 30 % ethyl acetate in petroleum ether) to provide the title compound: LCMS m/z 224.1 [M+H] + .
  • Step D 5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidine
  • 7-chloro-5-cyclopropyl-6-methoxy-pyrazolo[1,5-a]pyrimidine (6.70 g, 30.0 mmol) and 10% palladium on carbon (2.80 g) in methanol (40 mL), dichloromethane (40 mL) and triethylamine (8 mL) was stirred at room temperature under 15 psi of hydrogen for 6 hours.
  • Step E 5-cyclopropyl-3-iodo-6-methoxypyrazolo[1,5-a]pyrimidine
  • acetonitrile 15 mL
  • 1-iodopyrrolidine-2,5-dione 1.19 g, 5.29 mmol
  • Step F.3-(2-chloropyrimidin-4-yl)-5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidine A mixture of 5-cyclopropyl-3-iodo-6-methoxy-pyrazolo[1,5-a]pyrimidine (0.500 g, 1.59 mmol), tributyl-(2-chloropyrimidin-4-yl)stannane (0.961 g, 2.38 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.183 g, 0.159 mmol) in toluene (10 mL) was purged with nitrogen, and was then heated under nitrogen at 100 °C for 3 hours.
  • Step H 4-(5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidin-3-yl)-N-((3S,4S)-4- fluoropiperidin-3-yl)pyrimidin-2-amine
  • a solution of tert-butyl (3S,4S)-3-[[4-(5-cyclopropyl-6-methoxy-pyrazolo[1,5- a]pyrimidin-3-yl)pyrimidin-2-yl]amino]-4-fluoropiperidine-1-carboxylate (0.020 g, 0.041 mmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (0.50 mL, 0.770 g, 6.75 mmol).
  • Example 11 Exemplary Synthetic Procedure #11 (Compounds 10a – 12a) Compound 10a, 46-(5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidin-3-yl)-N-((3S,4S)-4- fluoropyrrolidin-3-yl)pyrazin-2-amine Step A.5-cyclopropyl-6-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5- a]pyrimidine
  • Step B.3-(6-bromopyrazin-2-yl)-5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidine A mixture of 5-cyclopropyl-6-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrazolo[1,5-a]pyrimidine (0.020 g, 0.063 mmol), 2,6-dibromopyrazine (0.030 g, 0.127 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.005 g, 0.006 mmol), and potassium phosphate (0.027 g, 0.127 mmol) in dioxane (3.0 mL) and water (1.0 mL) was degassed and purged with nitrogen, and was then heated at 85 °C for 3 hours under nitrogen atmosphere.
  • Step D 6-(5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidin-3-yl)-N-((3S,4S)-4- fluoropyrrolidin-3-yl)pyrazin-2-amine
  • a solution of tert-butyl (3S, 4S)-3-[[6-(5-cyclopropyl-6-methoxy-pyrazolo[1,5- a]pyrimidin-3-yl)pyrazin-2-yl]amino]-4-fluoropyrrolidine-1-carboxylate (0.050 g, 0.106 mmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (0.50 mL, 0.778 g, 6.82 mmol).
  • Example 12 Exemplary Synthetic Procedure #12 (Compounds 13a – 15a) Compound 15a, 4-(5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidin-3-yl)-5-fluoro-N- ((3S,4S)-4-fluoropiperidin-3-yl)pyrimidin-2-amine Step A.3-bromo-5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidine To a cooled 0 °C solution of 5-cyclopropyl-6-methoxy-pyrazolo[1,5-a]pyrimidine (0.700 g, 3.70 mmol) in acetonitrile (15.0 mL) was added 1-bromopyrrolidine-2,5-dione (0.658 g, 3.70 mmol).
  • Step B 5-cyclopropyl-6-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5- a]pyrimidine
  • 3-bromo-5-cyclopropyl-6-methoxy-pyrazolo[1,5-a]pyrimidine 0.050 g, 0.186 mmol
  • 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane 0.237 g, 0.932 mmol
  • methanesulfonate[2-[2- (methylamino)phenyl]phenyl]palladium tri-tert-butylphosphane 0.011 g, 0.019 mmol
  • potassium acetate 0.037 g, 0.373 mmol
  • Step C.3-(2-bromo-5-fluoropyrimidin-4-yl)-5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidine A mixture of 5-cyclopropyl-6-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrazolo[1,5-a]pyrimidine (0.050 g, 0.159 mmol), 2,4-dibromo-5-fluoro-pyrimidine (0.081 g, 0.317 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.012 g, 0.016 mmol), and potassium phosphate (0.067 g, 0.317 mmol) in dioxane (1.5 mL) and water (1.0 mL) was degassed and purged with nitrogen, and was then heated at 90 °C for 3 hours under nitrogen atmosphere
  • reaction was then cooled to room temperature, diluted with water (5 mL), and extracted with ethyl acetate (3 x 5 mL). The organic extracts were combined, washed with saturated aqueous sodium chloride solution (3 x 3 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure.
