STARCZYNOWSKI DANIEL (US)
THOMAS CRAIG (US)
ROSENBAUM JAN (US)
THE US SECRETARY DEPARTMENT OF HEALTH AND HUMAN SERVIC (US)
KUROME THERAPEUTICS INC (US)
| CLAIMS 1. A compound of Formula (I) or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof, wherein: A is selected from N and CR3, E is selected from N and CR4, G is selected from N and CR5, wherein no more than one of A, E, and G is N; R1 is H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, -C(=O)NR31aR31b, cycloalkyl, spiro-fused cycloalkyl, -O-cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, which methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, oxo, methanoyl (-COH), carboxy (- CO2H), nitro (-NO2), -NH2, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl which is substituted with cycloalkyl; R2 is H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, spiro-fused heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, which methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro- fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), - NH2, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, - CON(CH3)2, C1-C7 alkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl which is substituted with cycloalkyl; R3, R4, and R5 are independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, which methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl which is substituted with cycloalkyl; R6 is R7, R8, R9, R10, R11, R12, R13, R14 are independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1- C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, which methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more halogen; R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R29, R29, and R30 are independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (- CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, which methanoyl (-COH), carboxy (-CO2H), C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, cycloalkyl, spiro- fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more halogen; R31a and R31b are each independently selected from H, C1-C6 alkyl, -(CH2)a-(C3-C6 cycloalkyl), –(CH2)b-C2-C6 heterocyclyl, –(CH2)c-C3-C9 heteroaryl, -(C1-C6 alkyl)-O-(C1-C6 alkyl), wherein the C1-C6 alkyl, C3-C7 cycloalkyl, C2-C6 heterocyclyl, and C3-C9 heteroaryl are each independently optionally substituted with one or more of halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO2H), nitro (-NO2), -NH2, -N(CH3)2, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH2, -CON(CH3)2, C1-C7 alkyl, C1-C7 perfluorinated alkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, or C1-C7 alkyl which is substituted with cycloalkyl; a, b, and c are each independently selected from 0, 1, 2, 3, 4, 5, or 6; and m, n, o, p, q, r, s, t, u, v, w, and x are each independently selected from 0, 1, 2, 3, 4, or 5, where q+r+s+t is at least 1, and where u+v+w+x is at least 1. 2. The compound of claim 1, 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 CR22a; E is N or CR23a; G is N or CR24a; R20a is selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and -O-(C3- C6 cycloalkyl), wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, and wherein C3-C6 cycloalkyl and -O-(C3-C6 cycloalkyl) are each optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen; R21a is selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C12 spiro-fused cycloalkyl, -O-(C3-C6 cycloalkyl), C3-C9 heterocyclyl, and C5-C10 spiro-fused heterocyclyl, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, and wherein C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), and C3-C9 heterocyclyl are each optionally substituted with one or more substituents selected from C1-C6 alkyl, halogen, =O, and -OH; R22a, R23a, and R24a are each independently selected from H and halogen; R25a, R25a’, R26a, R26a’, R27a, and R27a’ are each independently selected from H, halogen, - OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more halogen atoms; and one of A, E, or G is N. 3. The compound of claim 2, wherein R20a is selected from halogen, unsubstituted C1-C6 alkoxy, C1-C6 alkoxy substituted with one or more F, unsubstituted C3-C6 cycloalkyl, and unsubstituted -O-(C3-C6 cycloalkyl); and/or wherein R21a is selected from C1-C6 alkyl substituted with one or more -OH; unsubstituted C1-C6 alkoxy; C1-C6 alkoxy substituted with one or more - OH and/or F; unsubstituted C3-C6 cycloalkyl; C3-C6 cycloalkyl substituted with one or more - CH3, -OH, and/or F; unsubstituted C3-C5 heterocyclyl comprising one oxygen, one nitrogen, or one oxygen and one nitrogen; C3-C5 heterocyclyl comprising one nitrogen and substituted with one or more -CH3, F, and/or =O; C7-C9 spiro-fused cycloalkyl; and C5-C8 spiro-fused heterocyclyl comprising one oxygen, one nitrogen, or one oxygen and one nitrogen. 4. The compound of claim 2 or 3, wherein at least one of (i)-(vi) applies: (i) R20a is H; (ii) R20a is selected from Cl, -OCH3, unsubstituted C3 cycloalkyl, (iii) R21a is H; (iv) R21a is selected from is -OCH2CH3, unsubstituted C3 cycloalkyl, unsubstituted C4 cycloalkyl, unsubstituted C5 cycloalkyl, unsubstituted C6 cycloalkyl, (v) R25a, R25a’, R26a, R26a’, R27a, and R27a’ are each H; or (vi) each of R25a, R26a, R26a’, R27a, and R27a’ is H and R25a is F. 5. The compound of any one of claims 2-4, wherein one of (i)-(iii) applies: (i) A is N, E is CR23a, and G is CR24a; (ii) A is CR22a, E is N, and G is CR24a; or (iii) A is CR22a, E is CR23a, and G is N. 6. The compound of claim 5, wherein one of (i)-(vi) applies: (i) A is N, E is CR23a, and G is CR24a, wherein R23a and R24a are each H; (ii) A is N, E is CR23a, and G is CR24a, wherein R23a is H and R24a is F or R23a is F and R24a is H; (iii) A is CR22a, E is N, and G is CR24a, wherein R22a and R24a are each H; (iv) A is CR22a, E is N, and G is CR24a, wherein R22a is F and R24a is H, R22a is H and R24a is F, or R22a and R24a are each F; (v) A is CR22a, E is CR23a, and G is N, wherein R22a and R23a are each H; or (vi) A is CR22a, E is CR23a, and G is N, wherein R22a is F and R23a is H or R22a is H and R23a is F. 7. The compound of any one of claims 2-6, wherein the compound Formula (IIa-2N) is selected from: or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. 8. The compound of claim 1, wherein 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; wherein: A is N or CR22b; E is N or CR23b; G is N or CR24b; is selected from R20b is selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and -O-(C3- C6 cycloalkyl), wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, and wherein C3-C6 cycloalkyl and -O-(C3-C6 cycloalkyl) are each optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen; R21b is selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C12 spiro-fused cycloalkyl, -O-(C3-C6 cycloalkyl), C3-C9 heterocyclyl, and C5-C10 spiro-fused heterocyclyl, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, and wherein C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), and C3-C9 heterocyclyl are each optionally substituted with one or more substituents selected from C1-C6 alkyl, halogen, =O, and -OH; R22b, R23b, and R24b are each independently selected from H and halogen; R25b, R25b’, R26b, R26b’, R27b, R27b’, R28b, R28b’, R29b, and R29b’ are each independently selected from H, halogen, -OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more halogen atoms; and one of A, E, or G is N. 9. The compound of claim 8, wherein R20b is selected from halogen, unsubstituted C1-C6 alkoxy, C1-C6 alkoxy substituted with one or more F, unsubstituted C3-C6 cycloalkyl, and unsubstituted -O-(C3-C6 cycloalkyl); and/or wherein R21b is selected from C1-C6 alkyl substituted with one or more -OH; unsubstituted C1-C6 alkoxy; C1-C6 alkoxy substituted with one or more - OH and/or F; unsubstituted C3-C6 cycloalkyl; C3-C6 cycloalkyl substituted with one or more - CH3, -OH, and/or F; unsubstituted C3-C5 heterocyclyl comprising one oxygen, one nitrogen, or one oxygen and one nitrogen; C3-C5 heterocyclyl comprising one nitrogen and substituted with one or more -CH3, F, and/or =O; C7-C9 spiro-fused cycloalkyl; and C5-C8 spiro-fused heterocyclyl comprising one oxygen, one nitrogen, or one oxygen and one nitrogen. 10. The compound of claim 8 or 9, wherein at least one of (i)-(vi) applies: (i) R20b is H; (ii) R20b is selected from Cl, -OCH3, , , unsubstituted C3 cycloalkyl, and (iii) R21b is H; (iv) R21b is selected from is -OCH2CH3, unsubstituted C3 cycloalkyl, unsubstituted C4 cycloalkyl, unsubstituted C5 cycloalkyl, unsubstituted C6 cycloalkyl, (v) and R25b, R25b’, R27b, R27b’, R28b, R28b,, R29b, and R29b’ are each H; or (vi) and R25b, R25b’, R27b, R27b’, R28b, R29b, and R29b’ are each H and R28b, is F. 11. The compound of any one of claims 8-10, wherein one of (i)-(iii) applies: (i) A is N, E is CR23b, and G is CR24b; (ii) A is CR22b, E is N, and G is CR24b; or (iii) A is CR22b, E is CR23b, and G is N. 12. The compound of claim 11, wherein one of (i)-(vi) applies: (i) A is N, E is CR23b, and G is CR24b, wherein R23b and R24b are each H; (ii) A is N, E is CR23b, and G is CR24b, wherein R23b is H and R24b is F or R23b is F and R24b is H; (iii) A is CR22b, E is N, and G is CR24b, wherein R22b and R24b are each H; (iv) A is CR22b, E is N, and G is CR24b, wherein R22b is F and R24b is H, R22b is H and R24b is F, or R22b and R24b are each F; (v) A is CR22b, E is CR23b, and G is N, wherein R22b and R23b are each H; or (vi) A is CR22b, E is CR23b, and G is N, wherein R22b is F and R23b is H or R22b is H and R23b is F. 13. The compound of any one of claims 8-12, wherein the compound Formula (IIb-2N) is selected from: , or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. 14. The compound of claim 1, 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: R20a is selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and -O-(C3- C6 cycloalkyl), wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, and wherein C3-C6 cycloalkyl and -O-(C3-C6 cycloalkyl) are each optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen; R21a is selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C12 spiro-fused cycloalkyl, -O-(C3-C6 cycloalkyl), C3-C9 heterocyclyl, and C5-C10 spiro-fused heterocyclyl, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, and wherein C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), and C3-C9 heterocyclyl are each optionally substituted with one or more substituents selected from C1-C6 alkyl, halogen, =O, and -OH; R22a, R23a, and R24a are each independently selected from H, CN, and halogen; and R25a, R25a’, R26a, R26a’, R27a, and R27a’ are each independently selected from H, halogen, - OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more halogen atoms. 15. The compound of claim 14, wherein R20a is selected from halogen, unsubstituted C1-C6 alkoxy, C1-C6 alkoxy substituted with one or more F, unsubstituted C3-C6 cycloalkyl, and unsubstituted -O-(C3-C6 cycloalkyl); and/or wherein R21a is selected from C1-C6 alkyl substituted with one or more -OH; unsubstituted C1-C6 alkoxy; C1-C6 alkoxy substituted with one or more - OH and/or F; unsubstituted C3-C6 cycloalkyl; C3-C6 cycloalkyl substituted with one or more - CH3, -OH, and/or F; unsubstituted C3-C5 heterocyclyl comprising one oxygen, one nitrogen, or one oxygen and one nitrogen; C3-C5 heterocyclyl comprising one nitrogen and substituted with one or more -CH3, F, and/or =O; C7-C9 spiro-fused cycloalkyl; and C5-C8 spiro-fused heterocyclyl comprising one oxygen, one nitrogen, or one oxygen and one nitrogen. 16. The compound of claim 14 or 15, wherein at least one of (i)-(viii) applies: (i) R20a is H; (ii) R20a is selected from Cl, -OCH3, unsubstituted C3 cycloalkyl, and (iii) R21a is H; (iv) R21a is selected from -OCH2CH3, unsubstituted C3 cycloalkyl, unsubstituted C4 cycloalkyl, unsubstituted C5 cycloalkyl, unsubstituted C6 cycloalkyl, (v) R22a, R23a, and R24a are each H; (vi) R22a is selected from F and CN, R23a is H, and R24a is H; R22a is H, R23a is H, and R24a is selected from F and CN; or R22a is selected from F and CN, R23a is H, and R24a is selected from F and CN; (vii) R25a, R25a’, R26a, R26a’, R27a, and R27a’ are each H; or (viii) each of R25a, R26a, R26a’, R27a, and R27a’ is H and R25a’ is F. 17. The compound of any one of claims 14-16, wherein the compound of Formula (IIa) is selected from: or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. 18. The compound of claim 1, wherein 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 R20b is selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and -O-(C3- C6 cycloalkyl), wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, and wherein C3-C6 cycloalkyl and -O-(C3-C6 cycloalkyl) are each optionally substituted with one or more substituents selected from C1-C6 alkyl and halogen; R21b is selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C12 spiro-fused cycloalkyl, -O-(C3-C6 cycloalkyl), C3-C9 heterocyclyl, and C5-C10 spiro-fused heterocyclyl, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, and wherein C3-C6 cycloalkyl, -O-(C3-C6 cycloalkyl), and C3-C9 heterocyclyl are each optionally substituted with one or more substituents selected from C1-C6 alkyl, halogen, =O, and -OH; R22b, R23b, and R24b are each independently selected from H, CN, and halogen; and R25b, R25b’, R26b, R26b’, R27b, R27b’, R28b, R28b,, R29b, and R29b’ are each independently selected from H, halogen, -OH, C1-C6 alkyl, and C1-C6 alkoxy, wherein C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more halogen atoms. 19. The compound of claim 18, wherein R20b is selected from halogen, unsubstituted C1-C6 alkoxy, C1-C6 alkoxy substituted with one or more F, unsubstituted C3-C6 cycloalkyl, and unsubstituted -O-(C3-C6 cycloalkyl); and/or wherein R21b is selected from C1-C6 alkyl substituted with one or more -OH; unsubstituted C1-C6 alkoxy; C1-C6 alkoxy substituted with one or more - OH and/or F; unsubstituted C3-C6 cycloalkyl; C3-C6 cycloalkyl substituted with one or more - CH3, -OH, and/or F; unsubstituted C3-C5 heterocyclyl comprising one oxygen, one nitrogen, or one oxygen and one nitrogen; C3-C5 heterocyclyl comprising one nitrogen and substituted with one or more -CH3, F, and/or =O; C7-C9 spiro-fused cycloalkyl; and C5-C8 spiro-fused heterocyclyl comprising one oxygen, one nitrogen, or one oxygen and one nitrogen. 20. The compound of claim 18 or 19, wherein at least one of (i)-(viii) applies: (i) R20b is H; (ii) R20b is selected from Cl, -OCH3, unsubstituted C3 cycloalkyl, and (iii) R21b is H; (iv) R21b is selected from is -OCH2CH3, unsubstituted C3 cycloalkyl, unsubstituted C4 cycloalkyl, unsubstituted C5 cycloalkyl, unsubstituted C6 cycloalkyl, (v) R22b, R23b, and R24a are each H; (vi) R22b is selected from F and CN, R23b is H, and R24b is H; R22b is H, R23b is H, and R24b is selected from F and CN; or R22b is selected from F and CN, R23b is H, and R24b is selected from F and CN; (vii) wherein R25b, R25b’, R27b, R27b’, R28b, R28b’, R29b, and R29b’ are each H; or (viii) wherein each of R25b, R25b’, R27b, R27b’, R28b, R29b, and R29b’ is H and R28b’ is F. 21. The compound of any one of claims 18-20, wherein the compound of Formula (IIb) is selected from: or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. 22. The compound of any one of claims 1-21, wherein the compound is an inhibitor of at least one of IRAK1, IRAK4, and FLT3. 23. The compound of any one of claims 1-22, wherein the compound is an inhibitor of IRAK1 and IRAK4. 24. The compound of any one of claims 1-22, wherein the compound is an inhibitor of IRAK1, IRAK4, and FLT3. 25. A composition comprising a compound of any one of claims 1-24 wherein the composition further comprises a formulary ingredient, an adjuvant, or a carrier. 26. The composition of claim 25, 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 mTOR inhibitor, a steroid or glucocorticoid, a steroid or glucocorticoid receptor modulator, an EZH2 inhibitor, a hedgehog (Hh) inhibitor, a Topoisomerase I inhibitor, a Topoisomerase II inhibitor, an aminopeptidase/Leukotriene A4 hydrolase inhibitor, a FLT3/Axl/ALK inhibitor, a FLT3/KIT/PDGFR, PKC, and/or KDR inhibitor, a Syk inhibitor, an E-selectin inhibitor, an NEDD8-activator, an MDM2 inhibitor, a PLK1 inhibitor, an Aura A inhibitor, an aurora kinase inhibitor, an EGFR inhibitor, an AuroraB/C/VEGFR1/2/3/FLT3/CSF-1R/Kit/PDGFRA/B inhibitor, an AKT 1, 2, and/or 3 inhibitor, a ABL1/2/SRC/EPHA2/LCK/YES1/KIT/PDGFRB/FYN inhibitor, a farnesyltransferase inhibitor, a BRAF/MAP2K1/MAP2K2 inhibitor, a Menin-KMT2A/MLL inhibitor, and a multikinase inhibitor. 27. The composition of claim 26, 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. 28. The composition of claim 27, wherein: the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof, the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof, the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone or a pharmaceutically acceptable salt of any one thereof, the CDK inhibitor is selected from CDK4/6 inhibitor Palbociclib, CDK7 inhibitor THZ1, and/or CDK9 inhibitors BAY1251152 and Atuveciclib, or a pharmaceutically acceptable salt of any one thereof, or DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof. 29. A method of treating a disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-24 or a composition of claim 25. 30. The method of claim 29, wherein the method comprises administering to the subject a composition comprising the therapeutically effective amount of the compound of claim 1 and a formulary ingredient, an adjuvant, or a carrier. 31. The method of claim 29 or 30, 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. 32. The method of any one of claims 29-31, wherein the administration comprises parenteral administration, mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration. 33. The method of any one of claims 29-32, 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. 34. The method of any one of claims 29-33, wherein the disease or disorder comprises a hematopoietic cancer. 35. The method of any one of claims 29-33, wherein 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, 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 (ii) at least one inflammatory disease or autoimmune disease selected from chronic inflammation, sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, Crohn’s disease, and colitis. 36. The method of any one of claims 29-35, further comprising administering to the subject one or more additional therapies selected from: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, a BTK inhibitor, a DNA methyltransferase inhibitor/hypomethylating agent, an anthracycline, a histone deacetylase (HDAC) inhibitor, a purine nucleoside analogue (antimetabolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor, an antibody- drug conjugate, an mAbs/immunotherapy, a Plk inhibitor, a MEK inhibitor, a CDK inhibitor, a CDK9 inhibitor, a CDK8 inhibitor, a retinoic acid receptor agonist, a TP53 activator, a CELMoD, a smoothened receptor antagonist, an ERK inhibitor including an ERK2/MAPK1 or ERK1/MAPK3 inhibitor, a PI3K inhibitor, an mTOR inhibitor, a steroid or glucocorticoid, a steroid or glucocorticoid receptor modulator, an EZH2 inhibitor, a hedgehog (Hh) inhibitor, a Topoisomerase I inhibitor, a Topoisomerase II inhibitor, an aminopeptidase/Leukotriene A4 hydrolase inhibitor, a FLT3/Axl/ALK inhibitor, a FLT3/KIT/PDGFR, PKC, and/or KDR inhibitor, a Syk inhibitor, an E-selectin inhibitor, an NEDD8-activator, an MDM2 inhibitor, a PLK1 inhibitor, an Aura A inhibitor, an aurora kinase inhibitor, an EGFR inhibitor, an AuroraB/C/VEGFR1/2/3/FLT3/CSF-1R/Kit/PDGFRA/B inhibitor, an AKT 1, 2, and/or 3 inhibitor, a ABL1/2/SRC/EPHA2/LCK/YES1/KIT/PDGFRB/FYN inhibitor, a farnesyltransferase inhibitor, a BRAF/MAP2K1/MAP2K2 inhibitor, a Menin-KMT2A/MLL inhibitor, and a multikinase inhibitor. 37. The method of claim 36, wherein the additional therapy is a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, or a DNA methyltransferase inhibitor. 38. The method of claim 37, wherein: the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof, the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof, the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone, or a pharmaceutically acceptable salt of any one thereof, the CDK inhibitor is selected from CDK4/6 inhibitor palbociclib, CDK7 inhibitor THZ1, and/or CDK9 inhibitors BAY1251152 and atuveciclib, or a pharmaceutically acceptable salt of any one thereof, or the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof. 39. The method of any one of claims 29-38, wherein the disease or disorder is a BCL2 inhibitor resistant disease or disorder. 40. The method of claim 39, wherein 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. 41. The method of any one of claims 29-38, wherein the disease or disorder is a FLT3 inhibitor resistant disease or disorder. 42. The method of claim 41, wherein the disease or disorder is FLT3 inhibitor resistant acute myeloid leukemia (AML), FLT3 inhibitor resistant refractory AML, or FLT3 inhibitor resistant relapsed AML. 43. The method of claim 36, wherein the compound of any one of claims 1-24 or the composition of claim 25 and the one or more additional therapies are administered together in one administration or composition. 44. The method of claim 36, wherein the compound of any one of claims 1-24 or the composition of claim 25 and the one or more additional therapies are administered separately in more than one administration or more than one composition. 45. The method of any one of claims 29-44, wherein the disease or disorder is alleviated by inhibiting at least one of IRAKI, IRAK4, and FLT3 in the subject. 46. The method of any one of claims 29-45, wherein the disease or disorder is alleviated by inhibiting IRAK1 and IRAK4 in the subject. 47. The method of any one of claims 29-45, wherein the disease or disorder is alleviated by inhibiting IRAKI, IRAK4, and FLT3 in the subject. 48. The method of any one of claims 29-47, wherein the compound is a compound of any one of Formula (I), Formula (Ila), Formula (lib), Formula (IIa-2N), Formula (IIb-2N), Formulas (Illa)-(IIIp), Formulas (IIIa-2N)-(IIIp-2N), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. |
FIELD
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.
CROSS-REFERENCE TO RELATED APPLICATIONS
The present application claims priority to U.S. Provisional Application No. 63/378,300, filed October 4, 2022 and U.S. Provisional Application No. 63/378,306, filed October 4, 2022, each of which is incorporated by reference herein in its entirety.
GOVERNMENT RIGHTS
This invention was made in the performance of a Cooperative Research and Development Agreement with the National Institutes of Health, an Agency of the Department of Health and Human Services. The Government of the United States has certain rights in this invention.
BACKGROUND
Myelodysplastic syndromes (MDS) are malignant, potentially fatal blood diseases that arise from a defective hematopoietic stem/progenitor cell, confer a predisposition to acute myeloid leukemia (AML) (Corey et al., 2007; Nimer, 2008), and often progress to chemotherapy-resistant secondary acute myeloid leukemia (sAML). A majority of patients having MDS die of marrow failure, immune dysfunction, and/or transformation to overt leukemia.
MDS are heterogeneous diseases with few treatment options, as there is a lack of effective medicines capable of providing a durable response. Current treatment options for MDS are limited but include allogeneic HSC transplantation, demethylating agents, and immunomodulatory therapies (Ebert, 2010). While hemopoietic stem cell (HSC) transplantation can be used as a curative treatment for MDS, this option is unavailable to many older patients, who instead receive supportive care and transfusions to ameliorate disease complications. Unfortunately, MDS clones can persist in the marrow even after HSC transplantation, and the disease invariably advances (Tehranchi et al., 2010). For advanced disease or high-risk MDS, patients may also receive immunosuppressive therapy, epigenetic modifying drugs, and/or chemotherapy (Greenberg, 2010). Despite recent progress, most MDS patients exhibit treatment-related toxicities or relapse (Sekeres, 2010a). Overall, the efficacy of these treatments is variable, and generally life expectancies are only slightly improved as compared to supportive care. The complexity and heterogeneity of MDS, and the lack of human xenograft models are obstacles which are challenging for identifying and evaluating novel molecular targets for this disease. Approximately 30% of MDS patients also develop aggressive AML due to acquisition of additional mutations in the defective hematopoietic stem/progenitor cell (HSPC) (Greenberg et al., 1997). AML is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute leukemia affecting adults, and its incidence increases with age. Although AML is a relatively rare disease, accounting for approximately 1.2% of cancer deaths in the United States, its incidence is expected to increase as the population ages. Several risk factors and chromosomal abnormalities have been identified, but the specific cause is not clear. As an acute leukemia, AML progresses rapidly and is typically fatal within weeks or months if left untreated. The prognosis for AML that arises from MDS is worse as compared to other types of AML. Several compounds are known to treat blood disorders and cancers (e.g. MDS, AML), but do so inadequately. While some known compounds, such as Quizartinib and Crenolanib, can be used to treat AML, some of these treatments do not result in complete remission or partial remission. In some instances, for example, treatment can result in adaptive resistance or selecting mutations that are resistant to inhibitors, as with Quizartinib, in particular, where repeated administration can lead to desensitization in tumor cell suppression of proliferation. In treating MDS and/or AML, it is important to develop therapies capable of inhibiting the adaptive resistance mechanism, to improve survival in the context of AML and MDS. There is also an unmet need in AML for drugs that increase overall survival, decrease the length of hospital stay as well as hospital readmission rates, overcome acquired resistance to other treatments, and increase the success rate for hematopoietic stem cell transplant. There is additionally a need for drugs for treating MDS which can slow the conversion rate to AML, and decrease transfusion dependence. It is therefore necessary to develop treatments and methods of effectively treating MDS and/or AML. Additionally, in doing so, it will be important to determine whether a patient is likely to be responsive to a particular treatment or method of treatment. Certain embodiments of the disclosure can address one or more of these issues. SUMMARY OF THE DISCLOSURE In one aspect, the present disclosure provides a compound of Formula (I) or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof, wherein: A is selected from N and CR 3 , E is selected from N and CR 4 , G is selected from N and CR 5 , wherein no more than one of A, E, and G is N; 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 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-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(CH 3 ) 2 , C 1 -C 7 alkyl, C 1 -C 7 perfluorinated alkyl, C 1 -C 7 alkoxy, C 1 -C 7 haloalkoxy, or C 1 -C 7 alkyl which is substituted with cycloalkyl; R 2 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, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, spiro-fused 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 fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, oxo, 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(CH 3 ) 2 , C 1 -C 7 alkyl, C 1 -C 7 perfluorinated alkyl, C 1 -C 7 alkoxy, C 1 -C 7 haloalkoxy, or C 1 -C 7 alkyl which is substituted with cycloalkyl; R 3 , R 4 , and R 5 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 fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, oxo, 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(CH 3 ) 2 , C 1 -C 7 alkyl, C 1 -C 7 perfluorinated alkyl, C 1 -C 7 alkoxy, C 1 -C 7 haloalkoxy, or C 1 -C 7 alkyl which is substituted with cycloalkyl; R 6 is R 7 , R 8 , R 9 , R 10 , R 11 , R 12 13 , R , 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 fused ring heteroaryl 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 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 fused ring heteroaryl is optionally substituted with one or more halogen; R 31a and R 31b are each independently selected from H, C 1 - C 6 alkyl, -(CH 2 ) a -(C 3 -C 6 cycloalkyl), –(CH 2 ) b -C 2 -C 6 heterocyclyl, –(CH 2 ) c -C 3 -C 9 heteroaryl, - (C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), wherein the C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 heterocyclyl, and C 3 -C 9 heteroaryl are each independently optionally substituted with one or more of halogen, hydroxy, oxo, 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(CH 3 ) 2 , C 1 -C 7 alkyl, C 1 -C 7 perfluorinated alkyl, C 1 -C 7 alkoxy, C 1 -C 7 haloalkoxy, or C 1 -C 7 alkyl which is substituted with cycloalkyl; a, b, and c are each independently selected from 0, 1, 2, 3, 4, 5, or 6; and m, n, o, p, q, r, s, t, u, v, w, and x are each independently selected from 0, 1, 2, 3, 4, or 5, where q+r+s+t is at least 1, and where u+v+w+x is at least 1. In one embodiment, 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 halogen; R 21a is selected from H, halogen, C 1 - C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 6 -C 12 spiro-fused cycloalkyl, -O-(C 3 -C 6 cycloalkyl), C 3 -C 9 heterocyclyl, and C 5 -C 10 spiro-fused heterocyclyl, 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, -O-(C 3 -C 6 cycloalkyl), and C 3 -C 9 heterocyclyl are each optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, halogen, =O, and -OH; R 22a , R 23a , and R 24a are each independently selected from H and halogen; R 25a , R 25a’ , R 26a , R 26a’ , R 27a , and R 27a’ are each independently selected from H, halogen, -OH, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy, wherein C 1 -C 6 alkyl and C 1 -C 6 alkoxy are each optionally substituted with one or more halogen atoms; and one of A, E, or G is N. In one embodiment, 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 and substituted with one or more -CH 3 , F, and/or =O; C 7 -C 9 spiro-fused cycloalkyl; and C 5 -C 8 spiro- fused heterocyclyl comprising one oxygen, one nitrogen, or one oxygen and one nitrogen. In one embodiment, at least one of (i)-(vi) applies: (i) R 20a is H; (ii) R 20a is selected from Cl, -OCH 3 , , , unsubstituted C 3 cycloalkyl, and (iii) R 21a is H; (iv) 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 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. In one embodiment, 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. In one embodiment, 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 23a , and G is N, wherein R 22a is F and R 23a is H or R 22a is H and R 23a is F. In one embodiment, the compound Formula (IIa-2N) is selected from: or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. In one embodiment, 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;
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 -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 21b is selected from H, halogen, C 1 - C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 6 -C 12 spiro-fused cycloalkyl, -O-(C 3 -C 6 cycloalkyl), C 3 -C 9 heterocyclyl, and C 5 -C 10 spiro-fused heterocyclyl, 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, -O-(C 3 -C 6 cycloalkyl), and C 3 -C 9 heterocyclyl are each optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, halogen, =O, and -OH; 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; and one of A, E, or G is N. In one embodiment, 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 and substituted with one or more -CH 3 , F, and/or =O; C 7 -C 9 spiro-fused cycloalkyl; and C 5 -C 8 spiro-fused heterocyclyl comprising one oxygen, one nitrogen, or one oxygen and one nitrogen. In one embodiment, at least one of (i)-(vi) applies: (i) R 20b is H; (ii) R 20b is selected from Cl, -OCH 3 , unsubstituted C 3 cycloalkyl, and R 21b is H; (iv) 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. In one embodiment, 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. In one embodiment, 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 23b , and G is N, wherein R 22b is F and R 23b is H or R 22b is H and R 23b is F. In one embodiment, the compound Formula (IIb-2N) is selected from: or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. In one embodiment, 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 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 6 -C 12 spiro-fused cycloalkyl, -O-(C 3 -C 6 cycloalkyl), C 3 -C 9 heterocyclyl, and C 5 -C 10 spiro-fused heterocyclyl, 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, -O- (C 3 -C 6 cycloalkyl), and C 3 -C 9 heterocyclyl are each optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, halogen, =O, and -OH; R 22a , R 23a , and R 24a are each independently selected from H, CN, and halogen; and R 25a , R 25a’ , R 26a , R 26a’ , R 27a , and R 27a’ 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. In one embodiment, 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 and substituted with one or more -CH 3 , F, and/or =O; C 7 -C 9 spiro-fused cycloalkyl; and C 5 -C 8 spiro-fused heterocyclyl comprising one oxygen, one nitrogen, or one oxygen and one nitrogen. In one embodiment, at least one of (i)- (viii) applies: (i) R 20a is H; (ii) R 20a is selected from Cl, -OCH 3 , unsubstituted C 3 cycloalkyl, and (iii) R 21a is H; (iv) 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 F and CN, R 23a is H, and R 24a is selected from F and CN; (vii) R 25a , R 25a’ , R 26a , R 26a’ , R 27a , and R 27a’ are each H; or (viii) each of R 25a , R 26a , R 26a’ , R 27a , and R 27a’ is H and R 25a’ is F. In one embodiment, the compound of Formula (IIa) is selected from:
or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. In one embodiment, 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 alkyl and halogen; R 21b is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 6 -C 12 spiro-fused cycloalkyl, -O-(C 3 -C 6 cycloalkyl), C 3 -C 9 heterocyclyl, and C 5 -C 10 spiro-fused heterocyclyl, 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, -O-(C 3 -C 6 cycloalkyl), and C 3 -C 9 heterocyclyl are each optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, halogen, =O, and -OH; R 22b , R 23b , and R 24b are each independently selected from H, CN, and halogen; and 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. In one embodiment, 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 and substituted with one or more -CH 3 , F, and/or =O; C 7 -C 9 spiro-fused cycloalkyl; and C 5 -C 8 spiro-fused heterocyclyl comprising one oxygen, one nitrogen, or one oxygen and one nitrogen. In one embodiment, at least one of (i)- (viii) applies: (i) R 20b is H; (ii) R 20b is selected from Cl, -OCH 3 , , , unsubstituted C 3 cycloalkyl, and (iii) R 21b is H; (iv) 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, (v) R 22b , R 23b , and R 24a are each H; (vi) 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 R 22b is selected from F and CN, R 23b is H, and R 24b is selected from F and CN; (vii) wherein R 25b , R 25b’ , R 27b , R 27b’ , R 28b , R 28b’ , R 29b , and R 29b’ are each H; or (viii) wherein 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, the compound of Formula (IIb) is selected from:
or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. In one embodiment, 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 at least one of IRAK1, IRAK4, and FLT3. In one embodiment, 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. In one embodiment, 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. In another aspect, the present disclosure provides 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. In one embodiment, 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 steroid or glucocorticoid, a steroid or glucocorticoid receptor modulator, an EZH2 inhibitor, a hedgehog (Hh) inhibitor, a Topoisomerase I inhibitor, a Topoisomerase II inhibitor, an aminopeptidase/Leukotriene A4 hydrolase inhibitor, a FLT3/Axl/ALK inhibitor, a FLT3/KIT/PDGFR, PKC, and/or KDR inhibitor, a Syk inhibitor, an E-selectin inhibitor, an NEDD8-activator, an MDM2 inhibitor, a PLK1 inhibitor, an Aura A inhibitor, an aurora kinase inhibitor, an EGFR inhibitor, an AuroraB/C/VEGFR1/2/3/FLT3/CSF-1R/Kit/PDGFRA/B inhibitor, an AKT 1, 2, and/or 3 inhibitor, a ABL1/2/SRC/EPHA2/LCK/YES1/KIT/PDGFRB/FYN inhibitor, a farnesyltransferase inhibitor, a BRAF/MAP2K1/MAP2K2 inhibitor, a Menin-KMT2A/MLL inhibitor, and a multikinase inhibitor. In one embodiment, the 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. In one embodiment, the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof, the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof, the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone or a pharmaceutically acceptable salt of any one thereof, the CDK inhibitor is selected from CDK4/6 inhibitor Palbociclib, CDK7 inhibitor THZ1, and/or CDK9 inhibitors BAY1251152 and Atuveciclib, or a pharmaceutically acceptable salt of any one thereof, or DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof. In yet another aspect, the present disclosure provides a method of treating a disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of Formula (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. In one embodiment, the method comprises administering to the subject a composition comprising the therapeutically effective amount of the compound of Formula (I) or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof, and a formulary ingredient, an adjuvant, or a carrier. In one embodiment, the disease or disorder is responsive to at least one of interleukin-1 receptor-associated kinase (IRAK) inhibition and fms-like tyrosine kinase 3 (FLT3) inhibition. In one embodiment, the administration comprises parenteral administration, mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration. In one embodiment, the compound is administered to the subject in an amount of from about 0.005 mg/kg subject body weight to about 1,000 mg /kg subject body weight. In one embodiment, the disease or disorder comprises a hematopoietic cancer. In one embodiment, 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, 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 (ii) at least one inflammatory disease or autoimmune disease selected from chronic inflammation, sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, Crohn’s disease, and colitis. In one embodiment, the method further comprises administering to the subject one or more additional therapies selected from: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, a BTK inhibitor, a DNA methyltransferase inhibitor/hypomethylating agent, an anthracycline, a histone deacetylase (HDAC) inhibitor, a purine nucleoside analogue (antimetabolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor, an antibody-drug conjugate, an mAbs/immunotherapy, a Plk inhibitor, a MEK inhibitor, a CDK inhibitor, a CDK9 inhibitor, a CDK8 inhibitor, a retinoic acid receptor agonist, a TP53 activator, a CELMoD, a smoothened receptor antagonist, an ERK inhibitor including an ERK2/MAPK1 or ERK1/MAPK3 inhibitor, a PI3K inhibitor, an mTOR inhibitor, a steroid or glucocorticoid, a steroid or glucocorticoid receptor modulator, an EZH2 inhibitor, a hedgehog (Hh) inhibitor, a Topoisomerase I inhibitor, a Topoisomerase II inhibitor, an aminopeptidase/Leukotriene A4 hydrolase inhibitor, a FLT3/Axl/ALK inhibitor, a FLT3/KIT/PDGFR, PKC, and/or KDR inhibitor, a Syk inhibitor, an E-selectin inhibitor, an NEDD8-activator, an MDM2 inhibitor, a PLK1 inhibitor, an Aura A inhibitor, an aurora kinase inhibitor, an EGFR inhibitor, an AuroraB/C/VEGFR1/2/3/FLT3/CSF-1R/Kit/PDGFRA/B inhibitor, an AKT 1, 2, and/or 3 inhibitor, a ABL1/2/SRC/EPHA2/LCK/YES1/KIT/PDGFRB/FYN inhibitor, a farnesyltransferase inhibitor, a BRAF/MAP2K1/MAP2K2 inhibitor, a Menin-KMT2A/MLL inhibitor, and a multikinase inhibitor. In one embodiment, the additional therapy is at least one of a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor. In one embodiment, the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof, the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof, the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone, or a pharmaceutically acceptable salt of any one thereof, the CDK inhibitor is selected from CDK4/6 inhibitor palbociclib, CDK7 inhibitor THZ1, and/or CDK9 inhibitors BAY1251152 and atuveciclib, or a pharmaceutically acceptable salt of any one thereof, or the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof. In one embodiment, the disease or disorder is a BCL2 inhibitor resistant disease or disorder. In one embodiment, the disease or disorder is 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. In one embodiment, the disease or disorder is a FLT3 inhibitor resistant disease or disorder. In one embodiment, the disease or disorder is FLT3 inhibitor resistant acute myeloid leukemia (AML), FLT3 inhibitor resistant refractory AML, or FLT3 inhibitor resistant relapsed AML. In one embodiment, 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. In one embodiment, 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. In one embodiment, 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. In one embodiment, 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. DETAILED DESCRIPTION The following related applications are incorporated by reference herein in their entirety, and for all purposes: International Publication No. WO 2018081738, TREATMENT OF DISEASES ASSOCIATED WITH ACTIVATED IRAK, filed October 30, 2017; U.S. Publication No.2021/0292843, TREATMENT OF DISEASES ASSOCIATED WITH ACTIVATED IRAK, filed April 4, 2019; International Publication No. WO 2014190163, Combination Therapy for MDS, filed May 22, 2014; U.S. Patent No.9,168,257, Combination Therapy for MDS, issued October 27, 2015; U.S. Patent No.9,504,706, Combination Therapy for MDS, issued November 29, 2016; U.S. Patent No.9,855,273, Combination Therapy for MDS, issued January 2, 2018; International Publication No. WO 2018038988, Compounds, Compositions, Methods for Treating Diseases, and Methods for Preparing Compounds, filed August 16, 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. Publication No.2022/0235042, Substituted Imidazo[l,2- a]-pyridines as IRAK 1/4 and FLT3 Inhibitors, filed January 28, 2022; International Publication No. WO 2020252487, Rational therapeutic targeting of oncogenic immune signaling states in myeloid malignancies via the ubiquitin conjugating enzyme UBE2N, filed June 15, 2020; International Publication No. WO 2022026935, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, filed July 31, 2021; International Publication No. WO 2022140647, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, filed December 23, 2021; International Publication No. 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. While embodiments encompassing the general disclosed concepts may take diverse forms, various embodiments will be described herein, with the understanding that the present disclosure is to be considered merely exemplary, and the general disclosed concepts are not intended to be limited to the disclosed embodiments. Some embodiments of the disclosure 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 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. Unless otherwise noted, 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. Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH 2 O- is equivalent to -OCH 2 -. As used herein, in relation to compounds of Formulae (I), (II), (III), etc., the term “attached” signifies a stable covalent bond, certain preferred points of attachment being apparent to those of ordinary skill in the art. As used herein (unless otherwise specified), the term “alkyl” means a monovalent, straight or branched hydrocarbon chain, which can be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e., C 1 -C 10 means one to ten carbons). For example, the terms “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. Examples of 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. As used herein (unless otherwise specified), the term “alkenyl” means a monovalent, straight or branched hydrocarbon chain that includes one or more (e.g., 1, 2, 3, or 4) double bonds. Double bonds can occur in any stable point along the chain and the carbon-carbon double bonds can have either the cis or trans configuration. For example, this definition shall include but is not limited to ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, 1,5-octadienyl, 1,4,7-nonatrienyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, ethylcyclohexenyl, butenylcyclopentyl, l-pentenyl-3-cyclohexenyl, and the like. Similarly, “heteroalkenyl” refers to heteroalkyl having one or more double bonds. Further examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2- propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1- hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, and 5-hexenyl. As used herein (unless otherwise specified), the term “alkynyl” means a monovalent, straight or branched hydrocarbon chain that includes one or more (e.g., 1, 2, 3, or 4) triple bonds and that also may optionally include one or more (e.g.1, 2, 3, or 4) double bonds in the chain. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1- butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2- hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl. As used herein (unless otherwise specified), the term “alkoxy” means any of the above alkyl, alkenyl, or alkynyl groups which is attached to the remainder of the molecule by an oxygen atom (alkyl-O-). Examples of alkoxy groups include, but are not limited to, methoxy (sometimes shown as MeO-), ethoxy, isopropoxy, propoxy, and butyloxy. The term “alkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, alkenyl, or alkynyl group, as exemplified, but not limited by, -CH 2 CH 2 CH 2 CH 2 -. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the compounds disclosed herein. A “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. As used herein (unless otherwise specified), the term “cycloalkyl” means a monovalent, monocyclic or bicyclic, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 membered hydrocarbon group. The rings can be saturated or partially unsaturated. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and bicycloalkyls (e.g., bicyclooctanes such as [2.2.2]bicyclooctane or [3.3.0]bicyclooctane, bicyclononanes such as [4.3.0]bicyclononane, and bicyclodecanes such as [4.4.0]bicyclodecane (decalin), or spiro compounds). For a monocyclic cycloalkyl, the ring is not aromatic. For a bicyclic cycloalkyl, if one ring is aromatic, then the other is not aromatic. For a bicyclic cycloalkyl, one or both rings can be substituted. The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, consisting of at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, and wherein the nitrogen and sulfur atoms can optionally be oxidized, and the nitrogen heteroatom can optionally be 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. Examples include, but are not limited to: -CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -NH-CH 3 , -CH 2 -CH 2 -N(CH 3 )-CH 3 , -CH 2 -S-CH 2 -CH 3 , -CH 2 -CH 2 , -S(O)-CH 3 , -CH 2 -CH 2 -S(O) 2 -CH 3 , -CH=CH-O-CH 3 , -Si(CH 3 ) 3 , -CH 2 -CH=N-OCH 3 , -CH=CH- N(CH 3 )-CH 3 , -O-CH 3 , -O-CH 2 -CH 3 , and -CN. Up to two heteroatoms can be consecutive, such as, for example, -CH 2 -NH-OCH 3 . Similarly, the term “heteroalkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH 2 -CH 2 -S-CH 2 -CH 2 - and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O) 2 R'- represents both -C(O) 2 R'- and -R'C(O) 2 -. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', -NR'R'', -OR', -SR', and/or -SO 2 R'. Where “heteroalkyl” is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R'' or the like, it will be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R'' or the like. As used herein (unless otherwise specified), the term “halogen” or “halo” means monovalent Cl, F, Br, or I. Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo(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. As used herein (unless otherwise specified), the term “aryl” means a monovalent, monocyclic or bicyclic, 5, 6, 7, 8, 9, 10, 11, or 12 member aromatic hydrocarbon group and also means polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently. A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tolyl, and xylyl. For an aryl that is bicyclic, one or both rings can be substituted. As used herein (unless otherwise specified), the term “heteroaryl” means a monovalent, monocyclic or bicyclic, 5, 6, 7, 8, 9, 10, 11, or 12 membered, hydrocarbon group, where 1, 2, 3, 4, 5, or 6 carbon atoms are replaced by a hetero atom independently selected from nitrogen, oxygen, or sulfur atom, and the monocyclic or bicyclic ring system is aromatic. Heteroaryl groups (or rings) can contain from one to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Thus, the term “heteroaryl” includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring). A 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a 6,6- fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Examples of heteroaryl groups include, but are not limited to, thienyl (or thiophenyl), furyl, indolyl, pyrrolyl, pyridinyl, pyrazinyl, oxazolyl, thiaxolyl, quinolinyl, pyrimidinyl, imidazolyl, triazolyl, tetrazolyl, 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. For a bicyclic heteroaryl, if one ring is aryl, then the other is heteroaryl. For a bicyclic heteroaryl, one or both rings can have one or more hetero atoms. For a bicyclic heteroaryl, one or both rings can be substituted. An “arylene” and a “heteroarylene,” alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. Accordingly, the term "aryl" can represent an unsubstituted, mono-, di- or trisubstituted monocyclic, polycyclic, biaryl and heterocyclic aromatic groups covalently attached at any ring position capable of forming a stable covalent bond, certain preferred points of attachment being apparent to those skilled in the art (e. g.3-indolyl, 4-imidazolyl). The aryl substituents are independently selected from the group consisting of halo, nitro, cyano, trihalomethyl, 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 alkyl, C 1-16 alkylcarbonylaminoC 0-16 alkyl, arylC 1-16 alkylcarbonylaminoC 0- 16 alkyl,-C 0-16 alkylCOOR 4 , -C 0-16 alkylCONR 5 R 6 wherein R 4 , R 5 and R 6 are independently selected from hydrogen, C 1 -C 11 alkyl, arylC 0 -C 11 alkyl, or R 5 and R 6 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with or without one C 1-16 alkyl, arylC 0 -C 16 alkyl, or C 0 -Cl 16 alkylaryl substituent. Aryl includes but is not limited to pyrazolyl and triazolyl. For brevity, the term “aryl” when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above. Thus, the terms “arylalkyl,” “aralkyl” and the like are meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like), or a sulfur atom. Accordingly, the terms "arylalkyl" and the like (e.g. (4- hydroxyphenyl)ethyl, (2-aminonaphthyl)hexyl, pyridylcyclopentyl) represents an aryl group as defined above attached through an alkyl group as defined above having the indicated number of carbon atoms. The terms “cycloalkyl” and “heterocycloalkyl,” also referred to as “heterocyclyl,” by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl,” respectively. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. As used herein (unless otherwise specified), the term “heterocycloalkyl” or “heterocyclyl” means a monovalent, monocyclic or bicyclic, 5, 6, 7, 8, 9, 10, 11, or 12 membered, hydrocarbon, where 1, 2, 3, 4, 5, or 6 carbon atoms are replaced by a hetero atom independently selected from nitrogen atom, oxygen atom, or sulfur atom, and the monocyclic or bicyclic ring system is not aromatic. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of heterocycloalkyl include, but are not limited to, 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, piperazin-3-yl, or piperazin-4-yl), piperidinyl (e.g., piperadin-1-yl, piperadin-2-yl, piperadin-3-yl, or piperadin-4-yl), and morpholinyl (e.g., morpholin-1-yl, morpholin-2-yl, morpholin-3-yl, or morpholin-4-yl,). For a bicyclic heterocyclyl, if one ring is aromatic (e.g., monocyclic aryl or heteroaryl), then the other ring is not aromatic. For a bicyclic heterocyclyl, one or both rings can have one or more hetero atoms. For a bicyclic heterocyclyl, one or both rings can be substituted and the like. A “cycloalkylene” and a “heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively. As used herein (unless otherwise specified), the term “hetero atom” means an atom selected from nitrogen atom, oxygen atom, or sulfur atom. As used herein (unless otherwise specified), the terms “hydroxy” or “hydroxyl” means a monovalent -OH group. The term “acyl” means, unless otherwise stated, -C(O)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. The term “oxo,” as used herein, means an oxygen that is double bonded to a carbon atom. The term “alkylsulfonyl,” as used herein, 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”). The term "carbonyloxy" represents a carbonyl group attached through an oxygen bridge. In the above definitions, the terms "alkyl" and "alkenyl" can be used interchangeably in so far as a stable chemical entity is formed, as would be apparent to those skilled in the art. The term “linker” refers to attachment groups interposed between substituents. In some embodiments, 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. Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl,” and “heteroaryl”, and so forth) includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided herein. As used herein (unless otherwise specified), the term “substituted” (e.g., as in substituted alkyl) means that one or more hydrogen atoms of a chemical group (with one or more hydrogen atoms) can be replaced by one or more non-hydrogen substituents selected from the specified options. The replacement can occur at one or more positions. The term “optionally substituted” means that one or more hydrogen atoms of a chemical group (with one or more hydrogen atoms) can be, but is not required to be substituted. 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 1 -C 7 perfluorinated alkyl, unsubstituted C 1 -C 7 alkoxy, unsubstituted C 1 -C 7 haloalkoxy, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (B) C 1 -C 7 alkyl, C 1 -C 7 heteroalkyl, C 1 -C 7 perfluorinated alkyl, C 1 -C 7 alkoxy, C 1 -C 7 haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, substituted with at least one substituent selected from: (i) -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 1 -C 7 perfluorinated alkyl, unsubstituted C 1 -C 7 alkoxy, unsubstituted C 1 -C 7 haloalkoxy, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (ii) C 1 -C 7 alkyl, C 1 -C 7 heteroalkyl, C 1 -C 7 perfluorinated alkyl, C 1 -C 7 alkoxy, C 1 -C 7 haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, substituted with at least one substituent selected from: (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 1 -C 7 perfluorinated alkyl, unsubstituted C 1 -C 7 alkoxy, unsubstituted C 1 -C 7 haloalkoxy, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (b) C 1 -C 7 alkyl, C 1 -C 7 heteroalkyl, C 1 -C 7 perfluorinated alkyl, C 1 -C 7 alkoxy, C 1 -C 7 haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, substituted with at least one substituent selected from: -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 1 -C 7 perfluorinated alkyl, unsubstituted C 1 -C 7 alkoxy, unsubstituted C 1 -C 7 haloalkoxy, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl. 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. The term “about” used in the context of a numeric value indicates a range of +/- 10% of the numeric value, unless expressly indicated otherwise. 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. As used herein, the term “sample” encompasses a sample obtained from a subject or patient. The sample can be of any biological tissue or fluid. Such samples include, but are not limited to, sputum, saliva, buccal sample, oral sample, blood, serum, mucus, plasma, urine, blood cells (e.g., white cells), circulating cells (e.g. stem cells or endothelial cells in the blood), tissue, core or fine needle biopsy samples, cell-containing body fluids, free floating nucleic acids, urine, stool, peritoneal fluid, and pleural fluid, tear fluid, or cells therefrom. Samples can also include sections of tissues such as frozen or fixed sections taken for histological purposes or microdissected cells or extracellular parts thereof. A sample to be analyzed can be tissue material from a tissue biopsy obtained by aspiration or punch, excision or by any other surgical method leading to biopsy or resected cellular material. Such a sample can comprise cells obtained from a subject or patient. In some embodiments, the sample is a body fluid that include, for example, blood fluids, serum, mucus, plasma, lymph, ascitic fluids, gynecological fluids, or urine but not limited to these fluids. In some embodiments, the sample can be a non- invasive sample, such as, for example, a saline swish, a buccal scrape, a buccal swab, and the like. As used herein, “blood” can include, for example, plasma, serum, whole blood, blood lysates, and the like. As used herein, the term “assessing” includes any form of measurement, and includes determining if an element is present or not. The terms “determining,” “measuring,” “evaluating,” “assessing,” “analyzing,” and “assaying” can be used interchangeably and can include quantitative and/or qualitative determinations. As used herein, the term “monitoring” with reference to a type of cancer refers to a method or process of determining the severity or degree of the type of cancer or stratifying the type of cancer based on risk and/or probability of mortality. In some embodiments, monitoring relates to a method or process of determining the therapeutic efficacy of a treatment being administered to a patient. As used herein, “outcome” can refer to an outcome studied. In some embodiments, “outcome” can refer to survival / mortality over a given time horizon. For example, “outcome” can refer to survival / mortality over 1 month, 3 months, 6 months, 1 year, 5 years, or 10 years or longer. In some embodiments, an increased risk for a poor outcome indicates that a therapy has had a poor efficacy, and a reduced risk for a poor outcome indicates that a therapy has had a good efficacy. As used herein, the term “high risk clinical trial” refers to one in which the test agent has “more than minimal risk” (as defined by the terminology used by institutional review boards, or IRBs). In some embodiments, a high risk clinical trial is a drug trial. 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. As used herein, the terms “modulated” or “modulation,” or “regulated” or “regulation” and “differentially regulated” can refer to both up regulation (i.e., activation or stimulation, e.g., by agonizing or potentiating) and down regulation (i.e., inhibition or suppression, e.g., by antagonizing, decreasing or inhibiting), unless otherwise specified or clear from the context of a specific usage. As used herein, the term “subject” refers to any suitable (e.g., treatable) member of the animal kingdom. In the methods, the subject is preferably a mammal. In the methods, the subject is preferably a human patient. In the methods, the subject may be a mammalian pediatric patient. In the methods, the pediatric patient is a mammalian (e.g., preferably human) patient under 18 years of age, while an adult patient is 18 or older. As used herein, the term “treating” (and its variations, such as “treatment” “treating,” “treat,” and the like) is, unless stated otherwise, to be considered in its broadest context and refers to obtaining a desired pharmacologic and/or physiologic effect. In particular, for example, the term “treating” may not necessarily imply or require that an animal is treated until total recovery. Accordingly, “treating” includes amelioration of the symptoms, relief from the symptoms or effects associated with a condition, decrease in severity of a condition, or preventing, preventively ameliorating symptoms, or otherwise reducing the risk of developing a particular condition. In some aspects, “treating” may not require or include prevention. As used herein, reference to “treating” an animal includes but is not limited to prophylactic treatment and therapeutic treatment. The effect can be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or can be therapeutic in terms of a partial or complete cure for a disease and/or adverse effect attributable to the disease. “Treatment,” as used herein, covers any treatment of a disease in a subject, preferably in a mammal (e.g., in a human), and may include one or more of: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., causing regression or elimination of the disease and/or relieving one or more disease symptoms. In particular aspects of the methods, such as conditions or disorders characterized by dysregulated IRAK expression or dysregulated (e.g., hyperactive) IRAK-mediated signaling pathway(s), treatment may be or include reducing such expression or signaling. “Treatment” can also encompass delivery of an agent or administration of a therapy in order to provide for a pharmacologic effect, even in the absence of a disease or condition. Any of the compositions (e.g., pharmaceutical compositions) described herein can be used to treat a suitable subject. “Therapeutically effective amount” means an amount effective to achieve a desired and/or beneficial effect. An effective amount can be administered in one or more administrations. In the methods, a therapeutically effective amount is an amount appropriate to treat an indication. By treating an indication is meant achieving any desirable effect, such as one or more of palliate, ameliorate, stabilize, reverse, slow, or delay disease progression, increase the quality of life, or to prolong life. Such achievement can be measured by any suitable method, such as measurement of tumor size or blood cell count, or any other suitable measurement. As used herein, the term “marker” or “biomarker” refers to a biological molecule, such as, for example, a nucleic acid, peptide, protein, hormone, and the like, whose presence or concentration can be detected and correlated with a known condition, such as a disease state. It can also be used to refer to a differentially expressed gene whose expression pattern can be utilized as part of a predictive, prognostic or diagnostic process in healthy conditions or a disease state, or which, alternatively, can be used in methods for identifying a useful treatment or prevention therapy. As used herein, an mRNA “isoform” is an alternative transcript for a specific mRNA or gene. This term includes pre-mRNA, immature mRNA, mature mRNA, cleaved or otherwise truncated, shortened, or aberrant mRNA, modified mRNA (e.g. containing any residue modifications, capping variants, polyadenylation variants, etc.), and the like. “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. Compounds and Compositions, Including Pharmaceutical Compositions In one aspect, the present disclosure provides a compound of Formula (I-5013-2N): or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof, wherein: A is selected from N and CR 3 , E is selected from N and CR 4 , and G is selected from N and CR 5 , wherein one of A, E, or G is N; 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 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, oxo, methanoyl (-COH), carboxy (- 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(CH 3 ) 2 , C 1 -C 7 alkyl, C 1 -C 7 perfluorinated alkyl, C 1 -C 7 alkoxy, C 1 -C 7 haloalkoxy, or C 1 -C 7 alkyl which is substituted with cycloalkyl; R 2 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, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, spiro-fused 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 fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, oxo, 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(CH 3 ) 2 , C 1 -C 7 alkyl, C 1 -C 7 perfluorinated alkyl, C 1 -C 7 alkoxy, C 1 -C 7 haloalkoxy, or C 1 -C 7 alkyl which is substituted with cycloalkyl; R 3 , R 4 , and R 5 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 fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, oxo, 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(CH 3 ) 2 , C 1 -C 7 alkyl, C 1 -C 7 perfluorinated alkyl, C 1 -C 7 alkoxy, C 1 -C 7 haloalkoxy, or C 1 -C 7 alkyl which is substituted with cycloalkyl; R 6 is
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 fused ring heteroaryl 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 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 fused ring heteroaryl is optionally substituted with one or more halogen; R 31a and R 31b are each independently selected from H, C 1 -C 6 alkyl, -(CH 2 ) a -(C 3 -C 6 cycloalkyl), –(CH 2 ) b -C 2 -C 6 heterocyclyl, –(CH 2 ) c -C 3 -C 9 heteroaryl, -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), wherein the C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 heterocyclyl, and C 3 -C 9 heteroaryl are each independently optionally substituted with one or more of halogen, hydroxy, oxo, 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(CH 3 ) 2 , C 1 -C 7 alkyl, C 1 -C 7 perfluorinated alkyl, C 1 -C 7 alkoxy, C 1 -C 7 haloalkoxy, or C 1 -C 7 alkyl which is substituted with cycloalkyl; a, b, and c are each independently selected from 0, 1, 2, 3, 4, 5, or 6; and m, n, o, p, q, r, s, t, u, v, w, and x are each independently selected from 0, 1, 2, 3, 4, or 5, where q+r+s+t is at least 1, and where u+v+w+x is at least 1. In another aspect, the present disclosure provides a compound of Formula (I-5013): 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 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, oxo, methanoyl (-COH), carboxy (- 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(CH 3 ) 2 , C 1 -C 7 alkyl, C 1 -C 7 perfluorinated alkyl, C 1 -C 7 alkoxy, C 1 -C 7 haloalkoxy, or C 1 -C 7 alkyl which is substituted with cycloalkyl; R 2 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, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, spiro-fused 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 fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, oxo, 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(CH 3 ) 2 , C 1 -C 7 alkyl, C 1 -C 7 perfluorinated alkyl, C 1 -C 7 alkoxy, C 1 -C 7 haloalkoxy, or C 1 -C 7 alkyl which is substituted with cycloalkyl; R 3 , R 4 , and R 5 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 fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, oxo, 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(CH 3 ) 2 , C 1 -C 7 alkyl, C 1 -C 7 perfluorinated alkyl, C 1 -C 7 alkoxy, C 1 -C 7 haloalkoxy, or C 1 -C 7 alkyl which is substituted with cycloalkyl; R 6 is 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 fused ring heteroaryl 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 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 fused ring heteroaryl is optionally substituted with one or more halogen; R 31a and R 31b are each independently selected from H, C 1 -C 6 alkyl, -(CH 2 ) a -(C 3 -C 6 cycloalkyl), –(CH 2 ) b -C 2 -C 6 heterocyclyl, –(CH 2 ) c -C 3 -C 9 heteroaryl, -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), wherein the C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 heterocyclyl, and C 3 -C 9 heteroaryl are each independently optionally substituted with one or more of halogen, hydroxy, oxo, 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(CH 3 ) 2 , C 1 -C 7 alkyl, C 1 -C 7 perfluorinated alkyl, C 1 -C 7 alkoxy, C 1 -C 7 haloalkoxy, or C 1 -C 7 alkyl which is substituted with cycloalkyl; a, b, and c are each independently selected from 0, 1, 2, 3, 4, 5, or 6; and m, n, o, p, q, r, s, t, u, v, w, and x are each independently selected from 0, 1, 2, 3, 4, or 5, where q+r+s+t is at least 1, and where u+v+w+x is at least 1. In yet another aspect, the present disclosure provides a compound of Formula (I) or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof, wherein: A is selected from N and CR 3 , E is selected from N and CR 4 , G is selected from N and CR 5 , wherein no more than one of A, E, and G is N; 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 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, oxo, methanoyl (-COH), carboxy (- 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(CH 3 ) 2 , C 1 -C 7 alkyl, C 1 -C 7 perfluorinated alkyl, C 1 -C 7 alkoxy, C 1 -C 7 haloalkoxy, or C 1 -C 7 alkyl which is substituted with cycloalkyl; R 2 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, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, spiro-fused 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 fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, oxo, 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(CH 3 ) 2 , C 1 -C 7 alkyl, C 1 -C 7 perfluorinated alkyl, C 1 -C 7 alkoxy, C 1 -C 7 haloalkoxy, or C 1 -C 7 alkyl which is substituted with cycloalkyl; R 3 , R 4 , and R 5 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 fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, oxo, 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(CH 3 ) 2 , C 1 -C 7 alkyl, C 1 -C 7 perfluorinated alkyl, C 1 -C 7 alkoxy, C 1 -C 7 haloalkoxy, or C 1 -C 7 alkyl which is substituted with cycloalkyl; R 6 is 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 fused ring heteroaryl 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 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 fused ring heteroaryl is optionally substituted with one or more halogen; R 31a and R 31b are each independently selected from H, C 1 -C 6 alkyl, -(CH 2 ) a -(C 3 -C 6 cycloalkyl), –(CH 2 ) b -C 2 -C 6 heterocyclyl, –(CH 2 ) c -C 3 -C 9 heteroaryl, -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), wherein the C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 heterocyclyl, and C 3 -C 9 heteroaryl are each independently optionally substituted with one or more of halogen, hydroxy, oxo, 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(CH 3 ) 2 , C 1 -C 7 alkyl, C 1 -C 7 perfluorinated alkyl, C 1 -C 7 alkoxy, C 1 -C 7 haloalkoxy, or C 1 -C 7 alkyl which is substituted with cycloalkyl; a, b, and c are each independently selected from 0, 1, 2, 3, 4, 5, or 6; and m, n, o, p, q, r, s, t, u, v, w, and x are each independently selected from 0, 1, 2, 3, 4, or 5, where q+r+s+t is at least 1, and where u+v+w+x is at least 1. In an embodiment of Formula (I), only one of A, E, and G is N. In an embodiment of Formula (I), none of A, E, and G is N. In an embodiment of Formula (I), Formula (I-5013), or Formula (I-5013-2N), at least one of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 is not H. In another embodiment, each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 is H. In an embodiment of Formula (I), Formula (I-5013), or Formula (I-5013-2N), 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. In an embodiment, 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). In some embodiments, 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). In some embodiments in Formula (I) or Formula (I-5013-2N), A is N, E is CR 4 , and G is CR 5 . In some embodiments, A is CR 3 , E is N, and G is CR 5 . In some embodiments, A is CR 3 , E is CR 4 , and G is N. In some embodiments in Formula (I), Formula (I-5013), or Formula (I-5013-2N), 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. In some embodiments, R 1 is H, Cl, -OCH 3 , C 3 cycloalkyl, -O-(C 3 cycloalkyl), In some embodiments, R 1 is not H. In some embodiments in Formula (I), Formula (I-5013), or Formula (I-5013-2N), 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. In some embodiments, 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. In some embodiments, R 2 is not H. In some embodiments, R 2 is C 3 cycloalkyl or . In some embodiments in Formula (I), Formula (I-5013), or Formula (I-5013-2N), 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(CH 3 ) 2 , C 1 -C 7 alkyl, C 1 -C 7 perfluorinated alkyl, C 1 -C 7 alkoxy, C 1 -C 7 haloalkoxy, or C 1 -C 7 alkyl which is substituted with cycloalkyl. In some embodiments, R 3 is H, halogen, hydroxy, -CN, methyl, -CF 3 , or methoxy. In some embodiments in Formula (I), Formula (I-5013), or Formula (I-5013-2N), 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, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH 2 , -CON(CH 3 ) 2 , C 1 -C 7 alkyl, C 1 -C 7 perfluorinated alkyl, C 1 -C 7 alkoxy, C 1 -C 7 haloalkoxy, or C 1 -C 7 alkyl which is substituted with cycloalkyl. In some embodiments, R 4 is H, halogen, hydroxy, -CN, methyl, -CF 3 , or methoxy. In some embodiments in Formula (I), Formula (I-5013), or Formula (I-5013-2N), 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, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH 2 , -CON(CH 3 ) 2 , C 1 -C 7 alkyl, C 1 -C 7 perfluorinated alkyl, C 1 -C 7 alkoxy, C 1 -C 7 haloalkoxy, or C 1 -C 7 alkyl which is substituted with cycloalkyl. In some embodiments, R 5 is H, halogen, hydroxy, -CN, methyl, -CF 3 , or methoxy. In some embodiments in Formula (I) or Formula (I-5013), R 3 is F or CN, R 5 is F or CN, and R 4 is H. In another embodiment, R 3 is H, R 4 is H, and R 5 is F or CN. In another embodiment, R 3 is F or CN, R 4 is H, and R 5 is H. In another embodiment, each of R 3 , R 4 , and R 5 are H. In some embodiments in Formula (I) or Formula (I-5013-2N), A is N, E is CR 4 , and G is CR 5 , wherein R 4 and R 5 are each H. In one embodiment of Formula (I) or Formula (I-5013-2N), 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. In another embodiment of Formula (I) or Formula (I-5013-2N), A is CR 3 , E is N, and G is CR 5 , wherein R 3 and R 5 are each H. In another embodiment of Formula (I) or Formula (I-5013-2N), 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. In another embodiment of Formula (I) or Formula (5013-2N), A is CR 3 , E is CR 4 , and G is N, wherein R 3 and R 4 are each H. In another embodiment of Formula (I) or Formula (5013-2N), 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. In some embodiments in Formula (I), Formula (I-5013), or Formula (I-5013-2N), 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 fused ring heteroaryl is optionally substituted with one or more halogen, hydroxy, oxo, 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(CH 3 ) 2 , C 1 -C 7 alkyl, C 1 -C 7 perfluorinated alkyl, C 1 -C 7 alkoxy, C 1 -C 7 haloalkoxy, or C 1 -C 7 alkyl which is substituted with cycloalkyl, provided that at least one of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 is not H. In another embodiment, each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 is H. In some embodiments in Formula (I), Formula (I-5013), or Formula (I-5013-2N), R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 are independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, which methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more halogen, hydroxy, oxo, 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(CH 3 ) 2 , C 1 -C 7 alkyl, C 1 -C 7 perfluorinated alkyl, C 1 -C 7 alkoxy, C 1 -C 7 haloalkoxy, or C 1 -C 7 alkyl which is substituted with cycloalkyl. In some embodiments, 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. In some embodiments in Formula (I), Formula (I-5013), or Formula (I-5013-2N), 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. In an embodiment in Formula (I), Formula (I-5013), or Formula (I-5013-2N), 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. In some embodiments, where 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. In another embodiment, R 6 is (Ia), m is 0, n is 2, o is 1, and p is 1. In some embodiments, 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. In another embodiment, 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. In particular embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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). In an embodiment, 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 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 6 -C 12 spiro-fused cycloalkyl, -O-(C 3 -C 6 cycloalkyl), C 3 -C 9 heterocyclyl, and C 5 -C 10 spiro-fused heterocyclyl, 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, -O-(C 3 -C 6 cycloalkyl), and C 3 -C 9 heterocyclyl are each optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, halogen, =O, and -OH; R 22a , R 23a , and R 24a are each independently selected from H, CN, and halogen; and R 25a , R 25a’ , R 26a , R 26a’ , R 27a , and R 27a’ 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. In an embodiment of Formula (IIa), 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. In another embodiment, 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. In one embodiment, 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 . In one embodiment, 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. In one embodiment, 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 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 . In one embodiment, R 21a is In one embodiment, R 21a is C 3 , C 4 , or C 5 heterocyclyl substituted with one or more halogen. In one embodiment, R 21a is C 3 , C 4 , or C 5 heterocyclyl substituted with one or more F. In one embodiment, R 21a is C 3 , C 4 , or C 5 heterocyclyl comprising one nitrogen and substituted with one or more F. In one embodiment, R 21a is . In another embodiment, R 21a is C 3 , C 4 , or C 5 heterocyclyl comprising one nitrogen and substituted with one or more =O. In one embodiment, R 21a is . In another embodiment, 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. In one embodiment, 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. In an embodiment, 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. In another embodiment, 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. In an embodiment of Formula (IIa), 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. 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 F. In an embodiment, 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) 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:
or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. In an embodiment, compound of Formula (IIa) 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 (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 C 1 -C 6 alkyl and halogen; R 21b is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 6 -C 12 spiro-fused cycloalkyl, -O-(C 3 -C 6 cycloalkyl), C 3 -C 9 heterocyclyl, and C 5 -C 10 spiro-fused heterocyclyl, 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, -O-(C 3 -C 6 cycloalkyl), and C 3 -C 9 heterocyclyl are each optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, halogen, =O, and -OH; R 22b , R 23b , and R 24b are each independently selected from H, CN, and halogen; and 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. In an embodiment of Formula (IIb), 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. In another embodiment, 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. In one embodiment, 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 . In one embodiment, 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. In one embodiment, 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 . In another embodiment, 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 . In one embodiment, R 21b is In another embodiment, R 21b is C 3 , C 4 , or C 5 heterocyclyl comprising one nitrogen and substituted with one or more =O. In one embodiment, R 21b is In one embodiment, R 21b is C 3 , C 4 , or C 5 heterocyclyl substituted with one or more halogen. In one embodiment, R 21b is C 3 , C 4 , or C 5 heterocyclyl substituted with one or more F. In one embodiment, R 21b is C 3 , C 4 , or C 5 heterocyclyl comprising one nitrogen and substituted with one or more F. In one embodiment, R 21b is In another embodiment, R 21b is C 6 -C 12 spiro-fused cycloalkyl. In one embodiment, 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. 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 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. In an embodiment, 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. In another embodiment, 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. In one embodiment, 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. 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 -CH 3 . In one embodiment, 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 . In an embodiment, the compound of Formula (IIb) has one or more stereocenters. In one embodiment, the compound of Formula (IIb) comprises a stereocenter where the moiety connects to the remaining portion of Formula (IIb). In one embodiment, 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’ . In an embodiment, the compound of Formula (IIb) 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 (llb) is selected from:
or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. In another embodiment 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). In some embodiments, R 6 is (Ib) and q, r, s, t, u, v, w, and x are independently 0, 1, or 2. In some embodiments, q is 0 or 1, r is 0 or 1, s is 0 or 1, t is 0 or 1, u is 0 or 1, v is 0 or 1, w is 0 or 1, and x is 0 or 1. In some embodiments, R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 are independently selected from H, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-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. In some embodiments, one or more of R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 are H. In some embodiments, 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. In one embodiment, 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:
wherein R 1 , R 2 , R 3 , R 4 , and R 5 are defined elsewhere herein. In an embodiment, 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 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 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 6 -C 12 spiro-fused cycloalkyl, -O-(C 3 -C 6 cycloalkyl), C 3 -C 9 heterocyclyl, and C 5 -C 10 spiro-fused heterocyclyl, 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, -O-(C 3 -C 6 cycloalkyl), and C 3 -C 9 heterocyclyl are each optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, halogen, =O, and -OH; R 22a , R 23a , and R 24a are each independently selected from H, CN, and halogen; R 25a , R 25a’ , R 26a , R 26a’ , R 27a , and R 27a’ are each independently selected from H, halogen, - OH, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy, wherein C 1 -C 6 alkyl and C 1 -C 6 alkoxy are each optionally substituted with one or more halogen atoms; and one of A, E, or G is N. In an embodiment in Formula (IIa-2N), 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. In another embodiment, 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. In one embodiment, 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 . In one embodiment, 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. In one embodiment, 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 . 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 . In one embodiment, R 21a is In one embodiment, R 21a is C 3 , C 4 , or C 5 heterocyclyl substituted with one or more halogen. In one embodiment, R 21a is C 3 , C 4 , or C 5 heterocyclyl substituted with one or more F. In one embodiment, R 21a is C 3 , C 4 , or C 5 heterocyclyl comprising one nitrogen and substituted with one or more F. In one embodiment, R 21a is . In another embodiment, R 21a is C 3 , C 4 , or C 5 heterocyclyl comprising one nitrogen and substituted with one or more =O. In one embodiment, R 21a is In another embodiment, 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. In one embodiment, 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. In one embodiment, 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. In one embodiment, 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 in Formula (IIa-2N), A is CR 22a , E is CR 23a , and G is N. In one embodiment, G is N, R 22a is H, and R 23a is H. In one embodiment, G is N, R 22a is halogen, and R 23a is H. In one embodiment, G is N, R 22a is F, and R 23a is H. In one embodiment, G is N, R 22a is H, and R 23a is halogen. In one embodiment, G is N, R 22a is H, and R 23a is F. In one embodiment, G is N, R 22a is CN, and R 23a is H. In one embodiment, G is N, R 22a is H, and R 23a is CN. In an embodiment in Formula (IIa-2N), 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. 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 F. In an embodiment, 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. In one embodiment, 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:
or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. In an embodiment, 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 -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 21b is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 6 -C 12 spiro-fused cycloalkyl, -O-(C 3 -C 6 cycloalkyl), C 3 -C 9 heterocyclyl, and C 5 -C 10 spiro-fused heterocyclyl, 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, -O-(C 3 -C 6 cycloalkyl), and C 3 -C 9 heterocyclyl are each optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, halogen, =O, and -OH; R 22b , R 23b , and R 24b are each independently selected from H, CN, 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; and one of A, E, or G is N. In an embodiment of Formula (IIb-2N), 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. In another embodiment, 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. In one embodiment, 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 . In one embodiment, 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. In one embodiment, 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 . In another embodiment, 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 . In one embodiment, R 21b is In another embodiment, R 21b is C 3 , C 4 , or C 5 heterocyclyl comprising one nitrogen and substituted with one or more =O. In one embodiment, R 21b is In one embodiment, R 21b is C 3 , C 4 , or C 5 heterocyclyl substituted with one or more halogen. In one embodiment, R 21b is C 3 , C4, or C 5 heterocyclyl substituted with one or more F. In one embodiment, R 21b is C 3 , C 4 , or C 5 heterocyclyl comprising one nitrogen and substituted with one or more F. In one embodiment, R 21b is In another embodiment, R 21b is C 6 -C 12 spiro-fused cycloalkyl. In one embodiment, 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. 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 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. In one embodiment, 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. In one embodiment, 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 in Formula (IIb-2N), A is CR 22b , E is CR 23b , and G is N. In one embodiment, G is N, R 22b is H, and R 23b is H. In one embodiment, G is N, R 22b is halogen, and R 23b is H. In one embodiment, G is N, R 22b is F, and R 23b is H. In one embodiment, G is N, R 22b is H, and R 23b is halogen. In one embodiment, G is N, R 22b is H, and R 23b is F. In one embodiment, G is N, R 22b is CN, and R 23b is H. In one embodiment, G is N, R 22b is H, and R 23b is CN. In an embodiment in Formula 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. In one embodiment, 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. 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 -CH 3 . In one embodiment, 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 . In an embodiment, 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). In one embodiment, 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’ . In an embodiment, the compound of Formula (IIb-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 (IIb-2N) is selected from:
or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. In another embodiment, R 6 of Formula (I) or Formula (I-5013-2N) is (Ib). In some embodiments, R 6 is (Ib) and q, r, s, t, u, v, w, and x are independently 0, 1, or 2. In some embodiments, q is 0 or 1, r is 0 or 1, s is 0 or 1, t is 0 or 1, u is 0 or 1, v is 0 or 1, w is 0 or 1, and x is 0 or 1. In some embodiments, R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 are independently selected from H, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-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. In some embodiments, one or more of R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 are H. In some embodiments, 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. In one embodiment, 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:
wherein one of A, E, or G is N, the remaining of A, E, and G are defined elsewhere herein, and R 1 and R 2 are each defined elsewhere herein. In some embodiments, 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. In one embodiment, 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. In one embodiment, 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. In some embodiments, 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. In an embodiment, one or more of R 3 , R 4 , R 5 is not H and is a substituent as defined elsewhere herein. Although not wishing to be limited by theory, it is believed that 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), Formula (IIb), Formulas (IIIa)-(IIIp), Formula (IIa-2N), Formula (IIb-2N), or Formulas (IIIa-2N)-(IIIp-2N). In an embodiment, the “small substituent” comprises a halogen atom. In one embodiment, the halogen atom is fluorine. In an embodiment, if the “small substituent” is too large, 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. Although not wishing to be limited by theory, it is believed that alkyl substituents (such as -CH 3 ) and alkoxy substituents (such as -OCH 3 ) are too large. In an embodiment, 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 . In an embodiment, 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 . In an embodiment, the amine NH is trans to the one R 6 substituent. In another embodiment, the amine NH is cis to the one R 6 substituent. In an embodiment, 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. In some embodiments, 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. In other embodiments, the compounds can be in various forms, such as uncharged molecules, components of molecular complexes, or non- irritating pharmacologically acceptable salts, including but not limited to hydrochloride, hydrobromide, sulphate, phosphate, nitrate, borate, acetate, maleate, tartrate, and salicylate. In some instances, for acidic compounds, salts can include metals, amines, or organic cations (e.g. quaternary ammonium). In yet other embodiments, simple derivatives of the compounds (e.g., ethers, esters, or amides) which have desirable retention and release characteristics but which are easily hydrolyzed by body pH, enzymes, or other suitable means, can be employed. In some embodiments, the compounds of the disclosure having a chiral center and can exist in and be isolated in optically active and racemic forms. In other embodiments, compounds may exhibit polymorphism. Some embodiments of the present disclosure encompass any racemic, optically active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound described herein, including isotopically-labeled and radio-labeled compounds. See e.g., Goding, 1986, Monoclonal Antibodies Principles and Practice; Academic Press, p.104. Such isomers can be isolated by standard resolution techniques, including e.g., fractional crystallization, chiral chromatography, and the like. See e.g., Eliel, E. L. & Wilen S. H., 1993, Stereochemistry in Organic Compounds; John Wiley & Sons, New York. The preparation of optically active forms can be accomplished by any suitable method, including but not limited to, resolution of the racemic form by recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In some embodiments, compounds disclosed herein have asymmetric centers and can occur as racemates, racemic mixtures, and as individual enantiomers or diastereoisomers, with all isomeric forms as well as mixtures thereof being contemplated for use in the compounds and methods described herein. The compounds contemplated for use in the compounds and methods described herein do not include those that are known in the art to be too unstable to synthesize and/or isolate. The compounds disclosed herein can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds can be radiolabeled with radioactive isotopes, such as for example tritium ( 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. In some embodiments, metabolites of the compounds disclosed herein are useful for the methods disclosed herein. In some embodiments, compounds contemplated herein may be provided in the form of a prodrug. The term “prodrug” refers to a compound that can be converted into a compound (e.g., a biologically active compound) described herein in vivo. Prodrugs can be useful for a variety of reason known in the art, including e.g., ease of administration due e.g., to enhanced bioavailability in oral administration, and the like. The prodrug can also have improved solubility in pharmaceutical compositions over the biologically active compounds. An example, without limitation, of a prodrug is a compound which is administered as an ester (i.e., the "prodrug") to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water solubility is beneficial. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, (ed. H. Bundgaard, Elsevier, 1985), which is hereby incorporated herein by reference for the limited purpose describing procedures and preparation of suitable prodrug derivatives. Certain compounds disclosed herein can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of contemplated compounds. Certain compounds of the present disclosure can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the compounds and methods contemplated herein and are intended to be within the scope disclosed herein. In certain embodiments, 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)) can be part of a composition and can be in an amount (by weight of the total composition) of at least about 0.0001%, at least about 0.001%, at least about 0.10%, at least about 0.15%, at least about 0.20%, at least about 0.25%, at least about 0.50%, at least about 0.75%, at least about 1%, at least about 10%, at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, at least about 99%, at least about 99.99%, no more than about 75%, no more than about 90%, no more than about 95%, no more than about 99%, or no more than about 99.99%, from about 0.0001% to about 99%, from about 0.0001% to about 50%, from about 0.01% to about 95%, from about 1% to about 95%, from about 10% to about 90%, or from about 25% to about 75%. In some embodiments, 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)) can be purified or isolated in an amount (by weight of the total composition) of at least about 0.0001%, at least about 0.001%, at least about 0.10%, at least about 0.15%, at least about 0.20%, at least about 0.25%, at least about 0.50%, at least about 0.75%, at least about 1%, at least about 10%, at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, at least about 99%, at least about 99.99%, no more than about 75%, no more than about 90%, no more than about 95%, no more than about 99%, no more than about 99.99%, from about 0.0001% to about 99%, from about 0.0001% to about 50%, from about 0.01% to about 95%, from about 1% to about 95%, from about 10% to about 90%, or from about 25% to about 75%. Methods for Preparing Compounds of the Disclosure 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). In certain embodiments, 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. Pharmaceutical Compositions and Formulations In one embodiment, the present disclosure 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. Exemplary therapeutic agents are described elsewhere herein. In another embodiment, 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. In one embodiment, 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. In another embodiment, 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. In one embodiment, 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. In another embodiment, 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 sequentially. In one embodiment, 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. Some embodiments of the present disclosure include 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)). In one embodiment, the composition comprising a compound of the disclosure further comprises one or more therapeutic agents described elsewhere herein. In one embodiment, the present disclosure includes a separate composition comprising one or more of the therapeutic agents described elsewhere herein. In certain embodiments, the composition is a pharmaceutical composition, such as compositions that are suitable for administration to animals (e.g., mammals, primates, monkeys, humans, canine, feline, porcine, mice, rabbits, rats, etc.). In some embodiments, there is provided a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient. The compound can be a compound of any of 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. The term “pharmaceutically acceptable salts” is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds disclosed herein contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds disclosed herein contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galacturonic acids and the like (see, for example, Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds disclosed herein contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. Compounds disclosed herein can exist as salts, such as with pharmaceutically acceptable acids. Accordingly, the compounds contemplated herein include such salts. Examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid. These salts can be prepared by methods known to those skilled in the art. The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents. Pharmaceutically acceptable salts of the compounds above, where a basic or acidic group is present in the structure, are also included within the scope of compounds contemplated herein. When an acidic substituent is present, such as -NHSO 3 H, -COOH and -P(O)(OH) 2 , there can be formed the ammonium, sodium, potassium, calcium salt, and the like, for use as the dosage form. Basic groups, such as amino or basic heteroaryl radicals, or pyridyl and acidic salts, such as hydrochloride, hydrobromide, acetate, maleate, pamoate, methanesulfonate, p-toluenesulfonate, and the like, can be used as the dosage form. Also, in the embodiments in which R-COOH is present, pharmaceutically acceptable esters can be employed, e. g. , methyl, ethyl, tert-butyl, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations. In some instances, the pharmaceutical composition is non-toxic, does not cause side effects, or both. In some embodiments, there may be inherent side effects (e.g., it may harm the patient or may be toxic or harmful to some degree in some patients). In some embodiments, 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)) can be part of a pharmaceutical composition and can be in an amount of at least about 0.0001%, at least about 0.001%, at least about 0.10%, at least about 0.15%, at least about 0.20%, at least about 0.25%, at least about 0.50%, at least about 0.75%, at least about 1%, at least about 10%, at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, at least about 99%, at least about 99.99%, no more than about 75%, no more than about 90%, no more than about 95%, no more than about 99%, no more than about 99.99%, from about 0.001% to about 99%, from about 0.001% to about 50%, from about 0.1% to about 99%, from about 1% to about 95%, from about 10% to about 90%, or from about 25% to about 75%. In some embodiments, the pharmaceutical composition can be presented in a dosage form which is suitable for the topical, subcutaneous, intrathecal, intraperitoneal, oral, parenteral, rectal, cutaneous, nasal, vaginal, or ocular administration route. In other embodiments, the pharmaceutical composition can be presented in a dosage form which is suitable for parenteral administration, 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. In some embodiments, the compounds disclosed herein can be administered orally as tablets, aqueous or oily suspensions, lozenges, troches, powders, granules, emulsions, capsules, syrups or elixirs. The composition for oral use can contain one or more agents selected from the group of sweetening agents, flavoring agents, coloring agents and preserving agents in order to produce pharmaceutically elegant and palatable preparations. Accordingly, there are also provided pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and one or more compounds disclosed herein. In some embodiments, tablets contain the acting ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients can be, for example, (1) inert diluents, such as calcium carbonate, lactose, calcium phosphate, carboxymethylcellulose, or sodium phosphate; (2) granulating and disintegrating agents, such as 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. These tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. For preparing pharmaceutical compositions from the compounds disclosed herein, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substance that can also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. A compound disclosed herein, in the form of a free compound or a pharmaceutically- acceptable pro-drug, metabolite, analogue, derivative, solvate or salt, can be administered, for in vivo application, parenterally by injection or by gradual perfusion over time. Administration can be intravenously, intraperitoneally, intramuscularly, subcutaneously, intracavity, or transdermally. For in vitro studies the compounds can be added or dissolved in an appropriate biologically acceptable buffer and added to a cell or tissue. In powders, the carrier is a finely divided solid in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from 5% to 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term “preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration. For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify. Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution. When parenteral application is needed or desired, particularly suitable admixtures for the compounds disclosed herein are injectable, sterile solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants, including suppositories. This suspension can be formulated according to known methods using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation can also a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles, carriers, and solvents that can be employed are water, Ringer’s solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. In particular, carriers for parenteral administration include aqueous solutions of dextrose, saline, pure water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene-block polymers, and the like. Ampoules are convenient unit dosages. The compounds disclosed herein can also be incorporated into liposomes or administered via transdermal pumps or patches. Pharmaceutical admixtures suitable for use in the pharmaceuticals compositions and methods disclosed herein include those described, for example, in PHARMACEUTICAL SCIENCES (17th Ed., Mack Pub. Co., Easton, PA) and WO 96/05309, the teachings of both of which are hereby incorporated by reference. In some embodiments, preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Frequently used carriers or auxiliaries include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycols and solvents, such as sterile water, alcohols, glycerol and polyhydric alcohols. Intravenous vehicles include fluid and nutrient replenishers. Parenteral vehicles include sodium chloride solution, Ringer’s dextrose, dextrose and sodium chloride, lactated Ringer’s intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer’s dextrose), and the like. Preservatives and other additives can also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, growth factors and inert gases and the like. Preservatives include antimicrobial, anti-oxidants, chelating agents and inert gases. Other pharmaceutically acceptable carriers include aqueous solutions, non-toxic excipients, including salts, preservatives, buffers and the like, as described, for instance, in Remington’s Pharmaceutical Sciences, 15th ed. Easton: Mack Publishing Co., 1405-1412, 1461-1487 (1975) and The National Formulary XIV., 14th ed. Washington: American Pharmaceutical Association (1975), the contents of which are hereby incorporated by reference. The pH and exact concentration of the various components of the pharmaceutical composition are adjusted according to routine skills in the art. See e.g., Goodman and Gilman (eds.), 1990, THE PHARMACOLOGICAL BASIS FOR THERAPEUTICS (7th ed.). Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, me thylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents. Aqueous suspensions normally contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspension. Such excipients can be (1) suspending agent such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; (2) dispersing or wetting agents which can be (a) naturally occurring phosphatide such as lecithin; (b) a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate ; (c) a condensation product of ethylene oxide with 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 monooleate Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations can contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. In some embodiments, the pharmaceutical composition can include one or more formulary ingredients. A “formulary ingredient” can be any suitable ingredient (e.g., suitable for the drug(s), for the dosage of the drug(s), for the timing of release of the drugs(s), for the disease, for the disease state, or for the delivery route) including, but not limited to, water (e.g., boiled water, distilled water, filtered water, pyrogen-free water, or water with chloroform), sugar (e.g., sucrose, glucose, mannitol, sorbitol, xylitol, or syrups made therefrom), ethanol, glycerol, glycols (e.g., propylene glycol), acetone, ethers, DMSO, surfactants (e.g., anionic surfactants, cationic surfactants, zwitterionic surfactants, or nonionic surfactants (e.g., polysorbates)), oils (e.g., animal oils, plant oils (e.g., coconut oil or arachis oil), or mineral oils), oil derivatives (e.g., ethyl oleate , glyceryl monostearate, or hydrogenated glycerides), excipients, preservatives (e.g., cysteine, methionine, antioxidants (e.g., vitamins (e.g., A, E, or C), selenium, retinyl palmitate, sodium citrate, citric acid, chloroform, or parabens, (e.g., methyl paraben or propyl paraben)), or combinations thereof. In certain embodiments, pharmaceutical compositions can be formulated to release the active ingredient (e.g., one or more compounds of the disclosure such as Formula (I), 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. Such formulations can include, for example, controlled release formulations such as various controlled release compositions and coatings. Other formulations (e.g., formulations of a pharmaceutical composition) can, in certain embodiments, include those incorporating the drug (or control release formulation) into food, food stuffs, feed, or drink. Some compounds can have limited solubility in water and therefore can require a surfactant or other appropriate co-solvent in the composition. Such co-solvents include: Polysorbate 20, 60, and 80; Pluronic F-68, F-84, and P-103; cyclodextrin; and polyoxyl 35 castor oil. Such co-solvents are typically employed at a level between about 0.01 % and about 2% by weight. 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. The compositions disclosed herein can additionally include components to provide sustained release and/or comfort. Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides, and finely-divided drug carrier substrates. These components are discussed in greater detail in U.S. Pat. Nos.4,911,920; 5,403,841; 5,212,162; and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes. There are provided various pharmaceutical compositions useful for ameliorating certain diseases and disorders. The pharmaceutical compositions according to one embodiment are prepared by formulating a compound disclosed herein in the form of a free compound or a pharmaceutically-acceptable pro-drug, metabolite, analogue, derivative, solvate or salt, either alone or together with other pharmaceutical agents, suitable for administration to a subject using carriers, excipients and additives or auxiliaries. Frequently used carriers or auxiliaries include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycols and solvents, such as sterile water, alcohols, glycerol and polyhydric alcohols. Intravenous vehicles include fluid and nutrient replenishers. There are provided various pharmaceutical compositions useful for ameliorating certain diseases and disorders. The pharmaceutical compositions according to one embodiment are prepared by formulating a compound disclosed herein in the form of a free compound or a pharmaceutically-acceptable pro-drug, metabolite, analogue, derivative, solvate or salt, either alone or together with other pharmaceutical agents, suitable for administration to a subject using carriers, excipients and additives or auxiliaries. Frequently used carriers or auxiliaries include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycols and solvents, such as sterile water, alcohols, glycerol and polyhydric alcohols. Intravenous vehicles include fluid and nutrient replenishers. Methods of Treating and Preventing Disease In addition to their ability to inhibit IRAK, IRAK inhibitors have been demonstrated to have selectivity for multiple kinases. In some embodiments, compounds described herein according to Formula (I), 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). The inhibitory action against one or more kinase, such as IRAK and FLT3, can allow for treatment and/or prevention of diseases in an animal (e.g., mammals, porcine, canine, avian (e.g., chicken), bovine, feline, primates, rodents, monkeys, rabbits, mice, rats, and humans) using a compound of the disclosure (e.g., Formula (I), 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) related to mutations in IRAK1, IRAK4, and/or FLT3 (e.g., mutations in the juxtamembrane region of FLT3, mutations in the kinase domain of FLT3, FLT3 point mutations, FLT3 internal tandem duplication mutations, the FLT3-ITD mutation, the D835Y FLT3 mutation, the D835V FLT3 mutation, the F691L FLT3 mutation, or the R834Q FLT3 mutation). In some embodiments, the compounds of the disclosure can inhibit the activity of one or more of FLT3, mutations of FLT3 (e.g., mutations in the juxtamembrane region of FLT3, mutations in the kinase domain of FLT3, FLT3 point mutations, FLT3 internal tandem duplication mutations, the FLT3-ITD mutation, the D835Y FLT3 mutation, the D835V FLT3 mutation, the F691L FLT3 mutation, or the R834Q FLT3 mutation), IRAK4 (interleukin-1 receptor associated kinase 4), isoforms of IRAK4, mutations of IRAK4, IRAK1 (interleukin-1 receptor associated kinase 1), isoforms of IRAK1, and/or mutations of IRAK1. In some embodiments, the compounds of the disclosure can inhibit the activity of one or both of FLT3 and mutations of FLT3 (e.g., mutations in the juxtamembrane region of FLT3, mutations in the kinase domain of FLT3, FLT3 point mutations, FLT3 internal tandem duplication mutations, the FLT3-ITD mutation, the D835Y FLT3 mutation, the D835V FLT3 mutation, the F691L FLT3 mutation, or the R834Q FLT3 mutation) and optionally inhibits one or more of IRAK4, isoforms of IRAK4, mutations of IRAK4, IRAK1, isoforms of IRAK1, or mutations of IRAK1. In some embodiments, the compounds of the disclosure can inhibit the activity of one or both of FLT3 and mutations of FLT3 (e.g., mutations in the juxtamembrane region of FLT3, mutations in the kinase domain of FLT3, FLT3 point mutations, FLT3 internal tandem duplication mutations, the FLT3-ITD mutation, the D835Y FLT3 mutation, the D835V FLT3 mutation, the F691L FLT3 mutation, or the R834Q FLT3 mutation) and optionally inhibits one or both of IRAK4 and IRAK1, or an isoform or mutation thereof. In some embodiments, the compounds of the disclosure can inhibit FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1. In some embodiments, compounds exhibit inhibitory activity against IRAK and/or FLT-3 with activities ≥ 1 µM, e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000 nM, or even greater. In some embodiments, the compounds exhibit inhibitory activity against IRAK and/or FLT-3 with activities between 0.1 nM and 1 nM, e.g., about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 or 1.0 nM. In some embodiments, compounds described herein exhibit inhibitory activity against IRAK and/or FLT-3 with activities ≤ 0.1 µM, e.g., about 1, 2, 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, or 100 nM. Ranges of values using a combination of any of the values recited herein as upper and/or lower limits are also contemplated, for example, but not limited to, 1-10 nM, 10-100 nM, 1-100 nM, 0.1-1 nM, 0.1-100 nM, 0.1-200 nM, 1-200 nM, 10-200 nM, 100-200 nM, 200-500 nM, 0.1-500 nM, 1-500 nM, 10-500 nM, 500-1000 nM, 0.1-1000 nM, 1-1000 nM, 10-1000 nM, or 100-1000 nM. In some embodiments, the inhibitory activity is less than 0.1 nM, less than 1 nM, less than 10 nM, less than 100 nM, or less than 1000 nM. In some embodiments, the inhibitory activity is in the range of about 1-10 nM, 10-100 nM, 0.1-1 µM, 1-10 µM, 10-100 µM, 100-200 µM, 200-500 µM, or even 500-1000 µM. It is understood that for purposes of quantification, the terms “activity,” “inhibitory activity,” “biological activity,” “IRAK activity,” “IRAK1 activity,” “IRAK4 activity,” “FLT-3 activity,” and the like in the context of an inhibitory compound disclosed herein can be quantified in a variety of ways known in the art. Unless indicated otherwise, as used herein such terms refer to IC 50 in the customary sense (i.e., concentration to achieve half-maximal inhibition. It is understood that for purposes of quantification, the terms “activity,” “inhibitory activity,” “biological activity,” “IRAK activity,” “IRAK1 activity,” “IRAK4 activity,” “FLT-3 activity,” and the like in the context of an inhibitory compound disclosed herein can be quantified in a variety of ways known in the art. Unless indicated otherwise, as used herein such terms refer to IC 5 0 in the customary sense (i.e., concentration to achieve half-maximal inhibition. In some embodiments, hematopoietic cancers that can be treated in an animal (e.g., mammals, porcine, canine, avian (e.g., chicken), bovine, feline, primates, rodents, monkeys, rabbits, mice, rats, and humans) using a compound of the disclosure (e.g., Formula (I), 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., anti- cancer therapies), cancers evolving from myelodysplastic syndromes, cancers evolving from myeloproliferative disease, and cancers of the B cells. In some embodiments, 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. In some embodiments, cancers characterized by dysregulated IRAK expression (IRAK1 and/or IRAK4) and/or IRAK-mediated intracellular signaling, can be treated, and include, but are not limited to, glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, Glioma, oral cancer, nasopharyngeal carcinoma, rectal cancer, stomach cancer, and uterine cancer, and the like, and combinations thereof. In some embodiments, 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. According to particular aspects of the disclosure, 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. In some embodiments, inflammatory and autoimmune diseases characterized by dysregulated (e.g., hyperactive) IRAK expression (IRAK1 and/or IRAK4) and/or IRAK-mediated intracellular signaling, can be treated, 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. In certain embodiments, MDS that can be treated in a subject (e.g., mammals, porcine, canine, avian (e.g., chicken), bovine, feline, primates, rodents, monkeys, rabbits, mice, rats, and humans) using a compound of the disclosure (e.g., Formula (I), 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 MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, MDS with a mutation in isocitrate dehydrogenase 2, refractory cytopenia with unilineage dysplasia (e.g., refractory anemia, refractory neutropenia, and refractory thrombocytopenia), refractory anemia with ring sideroblasts, refractory cytopenia with multilineage dysplasia (e.g., refractory cytopenia with multilineage dysplasia and ring sideroblasts and animals with pathological changes not restricted to red cells such as prominent white cell precursor and platelet precursor (megakaryocyte) dysplasia), refractory anemias with excess blasts I and II, 5q-syndrome, megakaryocyte dysplasia with fibrosis, and refractory cytopenia of childhood. In some embodiments, MDS that can be treated include, but are not limited to, MDS that is inherited, MDS with an increased risk of occurrence due to an inherited predisposition, MDS with an increased risk of occurrence due to other blood disorders, MDS with an increased risk of occurrence due to chemical exposure, MDS with an increased risk of occurrence due to ionizing radiation, MDS with an increased risk of occurrence due to cancer treatment (e.g., a combination of radiation and the radiomimetic alkylating agents such as busulfan, nitrosourea, or procarbazine (with a latent period of 5 to 7 years) or DNA topoisomerase inhibitors), MDS evolving from acquired aplastic anemia following immunosuppressive treatment and Fanconi's anemia, MDS with an increased risk due to an mutation in splicing factors, MDS with an increased risk due to a mutation in isocitrate dehydrogenase 1, and MDS with an increased risk due to a mutation in isocitrate dehydrogenase 2. Animals that can be treated include but are not limited to mammals, rodents, primates, monkeys (e.g., macaque, rhesus macaque, pig tail macaque), humans, canine, feline, porcine, avian (e.g., chicken), bovine, mice, rabbits, and rats. In the methods, the term “subject” may refer to both human and non-human subjects. In some instances, the subject is in need of the treatment (e.g., by showing signs of disease or MDS, or by having a low blood cell count). In some embodiments, MDS that can be treated in a subject (e.g., mammals, porcine, canine, avian (e.g., chicken), bovine, feline, primates, rodents, monkeys, rabbits, mice, rats, and humans) using a compound of the disclosure (e.g., Formula (I), 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 MDS that can be treated by inhibiting one or more of FLT3 (e.g., using FLT3 inhibitors), mutations of FLT3 (e.g., using inhibitors of FLT3 mutants), IRAK4 (e.g., using IRAK4 inhibitors), mutations of IRAK4 (e.g., using inhibitors of IRAK4 mutants), IRAK1 (e.g., using IRAK 1 inhibitors), and/or mutations of IRAK1 (e.g., using inhibitors of IRAK1 mutant). In certain embodiments, MDS that can be treated include, but are not limited to MDS that can be treated by inhibiting IRAK4 (or its mutations), MDS that can be treated by inhibiting and IRAK1 (or its mutations), or MDS that can be treated by inhibiting IRAK4 (or its mutations) and IRAK1 (or its mutations). In some embodiments, MDS that can be treated include, but are not limited to MDS that can be treated by inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1. In some embodiments, 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. In some embodiments, MDS that can be treated is characterized by MDS having enhanced IRAK4-Long expression and/or activity relative to IRAK4-Short, and/or wherein the MDS is not driven by FLT3 mutations but expresses IRAK4-Long, based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S (e.g. as described in U.S. Patent Application No.16/339,692; and Smith, M. A., et al. (2019). “U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies.” Nat Cell Biol 21(5):640-650. DOI: 10.1038/s41556-019-0314-5, both incorporated by reference herein in their entirety). In some embodiments, AML that can be treated in a subject (e.g., mammals, porcine, canine, avian (e.g., chicken), bovine, feline, primates, rodents, monkeys, rabbits, mice, rats, and humans) using a compound of the disclosure (e.g., Formula (I), 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 AML that is inherited, AML with an increased risk of occurrence due to an inherited predisposition, AML with one or more recurrent genetic abnormality (e.g., with inversions or translocations, such as MLLT3/MLL which is a translocation between chromosome 9 and 11 (“MLL”) AML with translocation between chromosomes 8 and 21, AML with translocation or inversion in chromosome 16, AML with translocation between chromosomes 9 and 11, APL (M3) with translocation between chromosomes 15 and 17, AML with translocation between chromosomes 6 and 9, AML with translocation or inversion in chromosome 3, and the like), AML (megakaryoblastic) with a translocation between chromosomes 1 and 22, AML with myelodysplasia-related changes, AML related to previous chemotherapy or radiation (such as, for example, alkylating agent-related AML, topoisomerase II inhibitor-related AML, and the like), AML not otherwise categorized (does not fall into above categories - similar to FAB classification; such as, for example, AML minimally differentiated (M0), AML with minimal maturation (M1), AML with maturation (M2), acute myelomonocytic leukemia (M4), acute monocytic leukemia (M5), acute erythroid leukemia (M6), acute megakaryoblastic leukemia (M7), acute basophilic leukemia, acute panmyelosis with fibrosis, and the like), myeloid sarcoma (also known as granulocytic sarcoma, chloroma or extramedullary myeloblastoma), undifferentiated and biphenotypic acute leukemias (also known as mixed phenotype acute leukemias), AML with an increased risk of occurrence due to other blood disorders, AML with an increased risk of occurrence due to chemical exposure, AML with an increased risk of occurrence due to ionizing radiation, AML evolving from myelodysplastic syndromes, AML evolving from myeloproliferative disease, AML with an increased risk due to an FLT3 mutation, AML with an increased risk due to an FLT3 mutation in the juxtamembrane region of FLT3, AML with an increased risk due to an FLT3 mutation of an internal tandem duplication in the juxtamembrane region of FLT3, AML with an increased risk due to an FLT3 mutation in the kinase domain of FLT3, AML with an increased risk due to the FLT3 mutation D835Y, AML with an increased risk due to the FLT3 mutation D835V, AML with an increased risk due to the FLT3 mutation F691L, and AML with an increased risk due to the FLT3 mutation R834Q, and the like. In some embodiments, AML that can be treated include AML that by inhibiting one or more of FLT3 (e.g., using FLT3 inhibitors), mutations of FLT3 (e.g., using inhibitors of FLT3 mutants), IRAK4 (e.g., using IRAK4 inhibitors), mutations of IRAK4 (e.g., using inhibitors of IRAK4 mutants), IRAK1 (e.g., using IRAK 1 inhibitors), and/or mutations of IRAK1 (e.g., using inhibitors of IRAK1 mutant). In certain embodiments, AML that can be treated include, but are not limited to AML that can be treated by inhibiting IRAK4 (or its mutations), MDS that can be treated by inhibiting and IRAK1 (or its mutations), or AML that can be treated by inhibiting IRAK4 (or its mutations) and IRAK1 (or its mutations). In some embodiments, AML that can be treated include, but are not limited to AML that can be treated by inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1. In some embodiments, 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. In