  • Example 13 Biological Data for Exemplary Compounds Kinase inhibitory data were obtained for various exemplary compounds prepared according to Examples 1-8 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.
  • 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.
  • the reagent used was as follows: Base Reaction buffer; 20 mM Hepes (pH 7.5), 10 mM MgCl 2 , 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.
  • the reaction procedure was as follows: 1) Substrates were prepared in freshly prepared Reaction Buffer.
  • Example 14 Biological Data for Exemplary Compounds
  • Kinase binding data were obtained for various exemplary compounds prepared according to Examples 1-8 using the DiscoverX KINOMEscan ® active site-directed competition binding site-directed assay protocol described below.
  • KINOMEscan ® assays do not require ATP.
  • the data report thermodynamic interaction affinities (Kd values), rather than IC 50 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.
  • coli 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.
  • blocking buffer SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT
  • Binding reactions were assembled by combining kinases, liganded affinity beads, and test compounds in 1x binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT).
  • Test compounds were prepared as 111x 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 (1x PBS, 0.05% Tween 20). The beads were then re-suspended in elution buffer (1x PBS, 0.05% Tween 20, 0.5 ⁇ M nonbiotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the eluates was measured by qPCR. 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 12.
  • the NanoBRET assay measures kinase engagement in real time in the context of the intact cell. Unlike the previously described biochemical kinase assay methodology, 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.
  • 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., (2016) 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 NanoBRETTM tracer, a NanoLuc ® substrate, and an extracellular NanoLuc ® inhibitor.
  • HEK-293 cells Upon expression of the luciferase-tagged kinase, cells will produce a strong BRET signal only in the presence of the NanoBRETTM 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 NanoBRETTM 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.
  • 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. 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 (LabcyteInc, Sunnyvale, CA).
  • Transfected cells were harvested and mixed with NanoBRETTracer Reagent and dispensed into 384 well plates and incubated at 37 oC in 5% CO 2 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 EnVisionplate reader.
  • the BRET Ratios were calculated.
  • BRET Ratio [(Acceptor sample ⁇ Donor sample) – (Acceptor no-tracer control ⁇ Donor no- tracer control)].
  • NanoBRETTM 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).
  • NanoBRETTM 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.
  • 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.
  • Example 16 Biological Data for Exemplary Compounds
  • Cellular potency data were obtained for various exemplary compounds prepared according to Examples 1-8 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.
  • 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 IRAK1/4 complex, and is not a composite measurement of activity that includes FLT3 kinase inhibition.
  • THP-1-Blue NF- ⁇ B cells (InvivoGen) carrying a stable integrated NF- ⁇ B-inducible secreted embryonic alkaline phosphatase (SEAP) reporter construct were plated at a concentration of 1 x 10 5 cells per well. The cells were stimulated with Pam3CSK4 (1ng/mL) or hIL1B (1ng/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 ⁇ M or 3 ⁇ M) with a final volume of 200 ⁇ L for 24 hours at 37 °C.
  • DMSO vehicle
  • serial dilutions of the test compounds (10 doses tested for each test compound, with a 1:10 dilution series starting at 1 ⁇ M or 3 ⁇ M) with a final volume of 200 ⁇ L for 24 hours at 37 °C.
  • 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., (2016) 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.
  • MOLM14 D835Y and MOLM14 F691L cells were grown in RPMI-1640 media supplemented with 20% fetal bovine serum (FBS).
  • FBS fetal bovine serum
  • cells were seeded into 1536-well white polystyrene tissue culture-treated Greiner plates using a Multidrop Combi dispenser (ThermoFisher), in final volume 5 ⁇ L 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 ⁇ M) via a 1536 pin-tool.
  • Example 18 Biological Data for Exemplary Compounds Kinase inhibitory data were obtained for various exemplary compounds prepared according to Examples 9-12 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.
  • 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. Although not wishing to be limited by theory, it is believed that 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.
  • the reagent used was as follows: Base Reaction buffer; 20 mM Hepes (pH 7.5), 10 mM MgCl 2 , 1 mM EGTA, 0.01% Brij35, 0.02 mg/ml BSA, 0.1 mM Na 3 VO 4 , 2 mM DTT, 1% DMSO.
  • Required cofactors were added individually to each kinase reaction.
  • 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.
  • KINOMEscan ® assays do not require ATP.
  • the data report thermodynamic interaction affinities (Kd values), rather than IC 50 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.)
  • Kinase-tagged T7 phage strains were prepared in an E. coli host derived from the BL21 strain. E. coli 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 1x binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT).
  • Test compounds were prepared as 111x stocks in 100% DMSO.
  • K d s were determined using an 11-point 3-fold compound dilution series with three DMSO control points. All compounds for K d 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 (1x PBS, 0.05% Tween 20). The beads were then re-suspended in elution buffer (1x PBS, 0.05% Tween 20, 0.5 ⁇ M nonbiotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the eluates was measured by qPCR. Binding constants (K d s) 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.
  • 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., (2016) 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 NanoBRETTM tracer, a NanoLuc ® substrate, and an extracellular NanoLuc ® inhibitor.
  • HEK-293 cells Upon expression of the luciferase-tagged kinase, cells will produce a strong BRET signal only in the presence of the NanoBRETTM 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 NanoBRETTM 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.
  • 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. 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 (LabcyteInc, Sunnyvale, CA).
  • Transfected cells were harvested and mixed with NanoBRETTracer Reagent and dispensed into 384 well plates and incubated at 37 oC in 5% CO 2 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 EnVisionplate reader.
  • the BRET Ratios were calculated.
  • BRET Ratio [(Acceptor sample ⁇ Donor sample) – (Acceptor no-tracer control ⁇ Donor no- tracer control)].
  • NanoBRETTM 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).
  • NanoBRETTM 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.
  • 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.
  • Example 21 Biological Data for Exemplary Compounds
  • Cellular potency data were obtained for various exemplary compounds prepared according to Examples 9-12 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.
  • 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 IRAK1/4 complex and is not a composite measurement of activity that includes FLT3 kinase inhibition.
  • THP-1-Blue NF- ⁇ B cells (InvivoGen) carrying a stable integrated NF- ⁇ B-inducible secreted embryonic alkaline phosphatase (SEAP) reporter construct were plated at a concentration of 1 x 10 5 cells per well. The cells were stimulated with Pam3CSK4 (1 ng/mL) or hIL1B (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 mM or 3 mM) with a final volume of 200 mL for 24 hours at 37 °C.
  • DMSO vehicle
  • serial dilutions of the test compounds (10 doses tested for each test compound, with a 1:10 dilution series starting at 1 mM or 3 mM) with a final volume of 200 mL for 24 hours at 37 °C.
  • test compound were transferred into individual wells (22 doses tested for each test compound, with a 1:2 dilution series starting at 10 mM) via a 1536 pin- tool.
  • Bortezomib final concentration 2.3 mM 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.
  • the table provides relative excess HSA values for compounds of the disclosure used in combination with venetoclax compared to gilteritinib hemifumarate used in combination with venetoclax.
  • 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.
  • the large negative excess HSA scores demonstrate that all tested combinations of venetoclax with a compound of the disclosure are synergistic at the drug concentration ranges listed. Table 23.
  • Table 24 provides combination outcomes for representative compounds with venetoclax in the Cell Titer Glo assay in THP1 (FLT3 wild type) cells at 48 hours.
  • the table provides relative excess HSA values for compounds of the disclosure used in combination with venetoclax compared to gilteritinib hemifumarate used in combination with venetoclax.
  • 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.
  • the large negative excess HSA scores demonstrate that all tested combinations of venetoclax with a compound of the disclosure are synergistic at the drug concentration ranges listed. When comparing the potencies at which synergy is observed, all compounds tested were found to be more potent in the MOLM14 (D835Y) cells versus the THP1 cells (data not shown). Table 24. Excess HSA scores for a combination therapy of compounds of the disclosure with venetoclax compared to gilteritinib hemifumarate obtained in THP1 cells in a 10 x 10 dataset Tables 23 and 24 demonstrate that synergy is seen in both the FLT3 mutant setting (D835Y cells) and the FLT3 WT (THP1 cells) setting.
  • the synergy is seen in a cell line that carries a FLT3 resistant mutation.
  • This is a cell line that has the FLT3ITD mutation and also the FLT3D835Y kinase domain mutation.
  • Synergy is observed over different concentration ranges in the two different cell line 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. More information on excess HSA scores can be found in Vlot, Anna H.
  • 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.
  • 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.
  • 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.

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Abstract

La présente invention concerne des composés de pyrazolo[1,5-a]pyrimidine et des compositions les comprenant qui inhibent IRAK et/ou FLT3. La présente invention concerne en outre des procédés d'utilisation des composés de pyrazolo[1,5-a]pyrimidine pour traiter une maladie ou un trouble tel qu'un cancer hématopoïétique, des syndromes myélodysplasiques (SMD), ou une leucémie myéloïde aiguë (LMA). Des modes de réalisation supplémentaires concernent un traitement de maladie à l'aide de combinaisons des composés inhibiteurs d'IRAK et/ou de FLT3 décrits avec d'autres thérapies, telles que des thérapies anticancéreuses.
PCT/US2023/034438 2022-10-04 2023-10-04 Composés inhibiteurs d'irak et de flt3 multi-cycliques et leurs utilisations Ceased WO2024076614A2 (fr)

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CN101932583A (zh) * 2007-12-19 2010-12-29 沃泰克斯药物股份有限公司 用作JAK2抑制剂的吡唑并[1,5-a]嘧啶类
CN108473498B (zh) * 2015-12-22 2021-11-02 豪夫迈·罗氏有限公司 作为IRAK4调节剂的吡唑并[1,5a]嘧啶衍生物
JP2023538242A (ja) * 2020-07-31 2023-09-07 チルドレンズ ホスピタル メディカル センター 多環式ｉｒａｋ及びｆｌｔ３阻害化合物、並びにその使用

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