some embodiments, AML that can be treated is characterized by AML having enhanced IRAK4-Long expression and/or activity relative to IRAK4-Short, and/or wherein the AML is not driven by FLT3 mutations but expresses IRAK4-Long, based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S (e.g. as described in U.S. Patent Application No.16/339,692; and Smith, M. A., et al. (2019). “U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies.” Nat Cell Biol 21(5): 640-650. DOI: 10.1038/s41556-019-0314-5, both incorporated by reference herein in their entirety). In some embodiments, hematopoietic cancers that can be treated in a subject (e.g., mammals, porcine, canine, avian (e.g., chicken), bovine, feline, primates, rodents, monkeys, rabbits, mice, rats, and humans) using a compound of the disclosure (e.g., Formula (I), 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 (e.g. MDS, AML, DLBCL, and the like, as described previously) that can be treated by inhibiting (e.g., reducing the activity or expression of) one or more of FLT3 (e.g., using FLT3 inhibitors), mutations of FLT3 (e.g., using inhibitors of FLT3 mutants), IRAK4 (e.g., using IRAK4 inhibitors), isoforms of IRAK4, mutations of IRAK4 (e.g., using inhibitors of IRAK4 mutants), IRAK1 (e.g., using IRAK 1 inhibitors), isoforms of IRAK1, or mutations of IRAK1 (e.g., using inhibitors of IRAK1 mutants). In certain embodiments, hematopoietic cancers that can be treated include, but are not limited to cancers that can be treated by inhibiting (e.g., reducing the activity or expression of) FLT3 (or its mutations) and IRAK4 (or its mutations), hematopoietic cancers that can be treated by inhibiting (e.g., reducing the activity or expression of) FLT3 (or its mutations) and 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). In some embodiments, hematopoietic cancer that can be treated include, but are not limited to hematopoietic cancer that can be treated by inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1. In some embodiments, 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. In some embodiments, hematopoietic cancer that can be treated is characterized by hematopoietic cancer having enhanced IRAK4-Long expression and/or activity relative to IRAK4-Short, and/or wherein the hematopoietic cancer is not driven by FLT3 mutations but expresses IRAK4-Long, based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S (e.g. as described in U.S. Patent Application No.16/339,692; and Smith, M. A., et al. (2019). “U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies.” Nat Cell Biol 21(5): 640-650. DOI: 10.1038/s41556-019-0314-5, both incorporated by reference herein in their entirety). In some embodiments, cancers that can be treated include, but are not limited to, glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, Glioma, oral cancer, nasopharyngeal carcinoma, rectal cancer, stomach cancer, and uterine cancer, and the like, and combinations thereof, that can be treated by inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1. In some embodiments, 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. In some embodiments, cancer that can be treated is characterized by cancer having enhanced IRAK4-Long expression and/or activity relative to IRAK4-Short, and/or wherein the cancer is not driven by FLT3 mutations but expresses IRAK4- Long, based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S (e.g. as described in U.S. Patent Application No.16/339,692; and Smith, M. A., et al. (2019). “U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies.” Nat Cell Biol 21(5): 640-650. DOI: 10.1038/s41556-019-0314-5, both incorporated by reference herein in their entirety). In some embodiments, inflammatory and autoimmune diseases characterized by dysregulated (e.g., hyperactive) IRAK expression (IRAK1 and/or IRAK4) and/or IRAK- mediated intracellular signaling, 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. In some embodiments, 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. In some embodiments, inflammatory and autoimmune disease that can be treated is characterized by inflammatory and autoimmune disease having enhanced IRAK4-Long expression and/or activity relative to IRAK4-Short, and/or wherein the inflammatory and autoimmune disease is not driven by FLT3 mutations but expresses IRAK4-Long, based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S (e.g. as described in U.S. Patent Application No.16/339,692; and Smith, M. A., et al. (2019). “U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies.” Nat Cell Biol 21(5): 640-650. DOI: 10.1038/s41556-019-0314-5, both incorporated by reference herein in their entirety). As related to treating MDS (e.g., MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2), treating can include but is not limited to prophylactic treatment and therapeutic treatment. As such, treatment can include, but is not limited to: preventing MDS (e.g., MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2); reducing the risk of MDS (e.g., MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2); ameliorating or relieving symptoms of MDS (e.g., MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2); eliciting a bodily response against MDS (e.g., MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2); inhibiting the development or progression of MDS (e.g., MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2); inhibiting or preventing the onset of symptoms associated with MDS (e.g., MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2); reducing the severity of MDS (e.g., MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2); causing a regression of MDS (e.g., MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2) or one or more of the symptoms associated with MDS (e.g., an increase in blood cell count); causing remission of MDS (e.g., MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2); causing remission of MDS (e.g., MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2) by preventing or minimizing FLT3 mutations (e.g., internal tandem duplication mutations or the D835Y mutation); preventing relapse of MDS (e.g., MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2); or preventing relapse of MDS (e.g., MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2) in animals that have intrinsic or acquired resistance to other MDS treatments. In some embodiments, treating does not include prophylactic treatment of MDS (e.g., preventing or ameliorating future MDS). As related to treating 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. As such, 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, 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); eliciting a bodily response against 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); inhibiting the development or progression 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); inhibiting or preventing the onset of symptoms associated with 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 severity of cancer (e.g., 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); causing a regression of cancer (e.g., 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) or one or more of the symptoms associated with cancer (e.g., a decrease in tumor size); causing remission of cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, bone marrow cancer, non-Hodgkin lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof, and the like); causing remission of cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, bone marrow cancer, non-Hodgkin lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof, and the like) by preventing or minimizing FLT3 mutations (e.g., internal tandem duplication mutations or the D835Y mutation); causing remission of acute myeloid leukemia by preventing or minimizing FLT3 mutations (e.g., internal tandem duplication mutations or the D835Y mutation); preventing relapse of cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, bone marrow cancer, non- Hodgkin lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof, and the like); preventing relapse of cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, bone marrow cancer, non-Hodgkin lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof, and the like) in animals that have intrinsic or acquired resistance to other cancer treatments (e.g., from some FLT3 inhibitors or from MLL); or preventing relapse of acute myeloid leukemia in animals that have intrinsic or acquired resistance to other cancer treatments (e.g., from some FLT3 inhibitors or from MLL). In some embodiments, treating does not include prophylactic treatment of cancer (e.g., preventing or ameliorating future cancer). 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)). In some embodiments, 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). In some embodiments, 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). Other embodiments include treatment after one or more of having a blood disorder, having myelodysplastic syndrome, having myeloproliferative disease, an occurrence of chemical exposure, an exposure to ionizing radiation, or a treatment for a hematopoietic cancer (e.g., with chemotherapy, ionizing radiation, or both). Some embodiments of the disclosure include a method for treating a subject (e.g., an animal such as a human or primate) with a composition comprising a compound of the disclosure (e.g., Formula (I), 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. In some embodiments, the method of treatment includes administering to a subject an effective amount of a composition comprising a compound of the disclosure (e.g., Formula (I), 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 used herein, the term “effective amount” refers to a dosage or a series of dosages sufficient to affect treatment (e.g., to treat MDS such as but not limited to MDS (e.g., MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2); or to treat a hematopoietic cancer, such as but not limited to acute myeloid leukemia, lymphoma, leukemia, bone marrow cancer, non-Hodgkin lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof, and the like) in a subject. In some embodiments, an effective amount can encompass a therapeutically effective amount, as disclosed herein. In certain embodiments, an effective amount can vary depending on the subject and the particular treatment being affected. The exact amount that is required can, for example, vary from subject to subject, depending on the age and general condition of the subject, the particular adjuvant being used (if applicable), administration protocol, and the like. As such, the effective amount can, for example, vary based on the particular circumstances, and an appropriate effective amount can be determined in a particular case. An effective amount can, for example, include any dosage or composition amount disclosed herein. In some embodiments, an effective amount of at least one compound of the disclosure (e.g., Formula (I), 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, about 5.5 mg/kg, about 6 mg/kg, about 6.5 mg/kg, about 7 mg/kg, about 7.5 mg/kg, about 8 mg/kg, about 10 mg/kg, about 12 mg/kg, or about 15 mg/kg. In regard to some embodiments, the dosage can be about 0.5 mg/kg body weight or about 6.5 mg/kg body weight. In some instances, an effective amount of at least one compound of the disclosure (e.g., Formula (I), 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/kg, about 0.05 mg/kg, about 0.1 mg/kg, about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 20 mg/kg, about 30 mg/kg, about 40 mg/kg, about 50 mg/kg, about 80 mg/kg, about 100 mg/kg, or about 150 mg/kg. In some embodiments, an effective amount of at least one compound of the disclosure (e.g., Formula (I), 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, primates, monkeys or humans) can be an amount of about 1 to about 1000 mg/kg body weight, about 5 to about 500 mg/kg body weight, about 10 to about 200 mg/kg body weight, about 25 to about 100 mg/kg body weight, about 1 mg/kg, about 2 mg/kg, about 5 mg/kg, about 10 mg/kg, about 25 mg/kg, about 50 mg/kg, about 100 mg/kg, about 150 mg/kg, about 200 mg/kg, about 300 mg/kg, about 400 mg/kg, about 500 mg/kg, about 600 mg/kg, about 700 mg/kg, about 800 mg/kg, about 900 mg/kg, or about 1000 mg/kg. In regard to some conditions, the dosage can be about 20 mg/kg human body weight or about 100 mg/kg human body weight. In some instances, an effective amount of at least one compound of the disclosure (e.g., Formula (I), 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/kg, about 25 mg/kg, about 50 mg/kg, about 100 mg/kg, about 150 mg/kg, about 200 mg/kg, about 300 mg/kg, about 400 mg/kg, about 500 mg/kg, about 600 mg/kg, about 700 mg/kg, about 800 mg/kg, about 900 mg/kg, or about 1000 mg/kg. In some embodiments, the treatments can also include one or more of surgical intervention, chemotherapy, radiation therapy, hormone therapies, immunotherapy, and adjuvant systematic therapies. Adjuvants may include but are not limited to chemotherapy (e.g., temozolomide), radiation therapy, antiangiogenic therapy (e.g., bevacizumab), and hormone therapies, such as administration of LHRH agonists; anti-estrogens, such as tamoxifen; high-dose progestogens; aromatase inhibitors; and/or adrenalectomy. Chemotherapy can be used as a single-agent or as a combination with known or new therapies. In some embodiments, the administration to a subject 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)) is an adjuvant cancer therapy or part of an adjuvant cancer therapy. Adjuvant treatments include treatments by the mechanisms disclosed herein and of cancers as disclosed herein, including, but not limited to tumors. Corresponding primary therapies can include, but are not limited to, surgery, chemotherapy, or radiation therapy. In some instances, the adjuvant treatment can be a combination of chemokine receptor antagonists with traditional chemotoxic agents or with immunotherapy that increases the specificity of treatment to the cancer and potentially limits additional systemic side effects. In still other embodiments, a compound of the disclosure (e.g., Formula (I), 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 used as adjuvant with other chemotherapeutic agents. The use 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)) may, in some instances, reduce the duration of the dose of both drugs and drug combinations reducing the side effects. In some embodiments, the administration to a subject may decrease the incidence of one or more symptoms associated with MDS / AML / a type of hematopoietic cancer. In some embodiments, the administration may decrease marrow failure, immune dysfunction, transformation to overt leukemia, or combinations thereof in said subject, as compared to a subject not receiving said composition. In some embodiments, the method may decrease a marker of viability of MDS cells or cancer cells in a subject. In one aspect, the method may decrease a marker of viability of MDS, AML, and/or cancer cells. The marker may be selected from survival over time, proliferation, growth, migration, formation of colonies, chromatic assembly, DNA binding, RNA metabolism, cell migration, cell adhesion, inflammation, or a combination thereof. Combination Therapies In one embodiment, 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. In some embodiments, the treatments disclosed herein can include use of other drugs (e.g., antibiotics) or therapies for treating disease, e.g. MDS / AML / a type of hematopoietic cancer. For example, antibiotics can be used to treat infections and can be combined with a compound of the disclosure to treat disease (e.g., infections). In other embodiments, intravenous immunoglobulin (IVIG) therapy can be used as part of the treatment regime (i.e., in addition to administration of the compound(s) of the disclosure). For example, treatment regimens for various types of cancers can involve one or more elements selected from chemotherapy, targeted therapy, alternative therapy, immunotherapy, and the like. Accordingly, in some embodiments, the compounds and/or compositions described herein can be used in one or more administrations to a subject, in combination with one or more BCL2 inhibitor, BTK inhibitor, chemotherapy, targeted therapy, alternative therapy, immunotherapy, DNA methyltransferase inhibitor/hypomethylating agent, anthracycline, histone deacetylase (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 one or more combinations thereof, where the compositions may be the same or different if there is more than one administration. In some embodiments, if there is more than one administration at least one composition used for at least one administration is different from the composition of at least one other administration. In one embodiment, the therapeutic agent comprises a BCL2 inhibitor. In one embodiment, the BCL2 inhibitor is venetoclax or a salt thereof. In one embodiment, the therapeutic agent comprises a DNA polymerase inhibitor. In one embodiment, the DNA polymerase inhibitor is cytidine. In one embodiment, the therapeutic agent comprises a cytidine deaminase inhibitor. In one embodiment, the cytidine deaminase inhibitor is zebularine. In one embodiment, the therapeutic agent comprises a DNMT inhibitor. In one embodiment, the DNMT inhibitor is zebularine, decitabine, or azacitidine. In one embodiment, the therapeutic agent comprises an immunomodulatory imide (cereblon modulator). In one embodiment, the immunomodulatory imide (cereblon modulator) is lenalidomide. In one embodiment, the therapeutic agent comprises a purine nucleoside antimetabolite. In one embodiment, the purine nucleoside antimetabolite is clofarabine. In one embodiment, the therapeutic agent comprises a Type II topoisomerase inhibitor/ DNA intercalator. In one embodiment, the Type II topoisomerase inhibitor/ DNA intercalator is vosaroxin. In one embodiment, the therapeutic agent comprises a hedgehog antagonist. In one embodiment, the hedgehog antagonist is glasdegib. In one embodiment, the therapeutic agent comprises an IDH1 inhibitor. In one embodiment, the IDH1 inhibitor is ivosidenib. In one embodiment, the therapeutic agent comprises an IDH2 inhibitor. In one embodiment, the IDH2 inhibitor is enasidenib. In one embodiment, the therapeutic agent comprises a ribonucleotide reductase inhibitor. In one embodiment, the ribonucleotide reductase inhibitor is gemcitabine. In one embodiment, the therapeutic agent comprises an adenosine deaminase inhibitor. In one embodiment, the adenosine deaminase inhibitor is cladribine. In one embodiment, the therapeutic agent comprises a Mek 1/2 inhibitor. In one embodiment, the Mek 1/2 inhibitor is trametinib. In one embodiment, the therapeutic agent comprises an ERK 1/2 inhibitor. In one embodiment, the ERK 1/2 inhibitor is ulixertinib. In one embodiment, the therapeutic agent comprises an AKT inhibitor. In one embodiment, the AKT inhibitor is capivasertib (AZD5363). In one embodiment, the therapeutic agent comprises a PTPN11/SHP2 inhibitor. In one embodiment, the PTPN11/SHP2 inhibitor is TNO-155. In one embodiment, the therapeutic agent comprises a glucocorticoid steroid. In one embodiment, the glucocorticoid steroid is selected from dexamethasone, methylprednisolone, prednisolone, cortisol, prednisone, betamethasone, triamcinolone, deflazacort, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone, and beclometasone. In one embodiment, the glucocorticoid steroid is selected from dexamethasone, methylprednisolone, and prednisolone. In one embodiment, the therapeutic agent comprises a menin inhibitor. In one embodiment, the menin inhibitor is SNDX-5613. In one embodiment, the therapeutic agent comprises an MDM2 inhibitor. In one embodiment, the MDM2 inhibitor is navtemadlin (AMG 232, KRT-232). In one embodiment, the therapeutic agent comprises a BTK inhibitor. In one embodiment, the BTK inhibitor is selected from ibrutinib, acalabrutinib, and zanubrutinib. In one embodiment, the therapeutic agent comprises a mutant/inactivated p53 reactivator. In one embodiment, the mutant/inactivated p53 reactivator is Eprenetapopt (APR- 246). In one embodiment, the therapeutic agent comprises a CDK inhibitor. The CDK inhibitor can be any CDK inhibitor known to a person of ordinary skill in the art. In one embodiment, the CDK inhibitor is a CKD1, CKD2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12, or CDK13 inhibitor or a combination thereof. 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In another embodiment, 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-Martínez, C. et al., Bioorganic & Medicinal Chemistry Letters, 2019, 29:126637; Di Sante, G. et al., Expert Review of Anticancer Therapy, 2019, 19(7): 569-587; Whittaker, S. R. et al., Pharmacology & Therapeutics, 2017, 173:83-105; Chou, J. et al., Cancer Discovery, 2020, 10:351-370; Galbraith, M. D. et al., Transcription, 2019, 10(2):118-136; Goel, B. et al., Current Topics in Medicinal Chemistry, 2020, 20:1535-1563; Heptinstall, A. B. et al., Future Medicinal Chemistry, 2018, 10(11): 1369-1388; each of which is incorporated herein by reference in its entirety. Exemplary CDK inhibitors include, but are not limited to: Compound 21 (PMID 27326333) CYC065; YKL-1-116; i-CDK9; JH-VII-49; JH-XI-10-02; SEL120-34A; MM-D37K; PF-06873600; BEY-1007; BEY-1107; birociclib (XZP-3297); FCN-437; TP-1287; BEBT-209; TQB-3616; AMG-925 (FLX-925); CS3002; HS-10342; terameprocol (EM-1421); NU-6102; CGP-60474; BMS-265246; NU-6027; Purvalanol A; Purvalanol B; RGB-286147; Indirubin; 7- Hydroxystaurosporine; BS-194; PHA-690509; Cdk4/6 Inhibitor IV; FCN437c;
candesartan cilexil; indocyanine green;
wherein X is N, Y is –C(=O)H, and Ar is X is N, Y is -CH 2 OH, and Ar is or X is CH, Y is -CH 2 OH, and Ar is wherein X is NH or O;
wherein 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;
wherein 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 tetrahydrofuran-3yl, X is Cl and n is 1, or R is -CH 3 , X is F and n is 2, or R is cyclopropane-1-1- yl, X is F and n is 1, or oxatan-3-yl, X is -CH 3 , and n is 1; wherein R is 1,2-oxazol-3yl or 3,4-difluorobenzen-1yl; wherein R is H, C(=O)NHCH 3 , -SO 2 NH 2 , SO 2 CH 3 , or 2,3-dihydroxpropan-1yl; wherein R is H, CH 3 , 2-aminoethyan-1yl, 3-aminopropan-1yl, or 2,3-dihydroxpropan-1yl; wherein R is H or -CH 3 ; wherein R is H, C(=O)NHCH 3 , or -SO 2 CH 3 ; wherein R is 3-fluorobenzyl or 3-fluoropyridin-3yl; wherein Aryl is 4-fluorophenyl, 4-trifluoromethylphenyl, 3- fluorophenyl, 4-methylphenyl, 2-ethylphenyl, or 3-pyridyl and R is H, cyclopropyl, cylcopentyl, or cycloheptyl; wherein R is 2-phenylethan-1yl or (furan-2- yl)methyl; wherein R is H or -C(=O)CH 2 OH; wherein R is -NHC(=O)CH 3 or -NHSO 2 CH 3 ; wherein R is H or isobutyl; wherein R is H and R’ is -CH 3 or R is -CN and R’ is H; wherein R is 3,4-dimethyl-1H-pyrazol-4-yl and R’ is -CH 3 or R is piperazin-1yl and R’ is H; wherein R is 2,6-dichlorophenyl, 2,3,4,5,6-tetrafluorophenyl, or 3-
fluorophenyl; wherein R is -CH 2 NCH 3 or H; wherein R is -CH 2 N(CH 3 ) 2 or H; wherein R is H, -SO 2 CH 3 , -CH 2 C(=O)N(CH 3 ) 2 , 4-carboxylic acid- cyclobutan-1yl, or (2(hydroxymethy)pyrrolidine-1-yl)-2-one-ethan-1yl, R’ is H or F, and R” is H or -CH 2 CH 3 ; wherein R 1 is -OH, R 2 is H, R 3 is H, and R 4 is H (meridianin A), R 1 is -OH, R 2 is H, R 3 is Br, and R 4 is H (meridianin B), R 1 is H, R 2 is Br, R 3 is H, and R 4 is H (meridianin C), R 1 is H, R 2 is H, R 3 is Br, and R 4 is H (meridianin D), or R 1 is - OH, R 2 is H, R 3 is H, and R 4 is Br (meridianin E); and wherein R is piperidin- 3yl, pyrrolodin-3yl, or morpholin-2yl. In one embodiment, the therapeutic agent comprises a BCL2 inhibitor and a DNMT inhibitor. In one embodiment, the therapeutic agent comprises venetoclax, or a salt thereof, and azacitidine, or a salt thereof. In particular, IRAK inhibitors have been demonstrated to have synergistic effects when administered in combination with an apoptosis modulator/inhibitor, such as a BCL2 inhibitor. As described in U.S. Patent Publication 2020/0199123 (incorporated herein by reference in its entirety), an exemplary apoptosis/BCL2 inhibitor has been shown to have a synergistic effect when used in combination with an exemplary IRAK inhibitor in multiple AML cell lines. Venetoclax was used as a representative apoptosis/BCL2 inhibitor. When a concentration of an exemplary IRAK inhibitor was combined with venetoclax, the potency of venetoclax was increased by an unexpectedly high ~50-fold. According to particular aspects of the disclosure, this synergistic combination allows for increased efficacy of venetoclax at lower doses, to provide for avoiding at least some of the toxicity observed in the clinic. According to particular aspects, the degree of interaction is dependent on the dose ratio combination that is used, with lower concentrations of the exemplary IRAK inhibitor providing larger shifts in the venetoclax IC 50 . This unexpected and dramatic shift in the venetoclax IC 50 is substantially more than an additive response and demonstrates the unexpected synergistic interaction of the two drugs even in cells line that do not express activated FLT3 mutants. Accordingly, the present disclosure encompasses methods for treating a disease or disorder which is responsive to inhibition of IRAK, comprising administration to a subject of a composition comprising an IRAK inhibiting compound, wherein some embodiments of the method can further involve administration of an apoptotic modulator. The apoptotic modulator may comprise a BTK and/or a BCL2 inhibitor. BTK and BCL2 inhibitors may be, for example, those known in the art. In some embodiments, the method may comprise the step of administering to the subject an apoptotic modulator. In some embodiments, the apoptotic modulator may comprise a BCL2 inhibitor selected from ABT-263 (Navitoclax), ABT-737, ABT-199 (venetoclax), GDC-0199, GX15-070 (Obatoclax) (all available from Abbott Laboratories), HA14-1, 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. One skilled in the art would appreciate that there are many known BCL2 inhibitors which can be used in accordance with the present disclosure. In some embodiments, the BCL2 inhibitor comprises venetoclax. In some embodiments, the administration step comprises administration to a subject of a composition comprising an IRAK inhibiting compound and a BCL2 inhibitor. In some embodiments, the administration step comprises administration of a composition comprising an IRAK inhibiting compound in combination with a composition comprising a BCL2 inhibitor. In some embodiments, 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. In some embodiments, the method can further involve administration to a subject of an immune modulator. The immune modulator can include, for example, Lenalidomide (Revlamid; Celgene Corporation). In some embodiments, the method can involve administration of an epigenetic modulator. The epigenetic modulator can include, for example, a hypomethylating agent such as azacitidine, decitabine, or a combination thereof. In some embodiments, the compounds and/or compositions described herein can be used in one or more administrations to a subject, together with or in combination with one or more BTK inhibitors, such as, for example, ibrutinib, or a salt, isomer, derivative or analog thereof. For example, the compounds and/or compositions described herein can be used in one or more administrations, together with or in combination with a DNA methyltransferase inhibitor/hypomethylating agent, such as, for example, 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, fludarabine, cladribine, and/or clofarabine, and the like; an isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor, such as, for example, ivosidenib (Tibsovo, for more information, see McCafferty, E. H. et al., Drugs & Therapy Perspectives, 2019, 35:160–166, which is incorporated herein by reference), AGI-6780, BAY1436032, FT-2102, IDH305, AGI-5198, ML309 (AGI-5027), GSK 321, and DC_H31, and/or enasidenib (Idhifa, for more information, see Dugan, J. et al., Expert Review of Clinical Pharmacology, 2018, 11:755-760, which is incorporated herein by reference), and the like; an antibody-drug conjugate, such as, for example, Anti-CD33 (e.g. Ac225-lintuzumab, vadastuximab, or gemtuzumab-ozogamicin) and/or Anti-CD45 (e.g. I 131 -apamistamab), and the like; an mAbs/Immunotherapy, such as, for example, 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, pembrolizumab, atezolizumab, avelumab, PDR001, MBG453), and/or Anti-CD47 (e.g.5F9 (Magrolimab, for more information see Sallman, D. A. et al., Blood, 2019, 134:569, which is incorporated by reference herein)), and the like; a Plk inhibitor, such as, for example, volasertib and/or rigosertib, and the like; a MEK inhibitor, such as, for example, trametinib, cobimetinib, selumetinib, pimasertib, and/or refametinib, and the like; a 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. et al., Journal of Experimental & Clinical Cancer Research, 2018, 37:36, which is incorporated herein by reference); 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 RARα agonist), Tamibarotene, Adapalene, Bexarotene, and the like; a TP53 activator (including a nonfunctional mutant TP53 reactivator), such as, for example, APR-246 (Eprenetapopt; for more information, see Ceder, S. et al., EMBO Mol. Med., 2021, 13:e10852, which is incorporated herein by reference), APR-548, RETRA, and/or PC14586 and the like; 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. et al., Cancer Discovery, 2018 8:185-195, which is incorporated herein by reference), SCH772984, ravoxertinib, MK-8353, PD98059, and/or VTX-11e, and the like; 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/or vistusertib (AZD2014), and the like; a steroid or glucocorticoid receptor modulator, such as, for example, an agonist comprising prednisolone, beclometasone, methylprednisolone, prednisone, fluticasone, budesonide, dexamethasone, and/or cortisol, and/or an antagonist comprising mifepristone, miricorilant, and/or onapristone, and/or another binding ligand comprising vamorolone (VBP15), and the like; and/or an EZH2 inhibitor, such as, for example, tazemetostat, and the like. In some embodiments, compounds and pharmaceutical compositions including the same can be used in prevention of secondary malignancies when used in combination with an EZH2 inhibitor. In an embodiment, 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. et al., Future Oncology, 2019, 15:3219- 3232, which is incorporated herein by reference), Vismodegib, Erismodegib, Erivedge, Sonidegib, Odomzo, Saridegib, Exelexis, and/or Taladegib; a BCL-2 inhibitor such as venetoclax (Venclexta), navitoclax, WEHI-539, and/or A-1331852; a DNA methyltransferase inhibitor/hypomethylating agent such as decitabine (for more information, see Stresemann, C. International Journal of Cancer, 2008, 123:8-13, which is incorporated herein by reference) or Cytarabine (for more information, see Löwenberg, B. et al., N. Engl. J. Med., 2011, 364:1027- 1036, which is incorporated herein by reference); a Topoisomerase I inhibitor such as Topotecan and/or Irinotecan; a Topoisomerase II inhibitor such as Mitoxantrone, Doxorubicin, and/or Daunorubicin; an aminopeptidase/Leukotriene A4 hydrolase inhibitor such as Bestatin (Ubenimex, for more information, see Hitzerd, S. M. et al., Amino Acids, 2014, 46:793–808, which is incorporated herein by reference), Ubenimex, and/or tosedostat; 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. R. et al., Blood, 2016, 128:2831, which is incorporated by reference herein), cerdulatinib (PRT062070), and/or 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. et al., Journal of Hematology & Oncology, 2016, 9:50, which is incorporated by reference herein), AMG-232, and/or CGM-097; a PLK1 inhibitor such as Onvansertib, BI2536, and/or Volasertib (for more information, see Van den Bossche, J. et al., Medicinal Research Reviews, 2016, 36:749-786, which is incorporated herein by reference); an Aura A inhibitor such as Alisertib (MLN8237; for more information, see Goldberg, S. L. et al., Leukemia Research Reports, 2014, 3:58-61, which is incorporated by reference herein), MLN8054, TAS-119, and/or erbumine (LY3295668); an aurora kinase inhibitor such as Alisertib, Danusertib, Barasertib, and/or Ilorasertib; an EGFR inhibitor such as Erlotinib, Dacomitinib, and/or Varlitinib; an AuroraB/C/VEGFR1/2/3/FLT3/CSF- 1R/Kit/PDGFRA/B inhibitor such as Ilorasertib (ABT-348; for more information, see Garcia- Manero, G. et al., Investigational New Drugs, 2015, 33:870–880, which is incorporated by reference herein); an AKT 1, 2, and/or 3 inhibitor such as Uprosertib (for more information, see Darici, S. et al., J. Clin. Med., 2020, 9:2934, which is incorporated by reference herein), 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. et al., Expert Opinion on Investigational Drugs, 2010, 19:689-698, which is incorporated by reference herein), lonafarnib, manumycin A, gingerol, gliotoxin, and/or α-hydroxy farnesyl phosphoric acid; a BRAF/MAP2K1/MAP2K2 inhibitor such as Trametinib; a Menin- KMT2A/MLL inhibitor such as Ko-539 and/or SNDX-5613 (for more information on Ko-539 and SNDX-5613, see Gundry, M. C. et al., Cancer Cell, 2020, 37:267-269, which is is incorporated by reference herein); an anti-metabolite such as Cytarabine, Floxuridine, 5- Fluorouracil, Prexasertib, Raltitrexed, and/or Methotrexate; and/or a multikinase inhibitor such as Dasatinib. In one embodiment, 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)). Lenalidomide induces the ubiquitination of casein kinase 1A1 (CK1α) by the E3 ubiquitin ligase CUL4–RBX1–DDB1–CRBN (known as CRL4CRBN), resulting in CK1α degradation. CK1α 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. In one embodiment, 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. However, more recent studies have demonstrated that induction therapy with cytarabine at lower dosages already produces maximal antileukemic effects for all response end points, suggesting a plateau in the dose–response relationship above this dose level and thus suggesting that high-dose cytarabine results in excessive toxic effects without therapeutic benefit. In one embodiment, 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. 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. Because DNA methylation affects cellular function through successive generations of cells without changing the underlying DNA sequence, 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. In two randomized controlled trials comparing azacitidine to supportive treatment, 16% of subjects with myelodysplastic syndrome who were randomized to receive azacitidine had a complete or partial normalization of blood cell counts and bone marrow morphology, compared to none who received supportive care, and about two- thirds of patients who required blood transfusions no longer needed them after receiving azacitidine. Azacitidine can also be used for the treatment of acute myeloid leukemia as a hypomethylating agent. Decitabine has shown significant clinical benefits in the treatment of myelodysplastic syndrome (MDS) by depleting DNA methyltransferase enzymes and inducing DNA demethylation and epigenetic reprogramming in vitro. Venclexta is a selective small- molecule inhibitor of BCL-2, an antiapoptotic protein. The overexpression of BCL-2 in cancer cells is associated with tumor-cell survival and resistance to chemotherapy. Therefore, 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. In one embodiment, 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. Monoclonal antibodies against CD47 are designed to interfere with recognition of CD47 by the SIRPα receptor on macrophages, thus blocking the "don't eat me" signal used by cancer cells to avoid being ingested by macrophages. 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. In one embodiment, 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 (SYK) 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. In one embodiment, 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. Using acute AML mouse models, it was shown that 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-κB pathways. In vivo AML blasts with highest E-selectin binding potential are 12-fold more likely to survive chemotherapy and main contributors to disease relapse. Therapeutic blockade of E-selectin using small molecule mimetic Uproleselan effectively inhibits this niche-mediated pro-survival signaling, dampens AML blast regeneration, and strongly synergizes with chemotherapy, doubling the duration of mouse survival over chemotherapy alone. In one embodiment, the compounds and/or compositions described herein are used in one or more administrations, together with or in combination with a CDK9 inhibitor such as Alvocidib. The cyclin-dependent kinase 9 (CDK9) pathway is dysregulated in AML and therefore targeting this pathway is an attractive approach to treat AML. Inhibition of CDK9 leads to downregulation of cell survival genes regulated by super enhancers such as MCL-1, MYC, and cyclin D1. As 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. In one embodiment, 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. When overexpressed in murine hematopoietic progenitors, Meningioma-1 (MN1) causes an aggressive AML characterized by an aberrant myeloid precursor-like gene expression program that shares features of KMT2A-rearranged (KMT2A-r) leukemia, including high levels of Hoxa and Meis1 gene expression. Menin (Men1) is also critical for the self-renewal of MN1-driven AML through the maintenance of a distinct gene expression program. Genetic inactivation of 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. These results nominate 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. Both compounds showed excellent pharmacokinetic properties and low toxicity profiles in pre-clinical studies. In one embodiment, 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 (HMAs), 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. However, remissions in TP53-mutant patients are brief with a median overall survival (OS) ranging from 5 to 12 months reflecting the significant unmet medical need for targeted therapies for patients with TP53-mutant MDS and AML. Eprenetapopt (APR-246) is converted to methylene quinuclidinone (MQ) that targets mutant p53 protein and perturbs cellular antioxidant balance. APR-246 is currently being tested in a phase III clinical trial in myelodysplastic syndrome (MDS). In some embodiments, the one or more therapeutic agents can be in the form of salts, optical and geometric isomers, and salts of isomers. In other embodiments, the therapeutic agent can be in various forms, such as uncharged molecules, components of molecular complexes, or non-irritating pharmacologically acceptable salts, including but not limited to hydrochloride, hydrobromide, sulphate, phosphate, nitrate, borate, acetate, maleate, tartrate, and salicylate. In some instances, for acidic compounds, salts can include metals, amines, or organic cations (e.g. quaternary ammonium). In yet other embodiments, simple derivatives of the therapeutic agents (e.g., ethers, esters, or amides) which have desirable retention and release characteristics but which are easily hydrolyzed by body pH, enzymes, or other suitable means, can be employed. In some embodiments, the therapeutic agent has a chiral center and can exist in and be isolated in optically active and racemic forms. In other embodiments, the therapeutic agent may exhibit polymorphism. Some embodiments of the present disclosure encompass any racemic, optically active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound described herein, including isotopically-labeled and radio-labeled compounds. See e.g., Goding, 1986, Monoclonal Antibodies Principles and Practice; Academic Press, p.104. Such isomers can be isolated by standard resolution techniques, including e.g., fractional crystallization, chiral chromatography, and the like. See e.g., Eliel, E. L. & Wilen S. H., 1993, Stereochemistry in Organic Compounds; John Wiley & Sons, New York. The preparation of optically active forms can be accomplished by any suitable method, including but not limited to, resolution of the racemic form by recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In some embodiments, the therapeutic agent has asymmetric centers and can occur as racemates, racemic mixtures, and as individual enantiomers or diastereoisomers, with all isomeric forms as well as mixtures thereof being contemplated for use in the compounds and methods described herein. The compounds contemplated for use in the compounds and methods described herein do not include those that are known in the art to be too unstable to synthesize and/or isolate. The therapeutic agents disclosed herein can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds can be radiolabeled with radioactive isotopes, such as for example tritium ( 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. In some embodiments, metabolites of the therapeutic agents disclosed herein are useful for the methods disclosed herein. In some embodiments, the therapeutic agents contemplated herein may be provided in the form of a prodrug. The term “prodrug” refers to a compound that can be converted into a compound (e.g., a biologically active compound) described herein in vivo. Prodrugs can be useful for a variety of reason known in the art, including e.g., ease of administration due e.g., to enhanced bioavailability in oral administration, and the like. The prodrug can also have improved solubility in pharmaceutical compositions over the biologically active compounds. An example, without limitation, of a prodrug is a compound which is administered as an ester (i.e., the "prodrug") to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water solubility is beneficial. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, (ed. H. Bundgaard, Elsevier, 1985), which is hereby incorporated herein by reference for the limited purpose describing procedures and preparation of suitable prodrug derivatives. Certain therapeutic agent disclosed herein can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of contemplated compounds. Certain the therapeutic agents of the present disclosure can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the compounds and methods contemplated herein and are intended to be within the scope disclosed herein. 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. For example, approved chemotherapies include abitrexate (Methotrexate Injection), abraxane (Paclitaxel Injection), adcetris (Brentuximab Vedotin Injection), adriamycin (Doxorubicin), adrucil Injection (5-FU (fluorouracil)), afinitor (Everolimus), afinitor Disperz (Everolimus), alimta (PEMETREXED), alkeran Injection (Melphalan Injection), alkeran Tablets (Melphalan), aredia (Pamidronate), arimidex (Anastrozole), aromasin (Exemestane), arranon (Nelarabine), arzerra (Ofatumumab Injection), avastin (Bevacizumab), beleodaq (Belinostat Injection), bexxar (Tositumomab), BiCNU (Carmustine), blenoxane (Bleomycin), blincyto (Blinatumoma b Injection), bosulif (Bosutinib), busulfex Injection (Busulfan Injection), campath (Alemtuzumab), camptosar (Irinotecan), caprelsa (Vandetanib), casodex (Bicalutamide), CeeNU (Lomustine), CeeNU Dose Pack (Lomustine), cerubidine (Daunorubicin), clolar (Clofarabine Injection), cometriq (Cabozantinib), cosmegen (Dactinomycin), cotellic (Cobimetinib), cyramza (Ramucirumab Injection), cytosarU (Cytarabine), cytoxan (Cytoxan), cytoxan Injection (Cyclophosphamide Injection), dacogen (Decitabine), daunoXome (Daunorubicin Lipid Complex Injection), decadron (Dexamethasone), depoCyt (Cytarabine Lipid Complex Injection), dexamethasone Intensol (Dexamethasone), dexpak Taperpak (Dexamethasone), docefrez (Docetaxel), doxil (Doxorubicin Lipid Complex Injection), droxia (Hydroxyurea), DTIC (Decarbazine), eligard (Leuprolide), ellence (Ellence (epirubicin)), eloxatin (Eloxatin (oxaliplatin)), elspar (Asparaginase), emcyt (Estramustine), erbitux (Cetuximab), erivedge (Vismodegib), erwinaze (Asparaginase Erwinia chrysanthemi), ethyol (Amifostine), etopophos (Etoposide Injection), eulexin (Flutamide), fareston (Toremifene), farydak (Panobinostat), faslodex (Fulvestrant), femara (Letrozole), firmagon (Degarelix Injection), fludara (Fludarabine), folex (Methotrexate Injection), folotyn (Pralatrexate Injection), FUDR (FUDR (floxuridine)), gazyva (Obinutuzumab Injection), gemzar (Gemcitabine), gilotrif (Afatinib), gleevec (Imatinib Mesylate), Gliadel Wafer (Carmustine wafer), Halaven (Eribulin Injection), Herceptin (Trastuzumab), Hexalen (Altretamine), Hycamtin (Topotecan), Hycamtin (Topotecan), Hydrea (Hydroxyurea), Ibrance (Palbociclib), Iclusig (Ponatinib), Idamycin PFS (Idarubicin), Ifex (Ifosfamide), Imbruvica (Ibrutinib), Inlyta (Axitinib), Intron A alfab (Interferon alfa-2a), Iressa (Gefitinib), Istodax (Romidepsin Injection), Ixempra (Ixabepilone Injection), Jakafi (Ruxolitinib), Jevtana (Cabazitaxel Injection), Kadcyla (Ado-trastuzumab Emtansine), Keytruda (Pembrolizumab Injection), Kyprolis (Carfilzomib), Lanvima (Lenvatinib), Leukeran (Chlorambucil), Leukine (Sargramostim), Leustatin (Cladribine), Lonsurf (Trifluridine and Tipiracil), Lupron (Leuprolide), Lupron Depot (Leuprolide), Lupron DepotPED (Leuprolide), Lynparza (Olaparib), Lysodren (Mitotane), Marqibo Kit (Vincristine Lipid Complex Injection), Matulane (Procarbazine), Megace (Megestrol), Mekinist (Trametinib; for more information, see Borthakur, G. et al., Blood, 2012, 120:677, which is incorporated by reference herein), Mesnex (Mesna), Mesnex (Mesna Injection), Metastron (Strontium-89 Chloride), Mexate (Methotrexate Injection), Mustargen (Mechlorethamine), Mutamycin (Mitomycin), Myleran (Busulfan), Mylotarg (Gemtuzumab Ozogamicin, for more information, see Norsworthy, K. J. et al., Oncologist, 2018, 23:1103-1108, which is incorporated herein by reference), Navelbine (Vinorelbine), Neosar Injection (Cyclophosphamide Injection), Neulasta (filgrastim), Neulasta (pegfilgrastim), Neupogen (filgrastim), Nexavar (Sorafenib), Nilandron (Nilandron (nilutamide)), Nipent (Pentostatin), Nolvadex (Tamoxifen), Novantrone (Mitoxantrone, for more information, see Fox, E. J., Neurology, 2004, 28(12 Suppl 6):S15-8, which is incorporated herein by reference), Odomzo (Sonidegib), Oncaspar (Pegaspargase), Oncovin (Vincristine), Ontak (Denileukin Diftitox), onxol (Paclitaxel Injection), opdivo (Nivolumab Injection), panretin (Alitretinoin), paraplatin (Carboplatin), perjeta (Pertuzumab Injection), platinol (Cisplatin), platinol (Cisplatin Injection), platinolAQ (Cisplatin), platinolAQ (Cisplatin Injection), pomalyst (Pomalidomide), prednisone Intensol (Prednisone), proleukin (Aldesleukin), purinethol (Mercaptopurine), reclast (Zoledronic acid), revlimid (Lenalidomide; for more information see Krönke, J. et al., Nature, 2015, 523:183-188, which is incorporated by reference herein), actimid (Pomalidomid), rheumatrex (Methotrexate), rituxan (Rituximab), roferonA alfaa (Interferon alfa- 2a), rubex (Doxorubicin), sandostatin (Octreotide), sandostatin LAR Depot (Octreotide), soltamox (Tamoxifen), sprycel (Dasatinib; for more information, see Duong, V. H. et al., Leukemia Research, 2013, 37:300-304, which is incorporated herein by reference), sterapred (Prednisone), sterapred DS (Prednisone), stivarga (Regorafenib), supprelin LA (Histrelin Implant), sutent (Sunitinib), sylatron (Peginterferon Alfa-2b Injection (Sylatron)), sylvant (Siltuximab Injection), synribo (Omacetaxine Injection), tabloid (Thioguanine), taflinar (Dabrafenib), tarceva (Erlotinib), targretin Capsules (Bexarotene), tasigna (Decarbazine), taxol (Paclitaxel Injection), taxotere (Docetaxel), temodar (Temozolomide), temodar (Temozolomide Injection), tepadina (Thiotepa), thalomid (Thalidomide), theraCys BCG (BCG), thioplex (Thiotepa), TICE BCG (BCG), toposar (Etoposide Injection), torisel (Temsirolimus), treanda (Bendamustine hydrochloride), trelstar (Triptorelin Injection), trexall (Methotrexate), trisenox (Arsenic trioxide), tykerb (lapatinib), unituxin (Dinutuximab Injection), valstar (Valrubicin Intravesical), vantas (Histrelin Implant), vectibix (Panitumumab), velban (Vinblastine), velcade (Bortezomib), vepesid (Etoposide), vepesid (Etoposide Injection), vesanoid (Tretinoin), vidaza (Azacitidine), vincasar PFS (Vincristine), vincrex (Vincristine), votrient (Pazopanib), vumon (Teniposide), wellcovorin IV (Leucovorin Injection), xalkori (Crizotinib), xeloda (Capecitabine), xtandi (Enzalutamide), yervoy (Ipilimumab Injection), yondelis (Trabectedin Injection), zaltrap (Ziv-aflibercept Injection), zanosar (Streptozocin), zelboraf (Vemurafenib), zevalin (Ibritumomab Tiuxetan), zoladex (Goserelin), zolinza (Vorinostat), zometa (Zoledronic acid), zortress (Everolimus), zydelig (Idelalisib), zykadia (Ceritinib), zytiga (Abiraterone), and the like, in addition to analogs and derivatives thereof. For example, approved targeted therapies include ado-trastuzumab emtansine (Kadcyla), afatinib (Gilotrif), aldesleukin (Proleukin), alectinib (Alecensa), alemtuzumab (Campath), axitinib (Inlyta), 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 (Sprycel), denosumab (Xgeva), dinutuximab (Unituxin), elotuzumab (Empliciti), erlotinib (Tarceva, for more information, see Boehrer, S. et al., Blood, 2008, 111:2170-2180, which is incorporated by reference herein), everolimus (Afinitor), gefitinib (Iressa), ibritumomab tiuxetan (Zevalin), ibrutinib (Imbruvica), idelalisib (Zydelig), imatinib (Gleevec), ipilimumab (Yervoy), ixazomib (Ninlaro), lapatinib (Tykerb), lenvatinib (Lenvima), necitumumab (Portrazza), nilotinib (Tasigna), nivolumab (Opdivo), obinutuzumab (Gazyva), ofatumumab (Arzerra, HuMax-CD20), olaparib (Lynparza),osimertinib (Tagrisso), palbociclib (Ibrance), panitumumab (Vectibix), panobinostat (Farydak), pazopanib (Votrient), pembrolizumab (Keytruda), pertuzumab (Perjeta), ponatinib (Iclusig), ramucirumab (Cyramza), rapamycin, regorafenib (Stivarga), rituximab (Rituxan, Mabthera), romidepsin (Istodax), ruxolitinib (Jakafi), siltuximab (Sylvant), sipuleucel- T (Provenge), sirolimus, sonidegib (Odomzo), sorafenib (Nexavar), sunitinib, tamoxifen, temsirolimus (Torisel), tocilizumab (Actemra), tofacitinib (Xeljanz), tositumomab (Bexxar), trametinib (Mekinist), trastuzumab (Herceptin), vandetanib (Caprelsa), vemurafenib (Zelboraf), venetoclax (Venclexta), vismodegib (Erivedge), vorinostat (Zolinza), ziv-aflibercept (Zaltrap), and the like, in addition to analogs and derivatives thereof. In an embodiment, the approved chemotherapy is an anthracycline, such as Doxorubicen, Daunarubicin, Epirubicin, and/or Idarubicin. In one embodiment, 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) Those skilled in the art can determine appropriate chemotherapy and/or targeted therapy and/or alternative therapy options, including treatments that have been approved and those that in clinical trials or otherwise under development. Some targeted therapies are also immunotherapies. Any relevant chemotherapy, target therapy, and alternative therapy treatment strategies can be utilized, alone or in combination with one or more additional cancer therapy, in the practice of the present disclosure. Immunotherapy In some embodiments, immunotherapies include cell-based immunotherapies, such as those involving cells which effect an immune response (such as, for example, lymphocytes, macrophages, natural killer (NK) cells, dendritic cells, cytotoxic T lymphocytes (CTL), antibodies and antibody derivatives (such as, for example, monoclonal antibodies, conjugated monoclonal antibodies, polyclonal antibodies, antibody fragments, radiolabeled antibodies, chemolabeled antibodies, etc.), immune checkpoint inhibitors, vaccines (such as, for example, cancer vaccines (e.g. tumor cell vaccines, antigen vaccines, dendritic cell vaccines, vector-based vaccines, etc.), e.g. oncophage, sipuleucel-T, and the like), immunomodulators (such as, for example, interleukins, cytokines, chemokines, etc.), topical immunotherapies (such as, for example, imiquimod, and the like), injection immunotherapies, adoptive cell transfer, oncolytic virus therapies (such as, for example, talimogene laherparepvec (T-VEC), and the like), immunosuppressive drugs, helminthic therapies, other non-specific immunotherapies, and the like. Immune checkpoint inhibitor immunotherapies are those that target one or more specific proteins or receptors, such as PD-1, PD-L1, CTLA-4, and the like. Immune checkpoint inhibitor immunotherapies include ipilimumab (Yervoy), nivolumab (Opdivo), pembrolizumab (Keytruda), and the like. Non-specific immunotherpaies include cytokines, interleukins, interferons, and the like. In some embodiments, an immunotherapy assigned or administered to a subject can include an interleukin, and/or interferon (IFN), and/or one or more suitable antibody-based reagent, such as denileukin diftitox and/or administration of an antibody-based reagent selected from the group consisting of ado-trastuzumab emtansine, alemtuzumab, atezolizumab, bevacizumab, blinatumomab, brentuximab vedotin, cetuximab, catumaxomab, gemtuzumab, ibritumomab tiuxetan, ilipimumab, natalizumab, nimotuzumab, nivolumab, ofatumumab, panitumumab, pembrolizumab, rituximab, tositumomab, trastuzumab, vivatuxin, and the like. In some embodiments, an immunotherapy assigned or administered to a subject can include an indoleamine 2,3-dioxygenase (IDO) inhibitor, adoptive T-cell therapy, virotherapy (T-VEC), and/or any other immunotherapy whose efficacy extensively depends on anti-tumor immunity. Those skilled in the art can determine appropriate immunotherapy options, including treatments that have been approved and those that in clinical trials or otherwise under development. Any relevant immunotherapy treatment strategies, alone or in combination with one or more additional cancer therapy, can be utilized in the practice of the present disclosure. Other Cancer Treatments In addition to chemotherapies, targeted therapies, alternative therapies, and immunotherapies, cancer can additionally be treated by other strategies. These include surgery, radiation therapy, hormone therapy, stem cell transplant, precision medicine, and the like; such treatments and the compounds and compositions utilized therein are known to those skilled in the art. Any such treatment strategies can be utilized in the practice of the present disclosure. Alternative treatment strategies have also been used with various types of cancers. Such treatment can be used alone or in combination with any other treatment modality. These include exercise, massage, relaxation techniques, yoga, acupuncture, aromatherapy, hypnosis, music therapy, dietary changes, nutritional and dietary supplements, and the like; such treatments are known to those skilled in the art. Any such treatment strategies can be utilized, alone or in combination with one or more additional cancer therapy, in the practice of the present disclosure. Dosage and Administration Routes Other embodiments 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. In some embodiments, 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 7 mg/kg, about 7.5 mg/kg, about 8 mg/kg, about 10 mg/kg, about 12 mg/kg, or about 15 mg/kg. In regard to some conditions, the dosage can be about 0.5 mg/kg human body weight or about 6.5 mg/kg human body weight. In some instances, some subjects (e.g., mammals, mice, rabbits, feline, porcine, or canine) can be administered a dosage of about 0.005 to about 50 mg/kg body weight, about 0.01 to about 15 mg/kg body weight, about 0.1 to about 10 mg/kg body weight, about 0.5 to about 7 mg/kg body weight, about 0.005 mg/kg, about 0.01 mg/kg, about 0.05 mg/kg, about 0.1 mg/kg, about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 20 mg/kg, about 30 mg/kg, about 40 mg/kg, about 50 mg/kg, about 80 mg/kg, about 100 mg/kg, or about 150 mg/kg. Of course, those skilled in the art will appreciate that it is possible to employ many concentrations in the methods of the present disclosure, and using, in part, the guidance provided herein, will be able to adjust and test any number of concentrations in order to find one that achieves the desired result in a given circumstance. In some embodiments, a dose or a therapeutically effective dose of a compound disclosed herein will be that which is sufficient to achieve a plasma concentration of the compound or its active metabolite(s) within a range set forth herein, e.g., about 1-10 nM, 10-100 nM, 0.1-1 µM, 1-10 µM, 10-100 µM, 100-200 µM, 200-500 µM, or even 500-1000 µM, preferably about 1-10 nM, 10-100 nM, or 0.1-1 µM. Without wishing to be bound by any theory, it is believed that such compounds are indicated in the treatment or management of hematopoietic cancers, such as, for example, MDS and/or AML and/or DLBCL, etc., as described herein. In other embodiments, 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) 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. For treatment of a subject, depending on activity of the compound, manner of administration, nature and severity of the disease or disorder, age and body weight of the subject, different daily doses can be used. 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. Typically, dosages used in vitro can provide useful guidance in the amounts useful for in situ administration of the pharmaceutical composition, and animal models can be used to determine effective dosages for treatment of particular disorders. Various considerations are described, e.g., in Langer, 1990, Science, 249: 1527; Goodman and Gilman's (eds.), 1990, Id., each of which is herein incorporated by reference and for all purposes. Dosages for parenteral administration of active pharmaceutical agents can be converted into corresponding dosages for oral administration by multiplying parenteral dosages by appropriate conversion factors. As to general applications, the parenteral dosage in mg/mL times 1.8 = the corresponding oral dosage in milligrams (“mg”). As to oncology applications, the parenteral dosage in mg/mL times 1.6 = the corresponding oral dosage in mg. An average adult weighs about 70 kg. See e.g., Miller-Keane, 1992, Encyclopedia & Dictionary of Medicine, Nursing & Allied Health, 5th Ed., (W. B. Saunders Co.), pp.1708 and 1651. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy. In some embodiments, the compounds and/or pharmaceutical compositions can include a unit dose of one or more compounds of the disclosure (e.g., compounds of Formula (I), 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. In certain embodiments, the carrier, vehicle or excipient can facilitate administration, delivery and/or improve preservation of the composition. In other embodiments, the one or more carriers, include but are not limited to, saline solutions such as normal saline, Ringer's solution, PBS (phosphate-buffered saline), and generally mixtures of various salts including potassium and phosphate salts with or without sugar additives such as glucose. Carriers can include aqueous and non-aqueous sterile injection solutions that can contain antioxidants, buffers, bacteriostats, bactericidal antibiotics, and solutes that render the formulation isotonic with the bodily fluids of the intended recipient; and aqueous and non- aqueous sterile suspensions, which can include suspending agents and thickening agents. In other embodiments, the one or more excipients can include, but are not limited to water, saline, dextrose, glycerol, ethanol, or the like, and combinations thereof. Nontoxic auxiliary substances, such as wetting agents, buffers, or emulsifiers may also be added to the composition. Oral formulations can include such normally employed excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, and magnesium carbonate. The quantity of active component in a unit dose preparation can be varied or adjusted from 0.1 mg to 10000 mg, more typically 1.0 mg to 1000 mg, most typically 10 mg to 500 mg, according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents. The compounds of the disclosure (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)) can be administered to subjects by any number of suitable administration routes or formulations. 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. As used herein, the term “subject”, unless stated otherwise, encompasses both human and non-human subjects. 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)) can be of any suitable route. Administration routes can be, but are not limited to the oral route, the parenteral route, the cutaneous route, the nasal route, the rectal route, the vaginal route, and the ocular route. In other embodiments, administration routes can be parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration. The choice of administration route can depend on the compound identity (e.g., the physical and chemical properties of the compound) as well as the age and weight of the animal, the particular disease (e.g., cancer or MDS), and the severity of the disease (e.g., stage or severity of cancer or MDS). Of course, combinations of administration routes can be administered, as desired. Some embodiments of the disclosure include a method for providing a subject with a composition comprising one or more compounds of the disclosure (e.g., Formula (I), 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. 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. Fingl et al., In: THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, Ch.1, p.l, 1975. The exact formulation, route of administration, and dosage can be chosen by the individual practitioner in view of the patient’s condition and the particular method in which the compound is used. For in vitro formulations, the exact formulation and dosage can be chosen by the individual practitioner in view of the patient’s condition and the particular method in which the compound is used. Clauses of the Disclosure The following clauses describe certain embodiments of the disclosure. Clause 1. A compound of Formula (I) or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof, wherein: A is selected from N and CR 3 , E is selected from N and CR 4 , and G is selected from N and CR 5 , wherein one of A, E, or G is N; 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 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, oxo, methanoyl (-COH), carboxy (- 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(CH 3 ) 2 , C 1 -C 7 alkyl, C 1 -C 7 perfluorinated alkyl, C 1 -C 7 alkoxy, C 1 -C 7 haloalkoxy, or C 1 -C 7 alkyl which is substituted with cycloalkyl; R 2 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, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, spiro-fused 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 fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, oxo, 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(CH 3 ) 2 , C 1 -C 7 alkyl, C 1 -C 7 perfluorinated alkyl, C 1 -C 7 alkoxy, C 1 -C 7 haloalkoxy, or C 1 -C 7 alkyl which is substituted with cycloalkyl; R 3 , R 4 , and R 5 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 fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, oxo, 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(CH 3 ) 2 , C 1 -C 7 alkyl, C 1 -C 7 perfluorinated alkyl, C 1 -C 7 alkoxy, C 1 -C 7 haloalkoxy, or C 1 -C 7 alkyl which is substituted with cycloalkyl; R 6 is 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 fused ring heteroaryl 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 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 fused ring heteroaryl is optionally substituted with one or more halogen; R 31a and R 31b are each independently selected from H, C 1 -C 6 alkyl, -(CH 2 ) a -(C 3 -C 6 cycloalkyl), – (CH 2 ) b -C 2 -C 6 heterocyclyl, –(CH 2 ) c -C 3 -C 9 heteroaryl, -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), wherein the C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 heterocyclyl, and C 3 -C 9 heteroaryl are each independently optionally substituted with one or more of halogen, hydroxy, oxo, 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(CH 3 ) 2 , C 1 -C 7 alkyl, C 1 -C 7 perfluorinated alkyl, C 1 -C 7 alkoxy, C 1 -C 7 haloalkoxy, or C 1 -C 7 alkyl which is substituted with cycloalkyl; a, b, and c are each independently selected from 0, 1, 2, 3, 4, 5, or 6; and m, n, o, p, q, r, s, t, u, v, w, and x are each independently selected from 0, 1, 2, 3, 4, or 5, where q+r+s+t is at least 1, and where u+v+w+x is at least 1. 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 -C 6 alkyl and halogen; R 21a is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 6 -C 12 spiro-fused cycloalkyl, -O-(C 3 -C 6 cycloalkyl), C 3 -C 9 heterocyclyl, and C 5 -C 10 spiro-fused heterocyclyl, 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, -O-(C 3 -C 6 cycloalkyl), and C 3 -C 9 heterocyclyl are each optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, halogen, =O, and -OH; R 22a , R 23a , and R 24a are each independently selected from H and halogen; R 25a , R 25a’ , R 26a , R 26a’ , R 27a , and R 27a’ are each independently selected from H, halogen, - OH, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy, wherein C 1 -C 6 alkyl and C 1 -C 6 alkoxy are each optionally substituted with one or more halogen atoms; and one of A, E, or G is N. 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 7. The compound of any one of clauses 2-5, wherein 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 and substituted with one or more -CH 3 , F, and/or =O; C 7 -C 9 spiro-fused cycloalkyl; and C 5 -C 8 spiro- fused heterocyclyl comprising one oxygen, one nitrogen, or one oxygen and one nitrogen. 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. The compound of any one of clauses 2-8, wherein A is N, E is CR 23a , and 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 12. The compound of any one of clauses 2-8, wherein A is CR 22a , E is N, and G is CR 24a . Clause 13. The compound of clause 12, wherein R 22a and R 24a are each H. Clause 14. The compound of clause 12, 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. Clause 15. The compound of any one of clauses 2-8, wherein A is CR 22a , E is CR 23a , and G is N. Clause 16. The compound of clause 15, wherein R 22a and R 23a are each H. Clause 17. The compound of clause 15, wherein R 22a is F and R 23a is H; or R 22a is H and R 23a is F. Clause 18. The compound of any one of clauses 2-17, wherein R 25a , R 25a’ , R 26a , R 26a’ , R 27a , and R 27a’ are each H. Clause 19. The compound of any one of clauses 2-18, wherein each of R 25a , R 26a , R 26a’ , R 27a , and R 27a’ is H and R 25a’ is F. Clause 20. The compound of any one of clauses 4, 5, 7, 8, 12, 13, 15-17, or 19 wherein the compound is selected from: Clause 21. The compound of clause 1, wherein 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: 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 -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 21b is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 6 -C 12 spiro-fused cycloalkyl, -O-(C 3 -C 6 cycloalkyl), C 3 -C 9 heterocyclyl, and C 5 -C 10 spiro-fused heterocyclyl, 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, -O-(C 3 -C 6 cycloalkyl), and C 3 -C 9 heterocyclyl are each optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, halogen, =O, and -OH; 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; and one of A, E, or G is N. 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 26. The compound of any one of clauses 21-24, wherein 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 and substituted with one or more -CH 3 , F, and/or =O; C 7 -C 9 spiro-fused cycloalkyl; and C 5 -C 8 spiro- fused heterocyclyl comprising one oxygen, one nitrogen, or one oxygen and one nitrogen. 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. The compound of any one of clauses 21-27, wherein A is N, E is CR 23b , and G is CR 24b . Clause 29. The compound of clause 28, wherein R 23b and R 24b are each H. 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. The compound of any one of clauses 21-27, wherein A is CR 22b , E is N, and G is CR 24b . Clause 32. The compound of clause 31, wherein R 22b and R 24b are each H. Clause 33. The compound of clause 31, 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. Clause 34. The compound of any one of clauses 21-27, wherein A is CR 22b , E is CR 23b , and G is N. Clause 35. The compound of clause 34, wherein R 22b and R 23b are each H. Clause 36. The compound of clause 34, wherein R 22b is F and R 23b is H; or R 22b is H and R 23b is F. Clause 37. The compound of any one of clauses 21-36, wherein Clause 38. The compound of clause 37, wherein R 25b , R 25b’ , R 27b , R 27b’ , R 28b , R 28b ,, R 29b , and R 29b’ are each H. Clause 39. The compound of clause 37, wherein 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 40. The compound of any one of clauses 23, 24, 26, 27, 31, 32, or 34-39, wherein the compound is selected from:
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. Clause 48. The 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 steroid or glucocorticoid, a steroid or glucocorticoid receptor modulator, an EZH2 inhibitor, a hedgehog (Hh) inhibitor, a Topoisomerase I inhibitor, a Topoisomerase II inhibitor, an aminopeptidase/Leukotriene A4 hydrolase inhibitor, a FLT3/Axl/ALK inhibitor, a FLT3/KIT/PDGFR, PKC, and/or KDR inhibitor, a Syk inhibitor, an E-selectin inhibitor, an NEDD8-activator, an MDM2 inhibitor, a PLK1 inhibitor, an Aura A inhibitor, an aurora kinase inhibitor, an EGFR inhibitor, an AuroraB/C/VEGFR1/2/3/FLT3/CSF- 1R/Kit/PDGFRA/B inhibitor, an AKT 1, 2, and/or 3 inhibitor, a ABL1/2/SRC/EPHA2/LCK/YES1/KIT/PDGFRB/FYN inhibitor, a farnesyltransferase inhibitor, a BRAF/MAP2K1/MAP2K2 inhibitor, a Menin-KMT2A/MLL inhibitor, and a multikinase inhibitor. 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. Clause 50. The composition of clause 49, wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof. Clause 51. The composition of clause 49, wherein the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof. Clause 52. The composition of clause 49, wherein the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone or a pharmaceutically acceptable salt of any one thereof. Clause 53. The composition of clause 49, wherein the CDK inhibitor is a CDK4 inhibitor, a CDK6 inhibitor, a CDK7 inhibitor, and/or a CDK9 inhibitor. Clause 54. The composition of clause 53, 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 55. The composition of clause 49, wherein the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof. Clause 56. A method of treating a disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of clauses 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. Clause 59. The method of 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 method of any one of clauses 56-60, wherein the disease or disorder comprises myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML). 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. Clause 64. The method of any one of clauses 56-60, wherein the disease or disorder comprises at least one cancer selected from glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, Glioma, oral cancer, nasopharyngeal carcinoma, rectal cancer, stomach cancer, and uterine cancer, or one or more inflammatory diseases or autoimmune disease characterized by overactive IRAK1 and/or IRAK4, or combinations thereof. 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. Clause 66. The method of any one of clauses 56-60, wherein the disease or disorder comprises: (i) MDS, MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, MDS with a mutation in isocitrate dehydrogenase 2; or (ii) AML with a splicing factor mutation, AML having enhanced IRAK4-Long expression and/or activity relative to IRAK4-Short, and/or wherein the AML is not driven by FLT3 mutations but expresses IRAK4-Long. Clause 67. The method of clause 66, wherein the MDS with a splicing factor mutation comprises MDS with a splicing factor mutation in U2AF1 or SF3B1 and the AML splicing factor mutation comprises AML with a splicing factor mutation in U2AF1 or SF3B1. Clause 68. The method of any one of clauses 56-60, wherein the disease or disorder comprises DLBCL, and wherein the DLBCL comprises a L265P MYD88 mutant (ABC) subtype of DLBCL or a S219C MYD88 mutant (GCB) subtype of DLBCL. Clause 69. The method of 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 mTOR inhibitor, a steroid or glucocorticoid, a steroid or glucocorticoid receptor modulator, an EZH2 inhibitor, a hedgehog (Hh) inhibitor, a Topoisomerase I inhibitor, a Topoisomerase II inhibitor, an aminopeptidase/Leukotriene A4 hydrolase inhibitor, a FLT3/Axl/ALK inhibitor, a FLT3/KIT/PDGFR, PKC, and/or KDR inhibitor, a Syk inhibitor, an E-selectin inhibitor, an NEDD8-activator, an MDM2 inhibitor, a PLK1 inhibitor, an Aura A inhibitor, an aurora kinase inhibitor, an EGFR inhibitor, an AuroraB/C/VEGFR1/2/3/FLT3/CSF-1R/Kit/PDGFRA/B inhibitor, an AKT 1, 2, and/or 3 inhibitor, a ABL1/2/SRC/EPHA2/LCK/YES1/KIT/PDGFRB/FYN inhibitor, a farnesyltransferase inhibitor, a BRAF/MAP2K1/MAP2K2 inhibitor, a Menin-KMT2A/MLL inhibitor, and a multikinase inhibitor. 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 73. The method of any one of clauses 56-72, wherein the disease or disorder is a BCL2 inhibitor resistant disease or disorder. Clause 74. The method of any one of clauses 56-72, wherein the disease or disorder is a venetoclax resistant disease or disorder. Clause 75. The method of any one of clauses 56-72, wherein the disease or disorder is BCL2 inhibitor resistant acute myeloid leukemia (AML). Clause 76. The method of any one of clauses 56-72, wherein the disease or disorder is venetoclax resistant acute myeloid leukemia (AML). Clause 77. The method of any one of clauses 56-72, wherein the disease or disorder is BCL2 inhibitor resistant refractory acute myeloid leukemia (AML). 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. Clause 82. The method of any one of clauses 56-71, wherein the disease or disorder is a BTK inhibitor resistant disease or disorder. Clause 83. The method of any one of clauses 56-71, wherein the disease or disorder is an ibrutinib resistant disease or disorder. Clause 84. The method of clause 71, wherein the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone, or a pharmaceutically acceptable salt of any one thereof. Clause 85. The method of any one of clauses 56-71, wherein the disease or disorder is sensitive to anti-inflammatory glucocorticoids. Clause 86. The method of any one of clauses 56-71, wherein the disease or disorder is a dexamethasone, methylprednisolone, or prednisolone resistant disease or disorder. Clause 87. The method of clause 71, 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 88. The method of any one of clauses 56-71, wherein the disease or disorder is a CDK inhibitor resistant disease or disorder. Clause 89. The method of any one of clauses 56-71, wherein the disease or disorder is a palbociclib, THZ1, BAY 12511152, or atuveciclib resistant disease or disorder. Clause 90. The method of clause 71, wherein the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof. Clause 91. The method of any one of clauses 56-71, wherein the disease or disorder is a DNA methyltransferase inhibitor resistant disease or disorder. Clause 92. The method of any one of clauses 56-71, wherein the disease or disorder is an azacitidine resistant disease or disorder. Clause 93. The method of any one of clauses 56-71, wherein the disease or disorder is a BCL2 inhibitor and DNA methyltransferase inhibitor resistant disease or disorder. Clause 94. The method of any one of clauses 56-71, wherein the disease or disorder is a venetoclax and azacitidine resistant disease or disorder. Clause 95. The method of clause 71, wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof and the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof. Clause 96. The method of any one of clauses 56-71, wherein the disease or disorder is a FLT3 inhibitor resistant disease or disorder. Clause 97. The method of any one of clauses 56-71, wherein the disease or disorder is FLT3 inhibitor resistant acute myeloid leukemia (AML). Clause 98. The method of any one of clauses 56-71, wherein the disease or disorder is FLT3 inhibitor resistant refractory acute myeloid leukemia (AML). Clause 99. The method of any one of clauses 56-71, wherein the disease or disorder is FLT3 inhibitor resistant relapsed acute myeloid leukemia (AML). Clause 100. The method of clause 69, wherein the compound of any one of clauses 1-46 or the composition of any one of clauses 47-55 and the one or more additional therapies are administered together in one administration or composition. Clause 101. The method of clause 69, wherein the compound of any one of clauses 1-46 or the composition of any one of clauses 47-55 and the one or more additional therapies are administered separately in more than one administration or more than one composition. Clause 102. The method of any one of clauses 56-101, wherein the disease or disorder is alleviated by inhibiting at least one of IRAK1, IRAK4, and FLT3 in the subject. Clause 103. The method of any one of clauses 56-102, wherein the disease or disorder is alleviated by inhibiting at least two of IRAK1, IRAK4, and FLT3 in the subject. Clause 104. The method of any one of clauses 56-103, wherein the disease or disorder is alleviated by inhibiting IRAK1 and IRAK4 in the subject. Clause 105. The method of any one of clauses 56-103, wherein the disease or disorder is alleviated by inhibiting IRAK1, IRAK4, and FLT3 in the subject. Clause 106. The method of any one of clauses 102, 103, or 105, wherein FLT3 is selected from WT FLT3, activated FLT3, and mutated FLT3. Clause 107. The method of clause 106, wherein the mutated FLT3 is D835Y mutated FLT3 or F691L mutated FLT3. Clause 108. The method of any one of clauses 56-107, wherein the compound is a compound of any one of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. Clause 201. 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 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, oxo, methanoyl (-COH), carboxy (- 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(CH 3 ) 2 , C 1 -C 7 alkyl, C 1 -C 7 perfluorinated alkyl, C 1 -C 7 alkoxy, C 1 -C 7 haloalkoxy, or C 1 -C 7 alkyl which is substituted with cycloalkyl; R 2 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, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, spiro-fused 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 fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, oxo, 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(CH 3 ) 2 , C 1 -C 7 alkyl, C 1 -C 7 perfluorinated alkyl, C 1 -C 7 alkoxy, C 1 -C 7 haloalkoxy, or C 1 -C 7 alkyl which is substituted with cycloalkyl; R 3 , R 4 , and R 5 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 fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, oxo, 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(CH 3 ) 2 , C 1 -C 7 alkyl, C 1 -C 7 perfluorinated alkyl, C 1 -C 7 alkoxy, C 1 -C 7 haloalkoxy, or C 1 -C 7 alkyl which is substituted with cycloalkyl; R 6 is 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 fused ring heteroaryl 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 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 fused ring heteroaryl is optionally substituted with one or more halogen; R 31a and R 31b are each independently selected from H, C 1 -C 6 alkyl, -(CH 2 ) a -(C 3 -C 6 cycloalkyl), –(CH 2 ) b -C 2 -C 6 heterocyclyl, –(CH 2 ) c -C 3 -C 9 heteroaryl, -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), wherein the C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 heterocyclyl, and C 3 -C 9 heteroaryl are each independently optionally substituted with one or more of halogen, hydroxy, oxo, 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(CH 3 ) 2 , C 1 -C 7 alkyl, C 1 -C 7 perfluorinated alkyl, C 1 -C 7 alkoxy, C 1 -C 7 haloalkoxy, or C 1 -C 7 alkyl which is substituted with cycloalkyl; a, b, and c are each independently selected from 0, 1, 2, 3, 4, 5, or 6; and m, n, o, p, q, r, s, t, u, v, w, and x are each independently selected from 0, 1, 2, 3, 4, or 5, where q+r+s+t is at least 1, and where u+v+w+x is at least 1. 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 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 6 -C 12 spiro-fused cycloalkyl, -O-(C 3 -C 6 cycloalkyl), C 3 -C 9 heterocyclyl, and C 5 -C 10 spiro-fused heterocyclyl, 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, -O-(C 3 -C 6 cycloalkyl), and C 3 -C 9 heterocyclyl are each optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, halogen, =O, and -OH; R 22a , R 23a , and R 24a are each independently selected from H and halogen; and R 25a , R 25a’ , R 26a , R 26a’ , R 27a , and R 27a’ 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 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 . Clause 206. The compound of any one of clauses 202-205, wherein R 21a is H. Clause 207. The compound of any one of clauses 202-205, wherein 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 and substituted with one or more -CH 3 , F, and/or =O; C 7 -C 9 spiro-fused cycloalkyl; and C 5 -C 8 spiro- fused heterocyclyl comprising one oxygen, one nitrogen, or one oxygen and one nitrogen. 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. The compound of any one of clauses 202-208, wherein R 22a , R 23a , and R 24a are each H. Clause 210. The compound of any one of clauses 202-208, wherein R 22a is F, R 23a is H, and R 24a is H; R 22a is H, R 23a is H, and R 24a is F; or R 22a is F, R 23a is H, and R 24a is F. Clause 211. The compound of any one of clauses 202-210, wherein R 25a , R 25a’ , R 26a , R 26a’ , R 27a , and R 27a’ are each H. Clause 212. The compound of any one of clauses 202-210, wherein each of R 25a , R 26a , R 26a’ , R 27a , and R 27a’ is H and R 25a’ is F. Clause 213. The compound of any one of clauses 204-212, wherein the compound is selected from: . Clause 214. The compound of clause 201, wherein 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 alkyl and halogen;
R 21b is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 6 -C 12 spiro-fused cycloalkyl, -O-(C 3 -C 6 cycloalkyl), C3-C9 heterocyclyl, and C5-C10 spiro-fused heterocyclyl, 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, -O-(C 3 -C 6 cycloalkyl), and C 3 -C 9 heterocyclyl are each optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, halogen, =O, and -OH;
R 22b , R 23b , and R 24b are each independently selected from H and halogen; and
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 215. The compound of clause 214, wherein R 20b is H.
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 217. The compound of clause 216, wherein R 20b is selected from Cl, -OCH 3 , unsubstituted C 3 cycloalkyl, and
Clause 218. The compound of any one of clauses 214-217, wherein R 21b is H.
Clause 219. The compound of any one of clauses 214-218, wherein 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 and substituted with one or more -CH 3 , F, and/or =O; C 7 -C 9 spiro-fused cycloalkyl; and C 5 -C 8 spiro- fused heterocyclyl comprising one oxygen, one nitrogen, or one oxygen and one nitrogen. 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. The compound of any one of clauses 214-220, wherein R 22b , R 23b , and R 24a are each H. Clause 222. The compound of any one of clauses 214-220, wherein R 22b is F, R 23b is H, and R 24b is H; R 22b is H, R 23b is H, and R 24b is F; or R 22b is F, R 23b is H, and R 24b is F. Clause 223. The compound of any one of clauses 214-222, wherein is Clause 224. The compound of clause 223, wherein R 25b , R 25b’ , R 27b , R 27b’ , R 28b , R 28b ,, R 29b , and R 29b’ are each H. Clause 225. The compound of clause 223, wherein 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. The compound of any one of clauses 201-226, wherein the compound is an inhibitor of at least one of IRAK1, IRAK4, and FLT3. 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. Clause 229. The compound of any one of clauses 201-228, wherein the compound is an inhibitor of IRAK1 and IRAK4. Clause 230. The compound of any one of clauses 201-228, wherein the compound is an inhibitor of IRAK1, IRAK4, and FLT3. Clause 231. The compound of any one of clauses 227, 228, or 230, wherein FLT3 is selected from WT FLT3, activated FLT3, and mutated FLT3. Clause 232. The compound of clause 231, wherein the mutated FLT3 is D835Y mutated FLT3 or F691L mutated FLT3. Clause 233. 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 smoothened receptor antagonist, an ERK inhibitor including an ERK2/MAPK1 or ERK1/MAPK3 inhibitor, a PI3K inhibitor, an mTOR inhibitor, a steroid or glucocorticoid, a steroid or glucocorticoid receptor modulator, an EZH2 inhibitor, a hedgehog (Hh) inhibitor, a Topoisomerase I inhibitor, a Topoisomerase II inhibitor, an aminopeptidase/Leukotriene A4 hydrolase inhibitor, a FLT3/Axl/ALK inhibitor, a FLT3/KIT/PDGFR, PKC, and/or KDR inhibitor, a Syk inhibitor, an E-selectin inhibitor, an NEDD8-activator, an MDM2 inhibitor, a PLK1 inhibitor, an Aura A inhibitor, an aurora kinase inhibitor, an EGFR inhibitor, an AuroraB/C/VEGFR1/2/3/FLT3/CSF- 1R/Kit/PDGFRA/B inhibitor, an AKT 1, 2, and/or 3 inhibitor, a ABL1/2/SRC/EPHA2/LCK/YES1/KIT/PDGFRB/FYN inhibitor, a farnesyltransferase inhibitor, a BRAF/MAP2K1/MAP2K2 inhibitor, a Menin-KMT2A/MLL inhibitor, and a multikinase inhibitor. 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. Clause 238. The composition of clause 235, wherein the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone or a pharmaceutically acceptable salt of any one thereof. Clause 239. The composition of clause 235, wherein the CDK inhibitor is a CDK4 inhibitor, a CDK6 inhibitor, a CDK7 inhibitor, and/or a CDK9 inhibitor. Clause 240. 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. The composition of clause 235, wherein the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof. Clause 242. A method of treating a disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of clauses 201-232 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 244. The method of 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. 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). Clause 249. The method of any one of clauses 242-246, 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. Clause 250. The method of any one of clauses 242-246, wherein the disease or disorder comprises at least one cancer selected from glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, Glioma, oral cancer, nasopharyngeal carcinoma, rectal cancer, stomach cancer, and uterine cancer, or one or more inflammatory diseases or autoimmune disease characterized by overactive IRAK1 and/or IRAK4, or combinations thereof. 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. Clause 252. The method of any one of clauses 242-246, wherein the disease or disorder comprises: (i) MDS, MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, MDS with a mutation in isocitrate dehydrogenase 2; or (ii) AML with a splicing factor mutation, AML having enhanced IRAK4-Long expression and/or activity relative to IRAK4-Short, and/or wherein the AML is not driven by FLT3 mutations but expresses IRAK4-Long. Clause 253. The method of clause 252, wherein the MDS with a splicing factor mutation comprises MDS with a splicing factor mutation in U2AF1 or SF3B1 and the AML splicing factor mutation comprises AML with a splicing factor mutation in U2AF1 or SF3B1. Clause 254. The method of any one of clauses 242-246, wherein the disease or disorder comprises DLBCL, and wherein the DLBCL comprises a L265P MYD88 mutant (ABC) subtype of DLBCL or a S219C MYD88 mutant (GCB) subtype of DLBCL. Clause 255. The method of 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 mTOR inhibitor, a steroid or glucocorticoid, a steroid or glucocorticoid receptor modulator, an EZH2 inhibitor, a hedgehog (Hh) inhibitor, a Topoisomerase I inhibitor, a Topoisomerase II inhibitor, an aminopeptidase/Leukotriene A4 hydrolase inhibitor, a FLT3/Axl/ALK inhibitor, a FLT3/KIT/PDGFR, PKC, and/or KDR inhibitor, a Syk inhibitor, an E-selectin inhibitor, an NEDD8-activator, an MDM2 inhibitor, a PLK1 inhibitor, an Aura A inhibitor, an aurora kinase inhibitor, an EGFR inhibitor, an AuroraB/C/VEGFR1/2/3/FLT3/CSF-1R/Kit/PDGFRA/B inhibitor, an AKT 1, 2, and/or 3 inhibitor, a ABL1/2/SRC/EPHA2/LCK/YES1/KIT/PDGFRB/FYN inhibitor, a farnesyltransferase inhibitor, a BRAF/MAP2K1/MAP2K2 inhibitor, a Menin-KMT2A/MLL inhibitor, and a multikinase inhibitor. 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. The method of any one of clauses 242-258, wherein the disease or disorder is a BCL2 inhibitor resistant disease or disorder. Clause 260. The method of any one of clauses 242-258, wherein the disease or disorder is a venetoclax resistant disease or disorder. Clause 261. The method of any one of clauses 242-258, wherein the disease or disorder is BCL2 inhibitor resistant acute myeloid leukemia (AML). Clause 262. The method of any one of clauses 242-258, wherein the disease or disorder is venetoclax resistant acute myeloid leukemia (AML). Clause 263. The method of any one of clauses 242-258, wherein the disease or disorder is BCL2 inhibitor resistant refractory acute myeloid leukemia (AML). Clause 264. The method of any one of clauses 242-258, wherein the disease or disorder is venetoclax resistant refractory acute myeloid leukemia (AML). Clause 265. The method of any one of clauses 242-258, wherein the disease or disorder is BCL2 inhibitor resistant relapsed acute myeloid leukemia (AML). Clause 266. The method of any one of clauses 242-258, wherein the disease or disorder is venetoclax resistant relapsed acute myeloid leukemia (AML). Clause 267. The method of clause 257, wherein the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof. Clause 268. The method of any one of clauses 242-258, wherein the disease or disorder is a BTK inhibitor resistant disease or disorder. Clause 269. The method of any one of clauses 242-258, wherein the disease or disorder is an ibrutinib resistant disease or disorder. Clause 270. The method of clause 257, wherein the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone, or a pharmaceutically acceptable salt of any one thereof. Clause 271. The method of any one of clauses 242-258, wherein the disease or disorder is sensitive to anti-inflammatory glucocorticoids. Clause 272. The method of any one of clauses 242-258, wherein the disease or disorder is a dexamethasone, methylprednisolone, or prednisolone resistant disease or disorder. Clause 273. The method of clause 257, 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 274. The method of any one of clauses 242-258, wherein the disease or disorder is a CDK inhibitor resistant disease or disorder. Clause 275. The method of any one of clauses 242-258, wherein the disease or disorder is a palbociclib, THZ1, BAY 12511152, or atuveciclib resistant disease or disorder. Clause 276. The method of clause 257, wherein the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof. Clause 277. The method of any one of clauses 242-258, wherein the disease or disorder is a DNA methyltransferase inhibitor resistant disease or disorder. Clause 278. The method of any one of clauses 242-258, wherein the disease or disorder is an azacitidine resistant disease or disorder. Clause 279. The method of any one of clauses 242-258, wherein the disease or disorder is a BCL2 inhibitor and DNA methyltransferase inhibitor resistant disease or disorder. Clause 280. The method of any one of clauses 242-258, wherein the disease or disorder is a venetoclax and azacitidine resistant disease or disorder. Clause 281. The method of clause 257, wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof and the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof. Clause 282. The method of any one of clauses 242-258, wherein the disease or disorder is a FLT3 inhibitor resistant disease or disorder. Clause 283. The method of any one of clauses 242-258, wherein the disease or disorder is FLT3 inhibitor resistant acute myeloid leukemia (AML). Clause 284. The method of any one of clauses 242-258, wherein the disease or disorder is FLT3 inhibitor resistant refractory acute myeloid leukemia (AML). Clause 285. The method of any one of clauses 242-258, wherein the disease or disorder is FLT3 inhibitor resistant relapsed acute myeloid leukemia (AML). Clause 286. The method of clause 255, wherein the compound of any one of clauses 201-232 or the composition of any one of clauses 233-241 and the one or more additional therapies are administered together in one administration or composition. Clause 287. The method of clause 255, wherein the compound of any one of clauses 201-232 or the composition of any one of clauses 233-241 and the one or more additional therapies are administered separately in more than one administration or more than one composition. Clause 288. The method of any one of clauses 242-287, wherein the disease or disorder is alleviated by inhibiting at least one of IRAK1, IRAK4, and FLT3 in the subject. Clause 289. The method of any one of clauses 242-288, wherein the disease or disorder is alleviated by inhibiting at least two of IRAK1, IRAK4, and FLT3 in the subject. Clause 290. The method of any one of clauses 242-289, wherein the disease or disorder is alleviated by inhibiting IRAK1 and IRAK4 in the subject. Clause 291. The method of any one of clauses 242-289, wherein the disease or disorder is alleviated by inhibiting IRAK1, IRAK4, and FLT3 in the subject. Clause 292. The method of any one of clauses 288, 289, or 291, wherein FLT3 is selected from WT FLT3, activated FLT3, and mutated FLT3. Clause 293. The method of clause 292, wherein the mutated FLT3 is D835Y mutated FLT3 or F691L mutated FLT3. Clause 294. The method of any one of clauses 242-293, wherein the compound is a compound of any one of Formula (IIa), Formula (IIb), Formulas (IIIa)-(IIIp), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof. Clause 301. A compound of Formula (I) or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof, wherein: A is selected from N and CR 3 , E is selected from N and CR 4 , G is selected from N and CR 5 , wherein no more than one of A, E, and G is N; 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 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, oxo, methanoyl (-COH), carboxy (- 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(CH 3 ) 2 , C 1 -C 7 alkyl, C 1 -C 7 perfluorinated alkyl, C 1 -C 7 alkoxy, C 1 -C 7 haloalkoxy, or C 1 -C 7 alkyl which is substituted with cycloalkyl; R 2 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, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, spiro-fused 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 fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, oxo, 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(CH 3 ) 2 , C 1 -C 7 alkyl, C 1 -C 7 perfluorinated alkyl, C 1 -C 7 alkoxy, C 1 -C 7 haloalkoxy, or C 1 -C 7 alkyl which is substituted with cycloalkyl; R 3 , R 4 , and R 5 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 fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, oxo, 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(CH 3 ) 2 , C 1 -C 7 alkyl, C 1 -C 7 perfluorinated alkyl, C 1 -C 7 alkoxy, C 1 -C 7 haloalkoxy, or C 1 -C 7 alkyl which is substituted with cycloalkyl; R 6 is
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 fused ring heteroaryl 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 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 fused ring heteroaryl is optionally substituted with one or more halogen; R 31a and R 31b are each independently selected from H, C 1 -C 6 alkyl, -(CH 2 ) a -(C 3 -C 6 cycloalkyl), –(CH 2 ) b -C 2 -C 6 heterocyclyl, –(CH 2 ) c -C 3 -C 9 heteroaryl, -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), wherein the C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 heterocyclyl, and C 3 -C 9 heteroaryl are each independently optionally substituted with one or more of halogen, hydroxy, oxo, 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(CH 3 ) 2 , C 1 -C 7 alkyl, C 1 -C 7 perfluorinated alkyl, C 1 -C 7 alkoxy, C 1 -C 7 haloalkoxy, or C 1 -C 7 alkyl which is substituted with cycloalkyl; a, b, and c are each independently selected from 0, 1, 2, 3, 4, 5, or 6; and m, n, o, p, q, r, s, t, u, v, w, and x are each independently selected from 0, 1, 2, 3, 4, or 5, where q+r+s+t is at least 1, and where u+v+w+x is at least 1. 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 from C 1 -C 6 alkyl and halogen; R 21a is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 6 -C 12 spiro-fused cycloalkyl, -O-(C 3 -C 6 cycloalkyl), C 3 -C 9 heterocyclyl, and C 5 -C 10 spiro-fused heterocyclyl, 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, -O-(C 3 -C 6 cycloalkyl), and C 3 -C 9 heterocyclyl are each optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, halogen, =O, and -OH; R 22a , R 23a , and R 24a are each independently selected from H and halogen; R 25a , R 25a’ , R 26a , R 26a’ , R 27a , and R 27a’ are each independently selected from H, halogen, - OH, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy, wherein C 1 -C 6 alkyl and C 1 -C 6 alkoxy are each optionally substituted with one or more halogen atoms; and one of A, E, or G is N. 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 306. The compound of any one of clauses 302-305, wherein R 21a is H. Clause 307. The compound of any one of clauses 302-305, wherein 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 and substituted with one or more -CH 3 , F, and/or =O; C 7 -C 9 spiro-fused cycloalkyl; and C 5 -C 8 spiro- fused heterocyclyl comprising one oxygen, one nitrogen, or one oxygen and one nitrogen. 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 any one of clauses 302-308, wherein A is N, E is CR 23a , and G is CR 24a . Clause 310. The compound of clause 309, wherein R 23a and R 24a are each H. Clause 311. The compound of clause 309, wherein R 23a is H and R 24a is F; or R 23a is F and R 24a is H. Clause 312. The compound of any one of clauses 302-308, wherein A is CR 22a , E is N, and G is CR 24a . Clause 313. The compound of clause 312, wherein R 22a and R 24a are each H. Clause 314. The compound of clause 312, 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. Clause 315. The compound of any one of clauses 302-308, wherein A is CR 22a , E is CR 23a , and G is N. Clause 316. The compound of clause 315, wherein R 22a and R 23a are each H. Clause 317. The compound of clause 315, wherein R 22a is F and R 23a is H; or R 22a is H and R 23a is F. Clause 318. The compound of any one of clauses 302-317, wherein R 25a , R 25a’ , R 26a , R 26a’ , R 27a , and R 27a’ are each H. Clause 319. The compound of any one of clauses 302-318, wherein each of R 25a , R 26a , R 26a’ , R 27a , and R 27a’ is H and R 25a’ is F. Clause 320. The compound of any one of clauses 304, 305, 307, 308, 312, 313, 315-317, or 319 wherein the compound is selected from:
or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof. Clause 321. The compound of clause 301, wherein 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; 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 -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 21b is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 6 -C 12 spiro-fused cycloalkyl, -O-(C 3 -C 6 cycloalkyl), C 3 -C 9 heterocyclyl, and C 5 -C 10 spiro-fused heterocyclyl, 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, -O-(C 3 -C 6 cycloalkyl), and C 3 -C 9 heterocyclyl are each optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, halogen, =O, and -OH; 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; and one of A, E, or G is N. 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 326. The compound of any one of clauses 321-324, wherein 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 and substituted with one or more -CH 3 , F, and/or =O; C 7 -C 9 spiro-fused cycloalkyl; and C 5 -C 8 spiro- fused heterocyclyl comprising one oxygen, one nitrogen, or one oxygen and one nitrogen. 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. The compound of any one of clauses 321-327, wherein A is N, E is CR 23b , and G is CR 24b . Clause 329. The compound of clause 328, wherein R 23b and R 24b are each H. Clause 330. The compound of clause 328, wherein R 23b is H and R 24b is F; or R 23b is F and R 24b is H. Clause 331. The compound of any one of clauses 321-327, wherein A is CR 22b , E is N, and G is CR 24b . Clause 332. The compound of clause 331, wherein R 22b and R 24b are each H. Clause 333. The compound of clause 331, 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. Clause 334. The compound of any one of clauses 321-327, wherein A is CR 22b , E is CR 23b , and G is N. Clause 335. The compound of clause 334, wherein R 22b and R 23b are each H. Clause 336. The compound of clause 334, wherein R 22b is F and R 23b is H; or R 22b is H and R 23b is F. Clause 337. The compound of any one of clauses 321-336, wherein . Clause 338. The compound of clause 337, wherein R 25b , R 25b’ , R 27b , R 27b’ , R 28b , R 28b ,, R 29b , and R 29b’ are each H. Clause 339. The compound of clause 337, wherein 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:
or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof. Clause 341. The compound of clause 301, 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 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 6 -C 12 spiro-fused cycloalkyl, -O-(C 3 -C 6 cycloalkyl), C 3 -C 9 heterocyclyl, and C 5 -C 10 spiro-fused heterocyclyl, 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, -O-(C 3 -C 6 cycloalkyl), and C 3 -C 9 heterocyclyl are each optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, halogen, =O, and -OH; R 22a , R 23a , and R 24a are each independently selected from H and halogen; and R 25a , R 25a’ , R 26a , R 26a’ , R 27a , and R 27a’ 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 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 346. The compound of any one of clauses 341-344, wherein 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 and substituted with one or more -CH 3 , F, and/or =O; C 7 -C 9 spiro-fused cycloalkyl; and C 5 -C 8 spiro- fused heterocyclyl comprising one oxygen, one nitrogen, or one oxygen and one nitrogen. 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. The compound of any one of clauses 341-347, wherein R 22a , R 23a , and R 24a are each H. Clause 349. The compound of any one of clauses 341-347, wherein R 22a is F, R 23a is H, and R 24a is H; R 22a is H, R 23a is H, and R 24a is F; or R 22a is F, R 23a is H, and R 24a is F. Clause 350. The compound of any one of clauses 341-349, wherein R 25a , R 25a’ , R 26a , R 26a’ , R 27a , and R 27a’ are each H. Clause 351. The compound of any one of clauses 341-349, wherein each of R 25a , R 26a , R 26a’ , R 27a , and R 27a’ is H and R 25a’ is F. Clause 352. The compound of any one of clauses 341-351, wherein the compound is selected from:
or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof. Clause 353. The compound of clause 301, wherein 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 alkyl and halogen; R 21b is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 6 -C 12 spiro-fused cycloalkyl, -O-(C 3 -C 6 cycloalkyl), C 3 -C 9 heterocyclyl, and C 5 -C 10 spiro-fused heterocyclyl, 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, -O-(C 3 -C 6 cycloalkyl), and C 3 -C 9 heterocyclyl are each optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, halogen, =O, and -OH; R 22b , R 23b , and R 24b are each independently selected from H, CN, and halogen; and 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 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 358. The compound of any one of clauses 353-356, wherein 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 and substituted with one or more -CH 3 , F, and/or =O; C 7 -C 9 spiro-fused cycloalkyl; and C 5 -C 8 spiro- fused heterocyclyl comprising one oxygen, one nitrogen, or one oxygen and one nitrogen. Clause 359. The compound of clause 358, 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 360. The compound of any one of clauses 353-359, wherein R 22b , R 23b , and R 24a are each H. Clause 361. The compound of any one of clauses 353-359, wherein R 22b is F or CN, R 23b is H, and R 24b is H; R 22b is H, R 23b is H, and R 24b is F or CN; or R 22b is F or CN, R 23b is H, and R 24b is F or CN. Clause 362. The compound of any one of clauses 353-360, wherein . Clause 363. The compound of clause 362, wherein R 25b , R 25b’ , R 27b , R 27b’ , R 28b , R 28b ,, R 29b , and R 29b’ are each H. Clause 364. The compound of clause 362, wherein 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 365. The compound of any one of clauses 353, 355, 356, or 358-364, wherein the compound is selected from:
or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof. 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. The 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 mTOR inhibitor, a steroid or glucocorticoid, a steroid or glucocorticoid receptor modulator, an EZH2 inhibitor, a hedgehog (Hh) inhibitor, a Topoisomerase I inhibitor, a Topoisomerase II inhibitor, an aminopeptidase/Leukotriene A4 hydrolase inhibitor, a FLT3/Axl/ALK inhibitor, a FLT3/KIT/PDGFR, PKC, and/or KDR inhibitor, a Syk inhibitor, an E-selectin inhibitor, an NEDD8-activator, an MDM2 inhibitor, a PLK1 inhibitor, an Aura A inhibitor, an aurora kinase inhibitor, an EGFR inhibitor, an AuroraB/C/VEGFR1/2/3/FLT3/CSF-1R/Kit/PDGFRA/B inhibitor, an AKT 1, 2, and/or 3 inhibitor, a ABL1/2/SRC/EPHA2/LCK/YES1/KIT/PDGFRB/FYN inhibitor, a farnesyltransferase inhibitor, a BRAF/MAP2K1/MAP2K2 inhibitor, a Menin-KMT2A/MLL inhibitor, and a multikinase inhibitor. 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. Clause 377. The composition of clause 374, wherein the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone or a pharmaceutically acceptable salt of any one thereof. Clause 378. The composition of clause 374, wherein 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 DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof. Clause 381. A method of treating a disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of clauses 301-371 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. Clause 383. The method of clause 381 or 382, 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. Clause 384. The method of any one of clauses 381-383, wherein the administration comprises parenteral administration, mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration. Clause 385. The method of any one of clauses 381-384, 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 386. The method of any one of clauses 381-385, wherein the disease or disorder comprises a hematopoietic cancer. Clause 387. The method of any one of clauses 381-385, wherein the disease or disorder comprises myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML). Clause 388. The method of any one of clauses 381-385, 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. Clause 389. The method of any one of clauses 381-385, wherein the disease or disorder comprises at least one cancer selected from glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, Glioma, oral cancer, nasopharyngeal carcinoma, rectal cancer, stomach cancer, and uterine cancer. Clause 390. The method of any one of clauses 381-385, 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, Crohn’s disease, colitis, or combinations thereof. Clause 391. The method of any one of clauses 381-385, wherein the disease or disorder comprises: (i) MDS, MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, MDS with a mutation in isocitrate dehydrogenase 2; or (ii) AML with a splicing factor mutation, AML having enhanced IRAK4-Long expression and/or activity relative to IRAK4-Short, and/or wherein the AML is not driven by FLT3 mutations but expresses IRAK4-Long. Clause 392. The method of clause 391, wherein the MDS with a splicing factor mutation comprises MDS with a splicing factor mutation in U2AF1 or SF3B1 and the AML splicing factor mutation comprises AML with a splicing factor mutation in U2AF1 or SF3B1. Clause 393. The method of any one of clauses 381-385, wherein the disease or disorder comprises diffuse large B-cell lymphoma (DLBCL), and wherein the DLBCL comprises a L265P MYD88 mutant (ABC) subtype of DLBCL or a S219C MYD88 mutant (GCB) subtype of DLBCL. Clause 394. The method of 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 mTOR inhibitor, a steroid or glucocorticoid, a steroid or glucocorticoid receptor modulator, an EZH2 inhibitor, a hedgehog (Hh) inhibitor, a Topoisomerase I inhibitor, a Topoisomerase II inhibitor, an aminopeptidase/Leukotriene A4 hydrolase inhibitor, a FLT3/Axl/ALK inhibitor, a FLT3/KIT/PDGFR, PKC, and/or KDR inhibitor, a Syk inhibitor, an E-selectin inhibitor, an NEDD8-activator, an MDM2 inhibitor, a PLK1 inhibitor, an Aura A inhibitor, an aurora kinase inhibitor, an EGFR inhibitor, an AuroraB/C/VEGFR1/2/3/FLT3/CSF-1R/Kit/PDGFRA/B inhibitor, an AKT 1, 2, and/or 3 inhibitor, a ABL1/2/SRC/EPHA2/LCK/YES1/KIT/PDGFRB/FYN inhibitor, a farnesyltransferase inhibitor, a BRAF/MAP2K1/MAP2K2 inhibitor, a Menin-KMT2A/MLL inhibitor, and a multikinase inhibitor. 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 398. The method of any one of clauses 381-396, wherein the disease or disorder is a BCL2 inhibitor resistant disease or disorder. Clause 399. The method of any one of clauses 381-396, wherein the disease or disorder is a venetoclax resistant disease or disorder. Clause 400. The method of any one of clauses 381-396, wherein the disease or disorder is BCL2 inhibitor resistant acute myeloid leukemia (AML). Clause 401. The method of any one of clauses 381-396, wherein the disease or disorder is venetoclax resistant acute myeloid leukemia (AML). Clause 402. The method of any one of clauses 381-396, wherein the disease or disorder is BCL2 inhibitor resistant refractory acute myeloid leukemia (AML). Clause 403. The method of any one of clauses 381-396, wherein the disease or disorder is venetoclax resistant refractory acute myeloid leukemia (AML). Clause 404. The method of any one of clauses 381-396, wherein the disease or disorder is BCL2 inhibitor resistant relapsed acute myeloid leukemia (AML). Clause 405. The method of any one of clauses 381-396, wherein the disease or disorder is venetoclax resistant relapsed acute myeloid leukemia (AML). Clause 406. The method of clause 396, wherein the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof. Clause 407. The method of any one of clauses 381-396, wherein the disease or disorder is a BTK inhibitor resistant disease or disorder. Clause 408. The method of any one of clauses 381-396, wherein the disease or disorder is an ibrutinib resistant disease or disorder. Clause 409. The method of clause 396, wherein the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone, or a pharmaceutically acceptable salt of any one thereof. Clause 410. The method of any one of clauses 381-396, wherein the disease or disorder is sensitive to anti-inflammatory glucocorticoids. Clause 411. The method of any one of clauses 381-396, wherein the disease or disorder is a dexamethasone, methylprednisolone, or prednisolone resistant disease or disorder. Clause 412. The method of clause 396, 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 413. The method of any one of clauses 381-396, wherein the disease or disorder is a CDK inhibitor resistant disease or disorder. Clause 414. The method of any one of clauses 381-396, wherein the disease or disorder is a palbociclib, THZ1, BAY 12511152, or atuveciclib resistant disease or disorder. Clause 415. The method of clause 396, wherein the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof. Clause 416. The method of any one of clauses 381-396, wherein the disease or disorder is a DNA methyltransferase inhibitor resistant disease or disorder. Clause 417. The method of any one of clauses 381-396, wherein the disease or disorder is an azacitidine resistant disease or disorder. Clause 418. The method of any one of clauses 381-396, wherein the disease or disorder is a BCL2 inhibitor and DNA methyltransferase inhibitor resistant disease or disorder. Clause 419. The method of any one of clauses 381-396, wherein the disease or disorder is a venetoclax and azacitidine resistant disease or disorder. Clause 420. The method of clause 396, wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof and the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof. Clause 421. The method of any one of clauses 381-396, wherein the disease or disorder is a FLT3 inhibitor resistant disease or disorder. Clause 422. The method of any one of clauses 381-396, wherein the disease or disorder is FLT3 inhibitor resistant acute myeloid leukemia (AML). Clause 423. The method of any one of clauses 381-396, wherein the disease or disorder is FLT3 inhibitor resistant refractory acute myeloid leukemia (AML). Clause 424. The method of any one of clauses 381-396, wherein the disease or disorder is FLT3 inhibitor resistant relapsed acute myeloid leukemia (AML). Clause 425. The method of clause 394, wherein the compound of any one of clauses 301-371 or the composition of clause 372 and the one or more additional therapies are administered together in one administration or composition. Clause 426. The method of clause 394, wherein the compound of any one of clauses 301-371 or the composition of clause 372 and the one or more additional therapies are administered separately in more than one administration or more than one composition. 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. The method of any one of clauses 381-432, wherein 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. Having described the disclosure in detail, it will be apparent that modifications, variations, and equivalent embodiments are possible without departing from the scope of the disclosure defined in the appended claims. Furthermore, it should be appreciated that all examples in the present disclosure are provided as non-limiting examples. EXAMPLES The following non-limiting examples are provided to further illustrate embodiments of the disclosure disclosed herein. It should be appreciated by those of skill in the art that the techniques disclosed in the examples that follow represent approaches that have been found to function well in the practice of the disclosure, and thus can be considered to constitute examples of modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments that are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure. List of abbreviations. In the accompanying procedures and schemes, abbreviations are used with the following meanings unless otherwise indicated: Ac = acetate; aq, aq. = aqueous; Ar = aryl; BOC, Boc = t-butyloxycarbonyl; Bn = benzyl; BSA = bovine serum albumin; Bu = butyl, t- Bu = tert-butyl; BuLi, n-BuLi = n-butyllithium; CBZ, Cbz = Benzyloxycarbonyl; conc, conc. = concentrated; c-Bu = cyclobutyl; c-Pr = cyclopropyl; Cy = cyclohexyl; DAST = (diethylamino)sulfur trifluoride; dba = dibenzylideneacetone; DCM = dichloromethane; DIAD = diisopropylazodicarboxylate; DIBAL, DIBAL-H = diisobutylaluminum hydride; DIEA = diisopropylethylamine; DMAC, DMA = dimethylacetamide; DME = 1,2-dimethoxyethane; DMEM = Dulbecco’s modified eagle medium; DMAP = 4-dimethylaminopyridine; DMF = N,N- dimethylformamide; DMSO = dimethylsulfoxide; eq. = equivalent(s); EDC = N-[3- (dimethylamino)propyl]-N-ethylcarbodiimide; EDTA = ethylenediaminetetraacetic acid; ESI = electrospray ionization; Et = ethyl; EtOAc = ethyl acetate; EtOH = ethanol; FBS = Fetal Bovine Serum; h, hr = hour; HATU = N-[(dimethylamino)-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 fluorescence; IPA, i-PrOH = isopropanol; iPr = isopropyl; LAH = lithium aluminum hydride; LCMS = liquid chromatography - mass spectroscopy; LHMDS = lithium bis(trimethylsilyl)amide; Me = methyl; MeOH = methanol; min, min. = minute; μW = microwave; NaHMDS = sodium bis(trimethylsilyl)amide; NIS = 1-iodoopyrrolidine-2,5-dione; NBS = 1-bromopyrrolidine-2,5- dione; NCS = 1-chloropyrrolidine-2,5-dione; NMP = N-methylpyrrolidinone; NMR = nuclear magnetic resonance; OMs, mesyl = methanesulfonyl; Oxone, OXONE = potassium peroxymonosulfate; PBS = phosphate buffered saline; Pd 2 dba 3 = tris(dibenzylidineacetone)dipalladium; Pd(dppf)Cl 2 = [1,1’- bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pd/C = palladium on activated carbon; Ph = phenyl; PMB = 4-methoxybenzyl; PMBCl = 1-(chloromethyl)-4-methoxybenzene; Pr = propyl; Py = pyridyl; QPhos = (1,2,3,4,5-pentaphenyl-1’-(di-tert-butylphosphino)ferrocen e; RT, rt = room temperature; RuPhos Pd G3 = (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'- biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesul fonate; sat. = saturated; TBAF = tetrabutylammonium fluoride; TBAI = tetrabutylammonium iodide; t-Bu = tert-butyl; TFA = trifluoroacetic acid; THF = tetrahydrofuran; TLC = thin layer chromatography; prep TLC = preparative thin layer chromatography; Tosyl = toluenesulfonyl; triflate, OTf = trifluoromethanesulfonate; triflic = trifluoromethanesulfonic; Xantphos = 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene; XPhos Pd G2 or XPhos-PD-G2 = chloro(2- dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-bip henyl)[2-(2’-amino-1,1’- biphenyl)]palladium(II). General Methods Unless otherwise stated, all reactions were carried out under an atmosphere of dry nitrogen in dried glassware. Indicated reaction temperatures refer to those of the reaction bath, while room temperature (rt) is noted as 25 °C. Unless otherwise noted, all solvents were of anhydrous quality purchased from Aldrich Chemical Co. and were used as received. Commercially available starting materials and reagents were purchased from commercial suppliers and were used as received. Analytical thin layer chromatography (TLC) was performed with Sigma Aldrich TLC plates (5 x 20 cm, 60 Å, 250 μm). Visualization was accomplished by irradiation under a 254 nm UV lamp. Chromatography on silica gel was performed using forced flow (liquid) of the indicated solvent system on Biotage KP-Sil pre-packed cartridges and using the Biotage SP-1 automated chromatography system. 1 H NMR spectra were recorded on a Varian Inova 400 MHz spectrometer. Chemical shifts are reported in ppm with the solvent resonance as the internal standard (DMSO-d62.50 ppm for 1 H). Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, br = broad, m = multiplet), coupling constants, and number of protons. Low resolution mass spectra (electrospray ionization) were acquired on an Agilent Technologies 6130 quadrupole spectrometer coupled to the HPLC system. Unless otherwise noted, all LCMS ions listed are [M+H]. If needed, products were purified via semi-preparative HPLC using the columns and mobile phases noted. Samples were analyzed for purity on an Agilent 1200 series LC/MS equipped with a Luna® C18 reverse phase (3 micron, 3 x 75 mm) column having a flow rate of 0.8 – 1.0 mL/min over a 7 minute gradient and an 8.5 minute run time (Method 1). Unless otherwise noted, the mobile phase was a mixture of acetonitrile (0.025% TFA) and H 2 O (0.05% TFA), with temperature maintained at 50 o C. Purity of final compounds was determined to be >95% using a 3 μL injection with quantitation by AUC at 220 and 254 nm (Agilent Diode Array Detector). Example 1 Exemplary Synthetic Procedure #1 (Compounds 1 – 6) Compound 1, 6-(5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidin-3-yl)-5-f luoro-N-((3S,4S)- 4-fluoropyrrolidin-3-yl)pyridin-2-amine Step A. methyl 3-cyclopropyl-2-methoxy-3-oxopropanoate To a solution of [acetoxy(phenyl)-λ3-iodanyl]acetate (11.33 g, 35.17 mmol) and boron trifluoride diethyl etherate (4.99 g, 35.2 mmol, 4.34 mL) in methanol (100 mL) was added methyl 3-cyclopropyl-3-oxo-propanoate (5.00 g, 35.2 mmol). The resulting reaction was stirred at room temperature for 2 hours, and was then concentrated under reduced pressure. The crude product thus obtained was purified by flash chromatography on silica gel (0 – 20% ethyl acetate in petroleum ether) to provide the title compound: 1 H NMR (400 MHz, CD 3 OD) δ 4.63 (s, 1 H), 3.81 (s, 3 H), 3.48 (s, 3 H), 2.53 – 2.32 (m, 1 H), 1.12 – 0.93 (m, 4 H). Step B.5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidin-7-ol To 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). The resulting reaction was heated at 120 °C for 16 hours, and was then cooled to room temperature and concentrated under reduced pressure. The crude product thus obtained was purified by flash chromatography on silica gel (0 – 100% ethyl acetate in petroleum ether) to provide the title compound: LCMS m/z 206.1 [M+H] + ; 1 H NMR (400 MHz, CD 3 OD) δ 7.88 (d, J = 2.1 Hz, 1 H), 6.13 (d, J = 2.0 Hz, 1 H), 3.89 (s, 3 H), 2.45 (m, 1 H), 1.33 – 1.21 (m, 2 H), 1.19 – 1.10 (m, 2 H). 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. The resulting crude product was purified by flash chromatography on silica gel (0 – 20% ethyl acetate in petroleum ether) to provide the title compound: LCMS m/z 224.05 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.08 (d, J = 2.3 Hz, 1 H), 6.55 (d, J = 2.4 Hz, 1 H), 3.98 (s, 3 H), 2.50 – 2.43 (m, 1 H), 1.29 – 1.23 (m, 2 H), 1.17 – 1.11 (m, 2 H). Step D.5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidine To a solution of 7-chloro-5-cyclopropyl-6-methoxy-pyrazolo[1,5-a]pyrimidine (1.10 g, 4.92 mmol) in methanol (10 mL) and dichloromethane (10 mL) were added triethylamine (0.498 g, 4.92 mmol, 0.685 mL) and 10% palladium on carbon (1.10 g). The resulting reaction mixture was stirred at room temperature under hydrogen (1 atm) for 2 hours. The reaction mixture was then filtered and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel (0 – 20% ethyl acetate in petroleum ether) to provide the title compound: LCMS m/z 189.9 [M+H] + ; 1H NMR (400 MHz, CD 3 OD) δ 8.33 (s, 1 H), 7.88 (d, J = 2.4 Hz, 1 H), 6.39 (d, J = 1.9 Hz, 1 H), 3.94 (s, 3 H), 2.57 – 2.50 (m, 1 H), 1.18 – 1.04 (m, 4 H). Step E.5-cyclopropyl-6-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxa borolan-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-dioxaborola n-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 and purged with nitrogen, and was then heated at 80 °C for 12 hours under nitrogen atmosphere. The reaction was then cooled to room temperature, filtered, and concentrated under reduced pressure. The resulting crude product was purified by HPLC (Welch Ultimate XB-NH2 column, 10 micron, 250 x 50 mm; 0 – 16% ethanol in heptane) to provide the title compound: LCMS m/z 316.2 [M+H] + . Step F.3-(6-bromo-3-fluoropyridin-2-yl)-5-cyclopropyl-6-methoxypy razolo[1,5-a]pyrimidine and 3-(6-bromo-5-fluoropyridin-2-yl)-5-cyclopropyl-6-methoxypyra zolo[1, 5-a]pyrimidine A mixture of 5-cyclopropyl-6-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxabo rolan-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 dioxane (6 mL) and water (2 mL) was degassed and purged with nitrogen, and was then heated at 80 °C for 3 hours under nitrogen atmosphere. 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. The collected solids were dried under reduced pressure to yield title compound 3-(6-bromo-5-fluoropyridin-2-yl)-5-cyclopropyl-6-methoxypyra zolo[1,5- a]pyrimidine): LCMS m/z 362.9 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.83 (s, 1 H), 8.48 (s, 1 H), 8.33 – 8.28 (m, 1 H), 7.93 (t, J = 8.3 Hz, 1 H), 3.96 (s, 3 H), 2.56 (m, 1 H), 1.23 – 1.19 (m, 4 H). From the preceding filtration, the filtrate was collected, concentrated under reduced pressure, and further purified by HPLC (Phenomenex Luna C18 column, 10 micron, 250 x 50 mm; 55 – 85% acetonitrile in water containing 0.04% trifluoroacetic acid) to give title compound 3-(6-bromo-3-fluoropyridin-2-yl)-5-cyclopropyl-6-methoxypyra zolo [1,5-a] pyrimidine): LCMS m/z 362.9 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.81 (s, 1 H), 8.38 (d, J = 1.3 Hz, 1 H), 7.79 – 7.73 (m, 1 H), 7.56 – 7.50 (m, 1 H), 3.96 (s, 3 H), 2.56 – 2.51 (m, 1 H), 1.20 – 1.07 (m, 4 H). 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 A mixture of 3-(6-bromo-3-fluoro-2-pyridyl)-5-cyclopropyl-6-methoxy-pyraz olo[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]-diphenyl-phosp hane (0.004 g, 0.004 mmol), (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.004 g, 0.006 mmol), and cesium carbonate (0.034 g, 0.103 mmol) in 2-methylbutan-2-ol (2 mL) was degassed and purged with nitrogen, and was then heated at 80 °C for 1 hour under nitrogen atmosphere. The reaction was then cooled to room temperature, filtered, and concentrated under reduced pressure to provide the title compound: LCMS m/z 487.2 [M+H] + . 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 To 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-pyrroli dine-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). The resulting reaction was stirred at room temperature for 1 hour, and was then concentrated under reduced pressure. The crude product thus obtained was purified by HPLC (Phenomenex Luna C18 column, 3 micron, 75 x 30 mm; 10 – 40% acetonitrile in water containing 0.04% trifluoroacetic acid) to provide the title compound: LCMS m/z 387.2 [M+H] + ; 1 H NMR (400 MHz, CD 3 OD) δ 8.44 (s, 1 H), 8.30 (d, J = 1.8 Hz, 1 H), 7.40 (t, J = 9.4 Hz, 1 H), 6.57 – 6.46 (m, 1 H), 5.62 – 5.40 (m, 1 H), 4.80 – 4.72 (m, 1 H), 3.99 (s, 3 H), 3.83 – 3.62 (m, 4 H), 2.67 – 2.54 (m, 1 H), 1.29 – 1.07 (m, 4 H). The compounds in Table 1 were all prepared using the synthetic procedures described in Example 1. Table 1. Additional compounds prepared according to Example 1. Example 2 Exemplary Synthetic Procedure #2 (Compounds 7 – 8) Compound 7, 6-(5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidin-3-yl)-5-f luoro-2-(((3S,4S)- 4-fluoropiperidin-3-yl)amino)nicotinonitrile Step A.2-chloro-6-(5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidi n-3-yl)-5- fluoronicotinonitrile A mixture of 5-cyclopropyl-6-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxabo rolan-2- yl)pyrazolo[1,5-a]pyrimidine (0.380 g, 1.21 mmol), 2,6-dichloro-5-fluoronicotinonitrile (0.230 g, 1.21 mmol), aqueous potassium phosphate solution (2.5 M, 0.965 mL), and [1,1- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.088 g, 0.121 mmol) in dioxane (10 mL) was degassed and purged with argon, and was then heated at 80 °C for 5 hours under argon atmosphere. 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 (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel (0 – 60% ethyl acetate in petroleum ether) to provide the title compound: LCMS m/z 343.9 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.44 (d, J = 2.3 Hz, 1 H), 8.06 (s, 1 H), 7.60 (d, J = 9.1 Hz, 1 H), 3.89 (s, 3 H), 2.57 – 2.44 (m, 1 H), 1.35 – 1.28 (m, 2 H), 1.15 – 1.08 (m, 2 H). Step B. tert-butyl (3S,4S)-3-((3-cyano-6-(5-cyclopropyl-6-methoxypyrazolo[1,5-a ]pyrimidin-3- yl)-5-fluoropyridin-2-yl)amino)-4-fluoropiperidine-1-carboxy late A mixture of 2-chloro-6-(5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidin- 3-yl)-5- fluoronicotinonitrile (0.040 g, 0.116 mmol), tert-butyl (3S,4S)-3-amino-4-fluoropiperidine-1- carboxylate (0.038 g, 0.175 mmol), methanesulfonato[2,2-bis(diphenylphosphino)-1,1- binaphthyl](2-amino-1,1-biphenyl-2-yl)palladium(II) (0.012 g, 0.012 mmol), (R)-(+)-2,2'- bis(diphenylphosphino)-1,1'-binaphthyl (0.007 g, 0.012 mmol), and cesium carbonate (0.114 g, 0.349 mmol) in tetrahydrofuran (3 mL) was degassed and purged with nitrogen, and was then heated at 80 °C for 16 hours under nitrogen atmosphere. The reaction was then cooled to room temperature, filtered, and concentrated under reduced pressure to provide the title compound: LCMS m/z 526.3 [M+H] + . Step C.6-(5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidin-3-yl)-5 -fluoro-2-(((3S,4S)-4- fluoropiperidin-3-yl)amino)nicotinonitrile To a solution of tert-butyl (3S,4S)-3-((3-cyano-6-(5-cyclopropyl-6-methoxypyrazolo[1,5- a]pyrimidin-3-yl)-5-fluoropyridin-2-yl)amino)-4-fluoropiperi dine-1-carboxylate (0.070 g, 0.133 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1.07 g, 9.42 mmol, 0.700 mL). The resulting reaction was stirred at room temperature for 2 hours, and was then concentrated under reduced pressure. The crude product thus obtained was purified by HPLC (Phenomenex Luna C18 column, 5 micron, 100 x 40 mm; 10 – 45% acetonitrile in water containing 0.04% trifluoroacetate acid) to provide the title compound: LCMS m/z 426.1 [M+H] + ; 1 H NMR (400 MHz, CD 3 OD) δ 8.51 (s, 1 H), 8.46 (d, J = 1.6 Hz, 1 H), 7.82 (d, J = 9.8 Hz, 1 H), 4.95 – 4.92 (m, 1 H), 4.91 – 4.90 (m, 1 H), 4.01 (s, 3 H), 3.69 – 3.59 (m, 1 H), 3.52 – 3.41 (m, 1 H), 3.32 – 3.18 (m, 2 H), 2.71 – 2.60 (m, 1 H), 2.43 – 2.30 (m, 1 H), 2.26 – 2.06 (m, 1 H), 1.31 – 1.22 (m, 2 H), 1.20 – 1.10 (m, 2 H). The compounds in Table 2 were all prepared using the synthetic procedures described in Example 2. Table 2. Additional compounds prepared according to Example 2. Example 3 Exemplary Synthetic Procedure #3 (Compounds 9 – 13) Compound 9, (R)-5-fluoro-6-(5-(2-hydroxypropan-2-yl)-6-methoxypyrazolo[1 ,5-a]pyrimidin-3- yl)-2-(piperidin-3-ylamino)nicotinonitrile Step A.7-hydroxy-6-methoxypyrazolo[1,5-a]pyrimidin-5(4H)-one To a 2 L round bottom flask were added 1H-pyrazol-5-amine (24.00 g, 288.8 mmol), ethanol (500 mL), sodium ethoxide (39.31 g, 577.7 mmol), and dimethyl 2-methoxymalonate (46.83 g, 288.8 mmol), in that order. The resulting reaction mixture was heated at 80 °C for 1 hour. The reaction was then cooled to room temperature and filtered. The collected solids were dried under reduced pressure to provide the title compound: LCMS m/z 182.0 [M+H] + ; 1 H NMR (400 MHz, CD 3 OD) δ 7.60 (d, J = 1.9 Hz, 1 H), 5.77 (d, J = 1.9 Hz, 1 H), 3.79 – 3.69 (s, 3 H). Step B.5,7-dichloro-6-methoxypyrazolo[1,5-a]pyrimidine A 1 L three-necked round bottom flask equipped with a magnetic stir bar, addition funnel, and thermometer was charged with 7-hydroxy-6-methoxypyrazolo[1,5-a]pyrimidin-5(4H)-one (25.00 g, 138.0 mmol) and 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. The resulting reaction mixture was heated at 120 °C for 4 hours, and was then cooled to room temperature and concentrated under reduced pressure. The crude product thus obtained was purified by flash chromatography on silica gel (0 – 10% ethyl acetate in petroleum ether) to provide the title compound: LCMS m/z 218.1 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.20 (d, J = 2.4 Hz, 1 H), 6.74 (d, J = 2.4 Hz, 1 H), 4.03 (s, 3 H). Step C.5-chloro-6-methoxypyrazolo[1,5-a]pyrimidine A 1 L three-necked round bottom flask equipped with a magnetic stir bar, addition funnel, and thermometer was charged with 5,7-dichloro-6-methoxypyrazolo[1,5-a]pyrimidine (6.00 g, 27.5 mmol), ethanol (120 mL), tetrahydrofuran (120 mL), and a solution of ammonium chloride (7.36 g, 137.6 mmol) in water (120 mL). The resulting reaction was cooled to 0 °C. 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). The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide the title compound: LCMS m/z 184.0 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.23 (s, 1 H), 7.98 (s, 1 H), 6.52 (d, J = 2.3 Hz, 1 H), 3.90 (s, 3 H). 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. The 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. The resulting crude product was purified by flash chromatography on silica gel (0 – 50% ethyl acetate in petroleum ether) to provide the title compound: LCMS m/z 190.0 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.17 (s, 1 H), 7.91 (s, 1 H), 6.54 (d, J = 2.3 Hz, 1 H), 5.78 (s, 1 H), 5.53 (s, 1 H), 3.82 (s, 3 H), 2.16 (s, 3 H). Step E.2-(6-methoxypyrazolo[1,5-a]pyrimidin-5-yl)propan-2-ol To a solution of 6-methoxy-5-(prop-1-en-2-yl)pyrazolo[1,5-a]pyrimidine (2.10 g, 11.1 mmol) in propan-2-ol (60 mL) was added phenylsilane (3.60 g, 33.3 mmol, 4.11 mL). The resulting mixture was purged with oxygen and cooled to 0 °C. A solution of tris[(Z)-1-tert- butyl-4,4-dimethyl-3-oxo-pent-1-enoxy]manganese (0.671 g, 1.11 mmol) in dichloromethane (20 mL) was then added, and the resulting reaction mixture was stirred at 0 °C for 1 hour under oxygen atmosphere. The reaction was then warmed to room temperature, filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel (0 – 100% ethyl acetate in petroleum ether) to provide the title compound: LCMS m/z 208.1 [M+H] + . Step F.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. 1-Bromopyrrolidine-2,5-dione (0.227 g, 1.27 mmol) was then added in several portions. The resulting reaction mixture was removed from the cold bath and stirred for 1 hour while warming to room temperature. The 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-y l)pyrazolo[1,5-a]pyrimidin- 5-yl)propan-2-ol A mixture of 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), and potassium acetate (0.069 g, 0.699 mmol) in dioxane (5 mL) was degassed and purged with nitrogen, and was then heated at 80 °C for 16 hours under nitrogen atmosphere. The reaction was then cooled to room temperature, filtered, and concentrated under reduced pressure to provide the title compound: LCMS m/z 334.1 [M+H] + ; 1 H NMR (400 MHz, CD 3 OD) δ 8.57 (s, 1 H), 8.11 (s, 1 H), 3.88 (s, 3 H), 1.53 (s, 6 H), 1.10 (s, 12 H). Step H.2-chloro-5-fluoro-6-(5-(2-hydroxypropan-2-yl)-6-methoxypyr azolo[1,5-a]pyrimidin-3- yl)nicotinonitrile A mixture of 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), and aqueous potassium phosphate solution (2.5 M, 2.28 mL) in dioxane (10 mL) was degassed and purged with nitrogen, and was then heated at 90 °C for 3 hours under nitrogen atmosphere. The reaction was then cooled to room temperature, filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel (0 – 50% ethyl acetate in petroleum ether) to provide the title compound: LCMS m/z 362.1[M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.11 (s, 1 H), 8.67 (d, J = 2.0 Hz, 1 H), 8.61 (d, J = 10.3 Hz, 1 H), 3.33 (s, 3 H), 1.58 (s, 6 H). Step I. tert-butyl (R)-3-((3-cyano-5-fluoro-6-(5-(2-hydroxypropan-2-yl)-6-metho xypyrazolo[1,5- a]pyrimidin-3-yl)pyridin-2-yl)amino)piperidine-1-carboxylate A mixture of 2-chloro-5-fluoro-6-[5-(1-hydroxy-1-methyl-ethyl)-6-methoxy- pyrazolo[1,5- a]pyrimidin-3-yl]pyridine-3-carbonitrile (0.050 g, 0.138 mmol), tert-butyl (R)-3- aminopiperidine-1-carboxylate (0.042 g, 0.207 mmol), methanesulfonato[2,2- bis(diphenylphosphino)-1,1-binaphthyl](2-amino-1,1-biphenyl- 2-yl)palladium(II) (0.014 g, 0.014 mmol), (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.002 g, 0.004 mmol), and cesium carbonate (0.009 g, 0.014 mmol) in 2-methylbutan-2-ol (3 mL) was degassed and purged with nitrogen, and was then heated at 80 °C for 16 hours under nitrogen atmosphere. The reaction was then cooled to room temperature, filtered, and concentrated under reduced pressure to provide the title compound: LCMS m/z 526.3 [M+H] + . Step J. (R)-5-fluoro-6-(5-(2-hydroxypropan-2-yl)-6-methoxypyrazolo[1 ,5-a]pyrimidin-3-yl)-2- (piperidin-3-ylamino)nicotinonitrile To a solution of tert-butyl (3R)-3-[[3-cyano-5-fluoro-6-[5-(1-hydroxy-1-methyl-ethyl)-6- methoxy-pyrazolo[1,5-a]pyrimidin-3-yl]-2-pyridyl]amino]piper idine-1-carboxylate (0.100 g, 0.190 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (770.00 mg, 6.75 mmol, 0.500 mL). The resulting reaction was stirred at room temperature for 1 hour, and was then concentrated under reduced pressure. The crude product thus obtained was purified by HPLC (Phenomenex Luna C18 column, 5 micron, 75 x 30 mm; 25 – 55% acetonitrile in water containing 0.1% trifluoroacetic acid) to provide the title compound: LCMS m/z 426.2 [M+H] + ; 1 H NMR (400 MHz, CD 3 OD) δ 8.79 (d, J = 1.0 Hz, 1 H), 8.65 (s, 1 H), 7.89 – 7.69 (m, 1 H), 4.76 – 4.74 (m, 1 H), 4.07 – 4.02 (s, 3 H), 3.94 (m, 1 H), 3.45 – 3.42 (m, 1 H), 3.15 – 3.01 (m, 1 H), 2.80 (t, J = 11.2 Hz, 1 H), 2.24 – 2.15 (m, 1 H), 2.15 – 2.06 (m, 1 H), 2.06 – 1.95 (m, 1 H), 1.85 (m, 1 H), 1.73 (d, J = 10.6 Hz, 6 H). The compounds in Table 3 were all prepared using the synthetic procedures described in Example 3. Table 3. Additional compounds prepared according to Example 3. Example 4 Exemplary Synthetic Procedure #4 (Compound 14) Compound 14, 6-(6-chloropyrazolo[1,5-a]pyrimidin-3-yl)-N-((3S,4S)-4-fluor opyrrolidin-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). The resulting reaction was stirred at room temperature for 2 hours, and was then concentrated under reduced pressure. The crude product thus obtained was rinsed with ethyl acetate (3 x 10 mL) and dried under reduced pressure to provide the title compound: LCMS m/z 154.1 [M+H] + . Step B.6-chloro-3-iodopyrazolo[1,5-a]pyrimidine To a solution of 6-chloropyrazolo[1,5-a]pyrimidine (1.14 g, 7.42 mmol) in dichloromethane (10 mL) was added 1-iodopyrrolidine-2,5-dione (1.84 g, 8.17 mmol). The resulting reaction was stirred at room temperature for 5 hours. The reaction was then filtered, and the collected solids were dried under reduced pressure. The crude product thus obtained was rinsed with dichloromethane (3 x 10 mL) and dried under reduced pressure to provide the title compound: LCMS m/z 280.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.2 (s, 1 H), 8.6 (s, 1 H), 8.3 (s, 1 H). 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. The reaction was then cooled to room temperature, filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel (0 – 30 % ethyl acetate in petroleum ether) to provide the title compound: LCMS m/z 308.9 [M+H] + . Step D. (3S,4S)-tert-butyl 3-((6-(6-chloropyrazolo[1,5-a]pyrimidin-3-yl)pyridin-2-yl)am ino)-4- fluoropyrrolidine-1-carboxylate A mixture of 3-(6-bromo-2-pyridyl)-6-chloro-pyrazolo[1,5-a]pyrimidine (0.030 g, 0.097 mmol), tert-butyl (3S,4S)-3-amino-4-fluoro-pyrrolidine-1-carboxylate (0.020 g, 0.097 mmol), cesium carbonate (0.079 g, 0.242 mmol), and (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'- biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesul fonate (0.008 g, 0.010 mmol) in tetrahydrofuran (3.0 mL) was degassed and purged with nitrogen, and was then heated at 80 °C for 10 hours under nitrogen atmosphere. The reaction was then cooled to room temperature, filtered, and concentrated under reduced pressure to provide the title compound: LCMS m/z 433.1 [M+H] + . Step E.6-(6-chloropyrazolo[1,5-a]pyrimidin-3-yl)-N-((3S,4S)-4-flu oropyrrolidin-3-yl)pyridin-2- amine To 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). The resulting reaction was stirred at room temperature for 2 hours, and was then filtered and concentrated under reduced pressure. The crude product thus obtained was purified by HPLC (Phenomenex Luna C18 column, 3 micron, 75 x 30 mm; 1 – 30% acetonitrile in water containing 0.1% TFA) to provide the title compound: LCMS m/z 333.1 [M+H] + ; 1 H NMR (400 MHz, CD 3 OD) δ 9.24 (d, J = 2.2 Hz, 1 H), 8.78 (s, 1 H), 8.66 (d, J = 2.2 Hz, 1 H), 7.75 (d, J = 7.5 Hz, 1 H), 7.62 (br t, J = 7.9 Hz, 1 H), 6.57 (d, J = 8.2 Hz, 1 H), 5.63 – 5.42 (m, 1 H), 4.75 ( dd, J = 15.4, 4.6 Hz, 1 H), 3.89 (dd, J = 12.6, 6.4 Hz, 1 H), 3.82 – 3.74 (m, 1 H), 3.72 – 3.63 (m, 2 H).
Example 5 Exemplary Synthetic Procedure #5 (Compound 15) Compound 15, 6-(6-cyclopropylpyrazolo[1,5-a]pyrimidin-3-yl)-N-((3S,4S)-4- fluoropyrrolidin- 3-yl)pyridin-2-amine Step A. (3S,4S)-tert-butyl 3-((6-(6-cyclopropylpyrazolo[1,5-a]pyrimidin-3-yl)pyridin-2- yl)amino)-4-fluoropyrrolidine-1-carboxylate A mixture of tert-butyl (3S,4S)-3-[[6-(6-chloropyrazolo[1,5-a]pyrimidin-3-yl)-2- pyridyl]amino]-4-fluoro-pyrrolidine-1-carboxylate (0.020 g, 0.046 mmol), cyclopropylboronic acid (0.008 g, 0.092 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1 ,1′- biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (0.004 g, 0.005 mmol), and aqueous potassium phosphate solution (1.0 M, 0.185 mL) in tetrahydrofuran (1.0 mL) was degassed and purged with nitrogen, and was then heated by microwave at 90 °C for 1 hour. The reaction was then cooled to room temperature, filtered, and concentrated under reduced pressure to provide the title compound: LCMS m/z 439.2 [M+H] + . Step B.6-(6-cyclopropylpyrazolo[1,5-a]pyrimidin-3-yl)-N-((3S,4S)- 4-fluoropyrrolidin-3- yl)pyridin-2-amine
To a solution of tert-butyl (3S,4S)-3-[[6-(6-cyclopropylpyrazolo[1,5-a]pyrimidin-3-yl)-2 - pyridyl]amino]-4-fluoro-pyrrolidine-1-carboxylate (0.030 g, 0.068 mmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (0.30 mL, 0.462 g, 4.05 mmol). The resulting reaction was stirred at room temperature for 1 hour, and was then filtered and concentrated under reduced pressure. The crude product thus obtained was purified by HPLC (Phenomenex Luna C18 column, 3 micron, 75 x 30 mm; 5 – 35% acetonitrile in water containing 0.1% TFA) to provide the title compound: LCMS m/z 339.1 [M+H] + ; 1 H NMR (400 MHz, CD 3 OD) δ 8.77 (br d, J = 13.9 Hz, 2 H), 8.61 (d, J = 2.2 Hz, 1 H), 7.77 (br s, 1 H), 7.74 – 7.69 (m, 1 H), 6.69 (br s, 1 H), 5.62 – 5.44 (m, 1 H), 4.76 (br dd, J = 14.0, 5.4 Hz, 1 H), 3.92 (dd, J = 12.8, 6.4 Hz, 1 H), 3.85 – 3.68 (m, 3 H), 2.15 – 2.04 (m, 1 H), 1.18 – 1.09 (m, 2 H), 0.93 – 0.83 (m, 2 H). Example 6 Exemplary Synthetic Procedure #6 (Compounds 16 – 18) Compound 16, 6-(6-(2,2-difluoroethoxy)pyrazolo[1,5-a]pyrimidin-3-yl)-N-(( 3S,4S)-4- fluoropyrrolidin-3-yl)pyridin-2-amine Step A. pyrazolo[1,5-a]pyrimidin-6-ol To a solution of potassium hydroxide (5.10 g, 90.9 mmol) in methanol (50.0 mL) was added 6-bromopyrazolo [1,5-a]pyrimidine (3.00 g, 15.2 mmol). The resulting reaction was heated at 65 °C for 5 hours. The 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. The resulting crude product was purified by flash chromatography on silica gel (0 – 60 % ethyl acetate in petroleum ether) to provide the title compound: 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.16 (s, 1 H), 8.53 (dd, J = 2.5, 0.8 Hz, 1 H), 8.43 (d, J = 2.5 Hz, 1 H), 8.05 (d, J = 2.4 Hz, 1 H), 6.70 – 6.64 (s, 1 H). Step B.6-(2,2-difluoroethoxy)pyrazolo[1,5-a]pyrimidine To a solution of 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). The organic extracts were combined, washed with saturated aqueous sodium chloride solution (5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product thus obtained was purified by flash chromatography on silica gel (0 – 40 % ethyl acetate in petroleum ether) to provide the title compound: 1 H NMR (400 MHz, CD 3 OD) δ 8.74 (d, J = 2.6 Hz, 1 H), 8.48 (d, J = 2.6 Hz, 1 H), 8.07 (d, J = 2.5 Hz, 1 H), 6.68 (dd, J = 2.4, 0.6 Hz, 1 H), 6.27 (tt, J = 54.6, 3.6 Hz, 1 H), 4.39 (dt, J = 13.7, 3.7 Hz, 2 H). Step C.6-(2,2-difluoroethoxy)-3-iodopyrazolo[1,5-a]pyrimidine To a cooled 0 °C solution of 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. The crude product thus obtained was purified by prep- TLC (petroleum ether : ethyl acetate = 3:1) to provide the title compound: LCMS m/z 325.9 [M+H] + ; 1 H NMR (400 MHz, CD 3 OD) δ 8.67 (d, J = 2.5 Hz, 1 H), 8.39 (d, J = 2.1 Hz, 1 H), 7.97 (s, 1 H), 6.27 (tt, J = 54.6, 3.6 Hz, 1 H), 4.28 (dt, J = 13.7, 3.6 Hz, 2 H). 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. The reaction was then cooled to room temperature, filtered, and concentrated under reduced pressure. The crude product thus obtained was purified by prep-TLC (petroleum ether: ethyl acetate = 3:1) to provide the title compound: LCMS m/z 355.0 [M+H] + ; 1 H NMR (400 MHz, CD 3 OD) δ 8.86 – 8.78 (m, 1 H), 8.73 – 8.64 (m, 1 H), 8.55 – 8.44 (m, 1 H), 8.11 (s, 1 H), 7.71 (t, J = 7.5 Hz, 1 H), 7.40 (d, J = 7.9 Hz, 1 H), 6.47 – 6.12 (m, 1 H), 4.49 – 4.36 (m, 2 H). Step E. (3S,4S)-tert-butyl 3-((6-(6-(2,2-difluoroethoxy)pyrazolo[1,5-a]pyrimidin-3-yl)p yridin-2- yl)amino)-4-fluoropyrrolidine-1-carboxylate A mixture of 3-(6-bromo-2-pyridyl)-6-(2,2-difluoroethoxy)pyrazolo[1,5-a]p yrimidine (0.080 g, 0.225 mmol), tert-butyl (3S,4S)-3-amino-4-fluoro-pyrrolidine-1-carboxylate (0.037 g, 0.180 mmol), cesium carbonate (0.220 g, 0.676 mmol), and (2-dicyclohexylphosphino-2',6'- diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1' biphenyl)] palladium(II)methanesulfonate (0.019 g, 0.023 mmol) in tetrahydrofuran (1.0 mL) was degassed and purged with nitrogen, and was then heated at 80 °C for 10 hours under nitrogen atmosphere. The reaction was then cooled to room temperature, filtered, and concentrated under reduced pressure to provide the title compound: LCMS m/z 479.3 [M+H] + . Step F.6-(6-(2,2-difluoroethoxy)pyrazolo[1,5-a]pyrimidin-3-yl)-N- ((3S,4S)-4-fluoropyrrolidin- 3-yl)pyridin-2-amine To a solution of tert-butyl (3S,4S)-3-[[6-[6-(2,2-difluoroethoxy)pyrazolo[1,5-a]pyrimidi n- 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). The resulting reaction was stirred at room temperature for 1 hour, and was then filtered and concentrated under reduced pressure. The crude product thus obtained was purified by HPLC (Phenomenex Luna C18 column, 5 micron, 100 x 40 mm; 1 – 21% acetonitrile in water containing 0.1% TFA) to provide the title compound: LCMS m/z 379.2 [M+H] + ; 1 H NMR (400 MHz, CD 3 OD) δ 8.94 (d, J = 2.6 Hz, 1 H), 8.80 – 8.76 (s, 1 H), 8.70 (d, J = 2.6 Hz, 1 H), 7.85 – 7.76 (s, 2 H), 6.74 (br d, J = 7.3 Hz, 1 H), 6.32 (tt, J = 54.6, 3.5 Hz, 1 H), 5.65 – 5.47 (m, 1 H), 4.89 – 4.76 (m, 1 H), 4.47 (dt, J = 13.7, 3.7 Hz, 2 H), 3.96 (dd, J = 12.9, 6.4 Hz, 1 H), 3.88 – 3.69 (m, 3 H). 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 (Compounds 19 – 21) 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. methyl 3-cyclopropyl-2-methoxy-3-oxopropanoate To a solution of (diacetoxyiodo)benzene (11.33 g, 35.17 mmol) and boron trifluoride diethyl etherate (4.99 g, 35.2 mmol, 4.34 mL) in methanol (100 mL) was added methyl 3- cyclopropyl-3-oxo-propanoate (5.00 g, 35.2 mmol). The resulting reaction was stirred at room temperature for 2 hours, and was then concentrated under reduced pressure. The crude product thus obtained was purified by flash chromatography on silica gel (0 – 20 % ethyl acetate in petroleum ether) to provide the title compound: LCMS m/z 173.07 [M+H] + . Step B.5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidin-7-ol To 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). The resulting reaction was heated at 120 °C for 16 hours, and was then cooled to room temperature and concentrated under reduced pressure. The crude product thus obtained was purified by flash chromatography on silica gel (0 – 10% methanol in dichloromethane) to provide the title compound: LCMS m/z 206.1 [M+H] + ; 1 H NMR (400 MHz, CD 3 OD) δ 7.88 (d, J = 2.1 Hz, 1 H), 6.13 (d, J = 2.0 Hz, 1 H), 3.89 (s, 3 H), 2.45 (tt, J = 8.6, 5.4 Hz, 1 H), 1.33 – 1.21 (m, 2 H), 1.19 – 1.10 (m, 2 H). 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. 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 A mixture of 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. The mixture was then filtered and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel (0 – 50 % ethyl acetate in petroleum ether) to provide the title compound: LCMS m/z 189.09 [M+H] + . Step E.5-cyclopropyl-3-iodo-6-methoxypyrazolo[1,5-a]pyrimidine To a cooled 0 °C solution of 5-cyclopropyl-6-methoxy-pyrazolo[1,5-a]pyrimidine (1.00 g, 5.29 mmol) in acetonitrile (15.0 mL) was added 1-iodopyrrolidine-2,5-dione (1.19 g, 5.29 mmol). The resulting reaction was then removed from the cold bath and stirred for 1 hour while warming to room temperature. The reaction mixture was then filtered, and the collected solids were rinsed with ethyl acetate and dried under reduced pressure to provide the title compound: LCMS m/z 315.99 [M+H] + ; 1 H NMR (400 MHz, CD 3 OD) δ 8.40 (s, 1 H), 7.92 (s, 1 H), 3.97 (s, 4 H), 2.63 – 2.54 (m, 1 H), 1.30 – 1.22 (m, 2 H), 1.16 – 1.11 (m, 2 H). Step F.3-(6-bromopyridin-2-yl)-5-cyclopropyl-6-methoxypyrazolo[1, 5-a]pyrimidine To a solution of 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. The reaction was then cooled to room temperature, filtered, and concentrated under reduced pressure. The crude product thus obtained was purified by flash chromatography on silica gel (0 – 50 % ethyl acetate in petroleum ether) to provide the title compound: LCMS m/z 347.0 [M+H] + . Step G. (3S,4S)-tert-butyl 3-((6-(5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidin-3- yl)pyridin-2-yl)amino)-4-fluoropyrrolidine-1-carboxylate
A mixture of 3-(6-bromo-2-pyridyl)-5-cyclopropyl-6-methoxy-pyrazolo[1,5-a ]pyrimidine (0.020 g, 0.058 mmol), tert-butyl (3S,4S)-3-amino-4-fluoro-pyrrolidine-1-carboxylate (0.012 g, 0.058 mmol), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2 -(2'-amino-1,1'- biphenyl)]palladium(II)methanesulfonate (0.005 g, 0.006 mmol), and cesium carbonate (0.047 g, 0.145 mmol) in tetrahydrofuran (2.0 mL) was degassed and purged with nitrogen, and was then heated at 80 °C for 2 hours under nitrogen atmosphere. The reaction was then cooled to room temperature, filtered, and concentrated under reduced pressure to provide the title compound: LCMS m/z 469.2 [M+H] + . Step H.6-(5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidin-3-yl)-N -((3S,4S)-4- fluoropyrrolidin-3-yl)pyridin-2-amine To 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-ca rboxylate (0.040 g, 0.085 mmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (0.50 mL, 0.778 g, 6.82 mmol). The resulting reaction was stirred at room temperature for 1 hour, and was then concentrated under reduced pressure. The crude product thus obtained was purified by HPLC (Phenomenex Luna C18 column, 3 micron, 75 x 30 mm; 1 – 30% acetonitrile in water containing 0.1% TFA) to provide the title compound: LCMS m/z 369.1 [M+H] + ; 1 H NMR (400 MHz, CD 3 OD) δ 8.50 (br s, 1 H), 8.38 (s, 1 H), 7.69 (br d, J = 7.5 Hz, 1 H), 7.58 (br d, J = 6.8 Hz, 1 H), 6.48 – 6.43 (m, 1 H), 5.46 (s, 1 H), 5.34 (br s, 1 H), 4.66 (br dd, J = 13.8, 4.0 Hz, 1 H), 3.89 (s, 3 H), 3.79 (dd, J = 12.6, 6.2 Hz, 1 H), 3.66 (s, 1 H), 3.64 – 3.50 (m, 2 H), 2.59 – 2.52 (m, 1 H), 1.28 – 1.09 (m, 5 H). The compounds in Table 5 were all prepared using the synthetic procedures described in Example 7. Table 5. Additional compounds prepared according to Example 7. 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). The resulting reaction was removed from the cold bath and stirred for 2 hours while warming to room temperature. The reaction was then concentrated under reduced pressure to give a crude product that was washed with 1:1 petroleum ether/ethyl acetate (15 mL) and filtered. The collected solids were dried under reduced pressure to provide the title compound: LCMS m/z 268.00 [M+H] + ; 1 H NMR (400 MHz, CD 3 OD) δ 8.37 (s, 1 H), 7.90 (s, 1 H), 3.95 (s, 3 H), 2.61 – 2.53 (m, 1 H), 1.28 – 1.18 (m, 2 H), 1.15 – 1.09 (m, 2 H). Step B.5-cyclopropyl-6-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxa borolan-2-yl)pyrazolo[1,5- a]pyrimidine A mixture of 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-dioxaborola n-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), and potassium acetate (0.037 g, 0.373 mmol) in toluene (3.0 mL) was degassed and purged with nitrogen, and was then heated at 80 °C for 12 hours under nitrogen atmosphere. The reaction was then cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (3 x 30 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 to provide the title compound: LCMS m/z 316.18 [M+H] + . Step C.3-(6-bromo-3,5-difluoropyridin-2-yl)-5-cyclopropyl-6-metho xypyrazolo[1,5- a]pyrimidine A mixture of 5-cyclopropyl-6-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxabo rolan-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 °C for 3 hours under nitrogen atmosphere. The reaction was then cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (3 x 30 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. The crude product thus obtained was purified by HPLC (Phenomenex Luna C18 column, 3 micron, 80 x 30 mm; 55 – 85% acetonitrile in water containing 0.1% TFA) to provide the title compound: LCMS m/z 381.01 [M+H] + . Step D. (3S,4S)-tert-butyl 3-((6-(5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidin-3-yl) -3,5- difluoropyridin-2-yl)amino)-4-fluoropiperidine-1-carboxylate A mixture of tert-butyl (3S,4S)-3-amino-4-fluoro-piperidine-1-carboxylate (0.021 g, 0.098 mmol), 3-(6-bromo-3,5-difluoro-2-pyridyl)-5-cyclopropyl-6-methoxy-p yrazolo[1,5-a]pyrimidine (0.025 g, 0.066 mmol), [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium[1-(2- diphenylphosphanyl-1-naphthyl)-2-naphthyl]-diphenyl-phosphan e (0.007 g, 0.007 mmol), (R)- (+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.006 g, 0.010 mmol), and cesium carbonate (0.064 g, 0.197 mmol) in 2-methylbutan-2-ol (1.5 mL) was degassed and purged with nitrogen, and was then heated at 80 °C for 7 hours under nitrogen atmosphere. The reaction was then cooled to room temperature and concentrated under reduced pressure to provide the title compound: LCMS m/z 519.23 [M+H] + . Step E.6-(5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidin-3-yl)-3 ,5-difluoro-N-((3S,4S)-4- fluoropiperidin-3-yl)pyridin-2-amine
To a solution of tert-butyl (3S,4S)-3-[[6-(5-cyclopropyl-6-methoxy-pyrazolo[1,5- a]pyrimidin-3-yl)-3,5-difluoro-2-pyridyl]amino]-4-fluoro-pip eridine-1-carboxylate (0.030 g, 0.058 mmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (0.30 mL, 0.462 g, 4.05 mmol). The resulting reaction was stirred at room temperature for 2 hours, and was then concentrated under reduced pressure. The crude product thus obtained was purified by HPLC (Phenomenex Luna C18 column, 3 micron, 75 x 30 mm; 14 – 45% acetonitrile in water containing 0.1% TFA) to provide the title compound: LCMS m/z 419.17 [M+H] + ; 1 H NMR (400 MHz, CD 3 OD) δ 8.42 (s, 1 H), 8.26 (s, 1 H), 7.44 (t, J = 9.7 Hz, 1 H), 5.01 (br s, 1 H), 4.86 (s, 3 H), 4.70 – 4.70 (m, 1 H), 4.69 – 4.63 (m, 1 H), 3.99 (s, 3 H), 3.60 (br s, 1 H), 3.44 – 3.40 (m, 1 H), 3.26 – 3.19 (m, 1 H), 2.63 – 2.57 (m, 1 H), 2.49 – 2.38 (m, 1 H), 2.16 – 2.08 (m, 1 H), 1.26 – 1.18 (m, 2 H), 1.16 – 1.07 (m, 2 H). The compounds in Table 6 were all prepared using the synthetic procedures described in Example 8. Table 6. Additional compounds prepared according to Example 8. Example 9 Exemplary Synthetic Procedure #9 (Compounds 1a – 3a) Compound 1a, 2-(3-(2-(((3S,4S)-4-fluoropyrrolidin-3-yl)amino)pyrimidin-4- yl)-6- methoxypyrazolo[1,5-a]pyrimidin-5-yl)propan-2-ol Step A.7-hydroxy-6-methoxypyrazolo[1,5-a]pyrimidin-5(4H)-one To a 2 L round bottom flask were added 1H-pyrazol-5-amine (24.00 g, 288.8 mmol), ethanol (500 mL), sodium ethoxide (39.31 g, 577.7 mmol), and dimethyl 2-methoxymalonate (46.83 g, 288.8 mmol), in that order. The resulting reaction mixture was heated at 80 °C for 1 hour. The reaction was then cooled to room temperature and filtered. The collected solids were dried under reduced pressure to provide the title compound: LCMS m/z 182.0 [M+H] + ; 1 H NMR (400 MHz, CD 3 OD) δ 7.60 (d, J = 1.9 Hz, 1 H), 5.77 (d, J = 1.9 Hz, 1 H), 3.79 – 3.69 (s, 3 H). Step B.5,7-dichloro-6-methoxypyrazolo[1,5-a]pyrimidine A 1 L three-necked round bottom flask equipped with a magnetic stir bar, addition funnel, and thermometer was charged with 7-hydroxy-6-methoxypyrazolo[1,5-a]pyrimidin-5(4H)-one (25.00 g, 138.0 mmol) and 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. The resulting reaction mixture was heated at 120 °C for 4 hours, and was then cooled to room temperature and concentrated under reduced pressure. The crude product thus obtained was purified by flash chromatography on silica gel (0 – 10% ethyl acetate in petroleum ether) to provide the title compound: LCMS m/z 218.1 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.20 (d, J = 2.4 Hz, 1 H), 6.74 (d, J = 2.4 Hz, 1 H), 4.03 (s, 3 H). Step C.5-chloro-6-methoxypyrazolo[1,5-a]pyrimidine A 1 L three-necked round bottom flask equipped with a magnetic stir bar, addition funnel, and thermometer was charged with 5,7-dichloro-6-methoxypyrazolo[1,5-a]pyrimidine (6.00 g, 27.5 mmol), ethanol (120 mL), tetrahydrofuran (120 mL), and a solution of ammonium chloride (7.36 g, 137.6 mmol) in water (120 mL). The resulting reaction was cooled to 0 °C. 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). The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide the title compound: LCMS m/z 184.0 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.23 (s, 1 H), 7.98 (s, 1 H), 6.52 (d, J = 2.3 Hz, 1 H), 3.90 (s, 3 H). 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. The 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. The resulting crude product was purified by flash chromatography on silica gel (0 – 50% ethyl acetate in petroleum ether) to provide the title compound: LCMS m/z 190.0 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.17 (s, 1 H), 7.91 (s, 1 H), 6.54 (d, J = 2.3 Hz, 1 H), 5.78 (s, 1 H), 5.53 (s, 1 H), 3.82 (s, 3 H), 2.16 (s, 3 H). Step E.2-(6-methoxypyrazolo[1,5-a]pyrimidin-5-yl)propan-2-ol To a solution of 6-methoxy-5-(prop-1-en-2-yl)pyrazolo[1,5-a]pyrimidine (2.10 g, 11.1 mmol) in propan-2-ol (60 mL) was added phenylsilane (3.60 g, 33.3 mmol, 4.11 mL). The resulting mixture was purged with oxygen and cooled to 0 °C. A solution of tris[(Z)-1-tert- butyl-4,4-dimethyl-3-oxo-pent-1-enoxy]manganese (0.671 g, 1.11 mmol) in dichloromethane (20 mL) was then added, and the resulting reaction mixture was stirred at 0 °C for 1 hour under oxygen atmosphere. The reaction was then warmed to room temperature, filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel (0 – 100% ethyl acetate in petroleum ether) to provide the title compound: LCMS m/z 208.1 [M+H] + . Step F.2-(3-iodo-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 (0.150 g, 0.724 mmol) in acetonitrile (1.5 mL) was cooled to 0 °C. N-Iodosuccinimide (0.163 g, 0.724 mmol) was then added in several portions. The resulting reaction mixture was removed from the cold bath and stirred for 2 hours while warming to room temperature. The reaction was then diluted with aqueous sodium hydroxide solution (2 N, 6 mL) and extracted with ethyl acetate (3 x 5 mL). The organic extracts were combined, washed with saturated aqueous sodium chloride solution (3 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide the title compound: LCMS m/z 333.9 [M+H] + . Step G.2-(3-(2-chloropyrimidin-4-yl)-6-methoxypyrazolo[1,5-a]pyri midin-5-yl)propan-2-ol A mixture of 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), and palladium tri- tert-butylphosphane (0.011 g, 0.021 mmol) in dioxane (5 mL) was degassed and purged with nitrogen, and was then heated at 100 °C for 16 hours under nitrogen atmosphere. The reaction was then cooled to room temperature, filtered, and concentrated under reduced pressure. The resulting crude product was purified by prep-TLC (SiO 2 , 100% ethyl acetate) to provide the title compound: LCMS m/z 320.0 [M+H] + . Step H. (3S,4S)-tert-butyl 3-fluoro-4-((4-(5-(2-hydroxypropan-2-yl)-6-methoxypyrazolo[1 ,5- a]pyrimidin-3-yl)pyrimidin-2-yl)amino)pyrrolidine-1-carboxyl ate A mixture of 2-(3-(2-chloropyrimidin-4-yl)-6-methoxypyrazolo[1,5-a]pyrimi din-5- yl)propan-2-ol (0.040 g, 0.125 mmol), (3S,4S)-tert-butyl 3-amino-4-fluoropyrrolidine-1- carboxylate (0.038 g, 0.188 mmol), methanesulfonato[2,2-bis(diphenylphosphino)-1,1- binaphthyl](2-amino-1,1-biphenyl-2-yl)palladium(II) (0.012 g, 0.013 mmol), (R)-(+)-2,2'- bis(diphenylphosphino)-1,1'-binaphthyl (0.008 g, 0.013 mmol), and cesium carbonate (0.122 g, 0.375 mmol) in 2-methylbutan-2-ol (4 mL) was degassed and purged with nitrogen, and was then heated at 80 °C for 4 hours under nitrogen atmosphere. The reaction was then cooled to room temperature, filtered, and concentrated under reduced pressure to provide the title compound: LCMS m/z 488.5 [M+H] + . Step I.2-(3-(2-(((3S,4S)-4-fluoropyrrolidin-3-yl)amino)pyrimidin- 4-yl)-6-methoxypyrazolo[1,5- a]pyrimidin-5-yl)propan-2-ol
To a solution of (3S,4S)-tert-butyl 3-fluoro-4-((4-(5-(2-hydroxypropan-2-yl)-6- methoxypyrazolo[1,5-a]pyrimidin-3-yl)pyrimidin-2-yl)amino)py rrolidine-1-carboxylate (0.070 g, 0.144 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.770 g, 6.75 mmol, 0.500 mL). The resulting reaction was stirred at room temperature for 1 hour, and was then concentrated under reduced pressure. The crude product thus obtained was purified by HPLC (Phenomenex Luna C18 column, 5 micron, 80 x 30 mm; 1 – 30% acetonitrile in water containing 0.04% trifluoroacetic acid) to provide the title compound: LCMS m/z 388.1 [M+H] + ; 1 H NMR (400 MHz, CD 3 OD) δ 8.88 – 8.68 (m, 2 H), 8.37 (br d, J = 5.4 Hz, 1 H), 8.08 – 7.87 (m, 1 H), 5.65 – 5.39 (m, 1 H), 4.81 – 4.76 (m, 1 H), 4.12 (s, 3 H), 3.95 – 3.65 (m, 4 H), 1.73 (s, 6 H). 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 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. 1-Bromopyrrolidine-2,5-dione (0.227 g, 1.27 mmol) was then added in several portions. The resulting reaction mixture was removed from the cold bath and stirred for 1 hour while warming to room temperature. The 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 B.2-(6-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y l)pyrazolo[1,5-a]pyrimidin- 5-yl)propan-2-ol A mixture of 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), and potassium acetate (0.069 g, 0.699 mmol) in dioxane (5 mL) was degassed and purged with nitrogen, and was then heated at 80 °C for 16 hours under nitrogen atmosphere. The reaction was then cooled to room temperature, filtered, and concentrated under reduced pressure to provide the title compound: LCMS m/z 334.1 [M+H] + ; 1 H NMR (400 MHz, CD 3 OD) δ 8.57 (s, 1 H), 8.11 (s, 1 H), 3.88 (s, 3 H), 1.53 (s, 6 H), 1.10 (s, 12 H). Step C.2-(3-(2-bromo-5-fluoropyrimidin-4-yl)-6-methoxypyrazolo[1, 5-a]pyrimidin-5- yl)propan-2-ol A mixture of 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), and 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 3 hours under nitrogen atmosphere. The reaction was then cooled to room temperature, filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel (0 – 50% ethyl acetate in petroleum ether) to provide the title compound: LCMS m/z 382.0 [M+H] + ; 1 H NMR (400 MHz, CD 3 OD) δ 8.82 (s, 1 H), 8.65 (d, J = 2.4 Hz, 1 H), 8.51 (d, J = 3.1 Hz, 1 H), 4.00 (s, 3 H), 1.65 (s, 6 H). Step D. tert-butyl (R)-3-((5-fluoro-4-(5-(2-hydroxypropan-2-yl)-6-methoxypyrazo lo[1,5- a]pyrimidin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxyla te A mixture of 2-(3-(2-bromo-5-fluoropyrimidin-4-yl)-6-methoxypyrazolo[1,5- a]pyrimidin- 5-yl)propan-2-ol (0.040 g, 0.105 mmol), tert-butyl (R)-3-aminopiperidine-1-carboxylate (0.031 g, 0.157 mmol), methanesulfonato[2,2-bis(diphenylphosphino)-1,1-binaphthyl]( 2-amino-1,1- biphenyl-2-yl)palladium(II) (0.010 g, 0.010 mmol), (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'- binaphthyl (0.007 g, 0.010 mmol), and cesium carbonate (0.102 g, 0.314 mmol) in 2- methylbutan-2-ol (3 mL) was degassed and purged with nitrogen, and was then heated at 80 °C for 16 hours under nitrogen atmosphere. The reaction was then cooled to room temperature, filtered, and concentrated under reduced pressure to provide the title compound: LCMS m/z 502.3 [M+H] + . Step E. (R)-2-(3-(5-fluoro-2-(piperidin-3-ylamino)pyrimidin-4-yl)-6- methoxypyrazolo[1,5- a]pyrimidin-5-yl)propan-2-ol To a solution of tert-butyl (R)-3-((5-fluoro-4-(5-(2-hydroxypropan-2-yl)-6- methoxypyrazolo[1,5-a]pyrimidin-3-yl)pyrimidin-2-yl)amino)pi peridine-1-carboxylate (0.070 g, 0.140 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.770 g, 6.75 mmol, 0.500 mL). The resulting reaction mixture was stirred at room temperature for 1 hour, and was then concentrated under reduced pressure. The crude product thus obtained was purified by HPLC (Phenomenex Luna C18 column, 5 micron, 150 x 30 mm; 3 – 30% acetonitrile in water containing 0.04% trifluoroacetate acid) to provide the title compound: LCMS m/z 402.1 [M+H] + ; 1 H NMR (400 MHz, CD 3 OD) δ 8.69 (s, 1 H), 8.53 (d, J = 2.8 Hz, 1 H), 8.15 (d, J = 3.9 Hz, 1 H), 4.33 – 4.21 (m, 1 H), 3.92 (s, 3 H), 3.76 – 3.68 (m, 1 H), 3.27 (d, J = 12.6 Hz, 1 H), 2.97 – 2.87 (m, 1 H), 2.76 (t, J = 10.9 Hz, 1 H), 2.11 – 1.95 (m, 2 H), 1.83 (m, 1 H), 1.72 – 1.63 (m, 1 H), 1.59 (d, J = 8.8 Hz, 6 H). 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. methyl 3-cyclopropyl-2-methoxy-3-oxopropanoate To a solution of (diacetoxyiodo)benzene (11.33 g, 35.17 mmol) and boron trifluoride diethyl etherate (4.99 g, 35.2 mmol, 4.34 mL) in methanol (100 mL) was added methyl 3- cyclopropyl-3-oxo-propanoate (5.00 g, 35.2 mmol). The resulting reaction was stirred at room temperature for 2 hours, and was then concentrated under reduced pressure. The crude product thus obtained was purified by flash chromatography on silica gel (0 – 20 % ethyl acetate in petroleum ether) to provide the title compound: LCMS m/z 173.07 [M+H] + . Step B.5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidin-7-ol To 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). The resulting reaction was heated at 120 °C for 16 hours, and was then cooled to room temperature and concentrated under reduced pressure. The crude product thus obtained was purified by flash chromatography on silica gel (0 – 10% methanol in dichloromethane) to provide the title compound: LCMS m/z 206.1 [M+H] + ; 1 H NMR (400 MHz, CD 3 OD) δ 7.88 (d, J = 2.1 Hz, 1 H), 6.13 (d, J = 2.0 Hz, 1 H), 3.89 (s, 3 H), 2.45 (tt, J = 8.6, 5.4 Hz, 1 H), 1.33 – 1.21 (m, 2 H), 1.19 – 1.10 (m, 2 H). 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. 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 A mixture of 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. The mixture was then filtered and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel (0 – 50 % ethyl acetate in petroleum ether) to provide the title compound: LCMS m/z 189.09 [M+H] + . Step E.5-cyclopropyl-3-iodo-6-methoxypyrazolo[1,5-a]pyrimidine To a cooled 0 °C solution of 5-cyclopropyl-6-methoxy-pyrazolo[1,5-a]pyrimidine (1.00 g, 5.29 mmol) in acetonitrile (15 mL) was added 1-iodopyrrolidine-2,5-dione (1.19 g, 5.29 mmol). The reaction was then removed from the cold bath and stirred for 1 hour while slowly warming to room temperature. The reaction was filtered, and the collected solids were triturated with ethyl acetate (5 mL) to provide the title compound: LCMS m/z 314.99 [M+H] + ; 1 H NMR (400 MHz, CD 3 OD) δ 8.40 (s, 1 H), 7.92 (s, 1 H), 3.97 (s, 3 H), 2.63 – 2.54 (m, 1 H), 1.30 – 1.22 (m, 2 H), 1.16 – 1.11 (m, 2 H). 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. The reaction was then cooled to room temperature and was quenched by addition of saturated aqueous ammonium chloride solution (15 mL) and saturated aqueous potassium fluoride solution (20 mL). The resulting mixture was stirred at room temperature for 30 minutes, and was then extracted with ethyl acetate (3 x 15 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. The resulting crude product was purified by flash chromatography on silica gel (0 – 100% ethyl acetate in petroleum ether) to provide the title compound: LCMS m/z 301.07 [M+H] + . Step G. (3S,4S)-tert-butyl 3-((4-(5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidin-3- yl)pyrimidin-2-yl)amino)-4-fluoropiperidine-1-carboxylate A mixture of 3-(2-chloropyrimidin-4-yl)-5-cyclopropyl-6-methoxy-pyrazolo[ 1,5- a]pyrimidine (0.030 g, 0.099 mmol), tert-butyl (3S,4S)-3-amino-4-fluoro-piperidine-1- carboxylate (0.033 g, 0.149 mmol), [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium ditertbutyl[2(2,4,6triisopropylphenyl)phenyl]phosphane (0.008 g, 0.010 mmol), and sodium tert- butoxide (2.0 M in THF, 0.10 mL) in 2-methylbutan-2-ol (1.0 mL) was degassed and purged with nitrogen, and was then heated at 80 °C for 2 hours under nitrogen atmosphere. The reaction was then cooled to room temperature, filtered, and concentrated under reduced pressure to provide the title compound: LCMS m/z 483.24 [M+H] + . Step H.4-(5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidin-3-yl)-N -((3S,4S)-4- fluoropiperidin-3-yl)pyrimidin-2-amine To 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). The resulting reaction was stirred at room temperature for 1 hour, and was then concentrated under reduced pressure. The crude product thus obtained was purified by HPLC (Phenomenex Luna C18 column, 3 micron, 75 x 30 mm; 1 – 30% acetonitrile in water containing 0.1% TFA) to provide the title compound: LCMS m/z 383.19 [M+H] + ; 1 H NMR (400 MHz, CD 3 OD) δ 8.76 (s, 1 H), 8.62 (s, 1 H), 8.25 (d, J = 6.3 Hz, 1 H), 7.91 (d, J = 6.1 Hz, 1 H), 4.98 (br dd, J = 8.6, 4.1 Hz, 1 H), 4.67 (dd, J = 8.6, 3.9 Hz, 1 H), 4.02 (s, 3 H), 3.77 – 3.69 (m, 1 H), 3.57 – 3.49 (m, 1 H), 3.26 – 3.17 (m, 2 H), 2.75 – 2.67 (m, 1 H), 2.50 (ddd, J = 18.7, 10.0, 3.9 Hz, 1 H), 2.20 – 2.05 (m, 1 H), 1.35 – 1.26 (m, 4 H). The compounds in Table 8 were all prepared using the synthetic procedures described in Example 10. Table 8. Additional compounds prepared according to Example 10. 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-dioxa borolan-2-yl)pyrazolo[1,5- a]pyrimidine
A mixture of 5-cyclopropyl-6-methoxy-pyrazolo[1,5-a]pyrimidine (2.00 g, 10.6 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (13.42 g, 52.85 mmol), (1,5- cyclooctadiene)(methoxy)iridium(I) dimer (0.420 g, 0.634 mmol), and 4-tert-butyl-2-(4-tert- butyl-2-pyridyl)pyridine (0.199 g, 0.740 mmol) in hexane (150 mL) was degassed and purged with nitrogen, and was then heated at 80 °C for 12 hours under nitrogen atmosphere. The reaction was then cooled to room temperature and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel (5 – 30% ethanol in heptane) to provide the title compound: LCMS m/z 316.18 [M+H] + . 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-dioxabo rolan-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. The 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 5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was triturated with methanol (3 x 5 mL) and filtered. The collected solids were then dried under reduced pressure to afford the title compound: LCMS m/z 347.9 [M+H] + . Step C. (3S,4S)-tert-butyl 3-((6-(5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidin-3- yl)pyrazin-2-yl)amino)-4-fluoropyrrolidine-1-carboxylate A mixture of 3-(6-bromopyrazin-2-yl)-5-cyclopropyl-6-methoxy-pyrazolo[1,5 - a]pyrimidine (0.050 g, 0.144 mmol), tert-butyl(3S,4S)-3-amino-4-fluoro-pyrrolidine-1- carboxylate (0.044 g, 0.217 mmol), cesium carbonate (0.118 g, 0.361 mmol), [2-(2- aminophenyl)phenyl]-methylsulfonyloxypalladium[1-(2-diphenyl phosphanyl-1-naphthyl)-2- naphthyl]-diphenyl-phosphane (0.014 g, 0.014 mmol), and (R)-(+)-2,2'-bis(diphenylphosphino)- 1,1'-binaphthyl (0.013 g, 0.022 mmol) in 2-methylbutan-2-ol (3.0 mL) was degassed and purged with nitrogen, and was then heated at 80 °C for 6 hours under nitrogen atmosphere. The reaction was then cooled to room temperature, filtered, and concentrated under reduced pressure to provide the title compound: LCMS m/z 470.1 [M+H] + . Step D.6-(5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidin-3-yl)-N -((3S,4S)-4- fluoropyrrolidin-3-yl)pyrazin-2-amine To 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-c arboxylate (0.050 g, 0.106 mmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (0.50 mL, 0.778 g, 6.82 mmol). The resulting reaction was stirred at room temperature for 1 hour, and was then concentrated under reduced pressure. The crude product thus obtained was purified by HPLC (Phenomenex Luna C18 column, 3 micron, 75 x 30 mm; 5 – 35% acetonitrile in water containing 0.1% TFA) to provide the title compound: LCMS m/z 370.0 [M+H] + ; 1 H NMR (400 MHz, CD 3 OD) δ 8.79 (s, 1 H), 8.52 (s, 1 H), 8.46 (s, 1 H), 7.75 (s, 1 H), 5.55 (s, 1 H), 5.42 (d, J = 3.0 Hz, 1 H), 4.84 – 4.77 (m, 1 H), 3.99 (s, 3 H), 3.95 – 3.90 (m, 1 H), 3.78 – 3.58 (m, 3 H), 2.68 – 2.61 (m, 1 H), 1.32 – 1.18 (m, 4 H). The compounds in Table 9 were all prepared using the synthetic procedures described in Example 11. Table 9. Additional compounds prepared according to Example 11. Example 12 Exemplary Synthetic Procedure #12 (Compounds 13a – 15a) Compound 15a, 4-(5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidin-3-yl)-5-f luoro-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). The resulting reaction was removed from the cold bath and stirred for 2 hours while warming to room temperature. The reaction was then concentrated under reduced pressure to give a crude product that was washed with 1:1 petroleum ether/ethyl acetate (15 mL) and filtered. The collected solids were dried under reduced pressure to provide the title compound: LCMS m/z 268.00 [M+H] + ; 1 H NMR (400 MHz, CD 3 OD) δ 8.37 (s, 1 H), 7.90 (s, 1 H), 3.95 (s, 3 H), 2.61 – 2.53 (m, 1 H), 1.28 – 1.18 (m, 2 H), 1.15 – 1.09 (m, 2 H). Step B.5-cyclopropyl-6-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxa borolan-2-yl)pyrazolo[1,5- a]pyrimidine A mixture of 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-dioxaborola n-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), and potassium acetate (0.037 g, 0.373 mmol) in toluene (3.0 mL) was degassed and purged with nitrogen, and was then heated at 80 °C for 12 hours under nitrogen atmosphere. The reaction was then cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (3 x 30 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 to provide the title compound: LCMS m/z 316.18 [M+H] + . Step C.3-(2-bromo-5-fluoropyrimidin-4-yl)-5-cyclopropyl-6-methoxy pyrazolo[1,5-a]pyrimidine A mixture of 5-cyclopropyl-6-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxabo rolan-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. The 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. The resulting crude product was purified by flash chromatography on silica gel (0 – 100 % ethyl acetate in petroleum ether) to provide the title compound: LCMS m/z 364.01 [M+H] + ; 1 H NMR (400 MHz, CD 3 OD) δ 8.55 (s, 1 H), 8.53 (d, J = 1.8 Hz, 1 H), 8.47 (d, J = 3.1 Hz, 1 H), 4.02 – 4.00 (m, 3 H), 2.68 – 2.60 (m, 1 H), 1.37 – 1.33 (m, 3 H), 1.32 – 1.27 (m, 2 H). Step D. (3S,4S)-tert-butyl 3-((4-(5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidin-3-yl) -5- fluoropyrimidin-2-yl)amino)-4-fluoropiperidine-1-carboxylate A mixture of 3-(2-bromo-5-fluoro-pyrimidin-4-yl)-5-cyclopropyl-6-methoxy- pyrazolo[1,5- a]pyrimidine (0.020 g, 0.055 mmol), tert-butyl (3S,4S)-3-amino-4-fluoropiperidine-1- carboxylate (0.018 g, 0.082 mmol), [2-(2-aminophenyl)phenyl]-methylsulfonyloxy palladium[1- (2-diphenylphosphanyl-1-naphthyl)-2-naphthyl]-diphenylphosph ane (0.005 g, 0.005 mmol), (R)- (+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.005 g, 0.008 mmol), and cesium carbonate (0.054 g, 0.165 mmol) in 2-methylbutan-2-ol (1.5 mL) was degassed and purged with nitrogen, and was then heated at 80 °C for 6 hours under nitrogen atmosphere. The reaction was then cooled to room temperature, filtered, and concentrated under reduced pressure to provide the title compound: LCMS m/z 502.23 [M+H] + . Step E.4-(5-cyclopropyl-6-methoxypyrazolo[1,5-a]pyrimidin-3-yl)-5 -fluoro-N-((3S,4S)-4- fluoropiperidin-3-yl)pyrimidin-2-amine
To a solution of tert-butyl (3S,4S)-3-[[4-(5-cyclopropyl-6-methoxy-pyrazolo[1,5- a]pyrimidin-3-yl)-5-fluoro-pyrimidin-2-yl]amino]-4-fluoro-pi peridine-1-carboxylate (0.045 g, 0.090 mmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (0.50 mL, 0.778 g, 6.82 mmol). The resulting reaction was stirred at room temperature for 1 hour, and was then filtered and concentrated under reduced pressure. The crude product thus obtained was purified by HPLC (Phenomenex Luna C18 column, 3 micron, 75 x 30 mm; 10 – 40% acetonitrile in water containing 0.1% TFA) to provide the title compound: LCMS m/z 402.18 [M+H] + ; 1 H NMR (400 MHz, CD 3 OD) δ 8.51 (s, 1 H), 8.48 (d, J = 1.6 Hz, 1 H), 8.26 (d, J = 3.3 Hz, 1 H), 4.99 (dt, J = 3.5, 7.1 Hz, 1 H), 4.55 – 4.48 (m, 1 H), 4.00 (s, 3 H), 3.60 (td, J = 3.5, 12.9 Hz, 1 H), 3.42 (td, J = 4.4, 8.5 Hz, 1 H), 3.35 (br d, J = 7.1 Hz, 1 H), 3.22 (ddd, J = 4.1, 8.3, 12.8 Hz, 1 H), 2.68 – 2.61 (m, 1 H), 2.49 – 2.35 (m, 1 H), 2.19 – 2.05 (m, 1 H), 1.32 – 1.26 (m, 2 H), 1.20 – 1.12 (m, 2 H). Table 10. Additional compounds prepared according to Example 12. 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. Unlike kinase binding assays that measure competition for ATP, the HotSpot Kinase Assay is a functional assay that measures catalytic activity; as such it measures relative functional potency regardless of the mechanism of enzyme inhibition. This assay uses the form of the various enzymes that are easiest to express, which may not necessarily be the form of the enzyme that exist in the cell. (Sometimes the carboxy terminus has been truncated to aid in expression, or, if it is a receptor kinase, the enzyme itself is isolated from the other parts of the receptor that are involved in regulating kinase activity.) 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. 2) Any required cofactors were delivered to the substrate solution above. 3) Kinase was delivered into the substrate solution and gently mixed. 4) Compounds were delivered in 100% DMSO into the kinase reaction mixture by Acoustic technology (Echo550; nanoliter range), followed by incubation for 20 min at room temp. 5) 33 P-ATP was delivered into the reaction mixture to initiate the reaction. 6) The mixture was incubated for 2 hours at room temperature. 7) Kinase activity was detected by P81 filter-binding method. Table 11. Biological data obtained in accordance with the protocol described in Example 13. 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. Unlike other kinase competitive binding site assays, KINOMEscan ® assays do not require ATP. As a result, 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. 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 μM 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. Biological data obtained in accordance with the protocol described in Example 14. Table 13. Biological data obtained in accordance with the protocol described in Example 14. Example 15 Biological Data for Exemplary Compounds Kinase cellular potency data were obtained for various exemplary compounds prepared according to Examples 1-8 using the Reaction Biology NanoBRET assay protocol described below. The NanoBRET assay measures kinase engagement in real time in the context of the intact cell. Unlike the previously described biochemical kinase assay 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. As such, the assay provides a more relevant assessment of kinase potency and selectivity that would be expected to be observed in the native cellular environment, where potency is often considerably lower than that observed in the isolated biochemical assays (Vasta, J.D. et al., (2018) Cell Chem. Biol.25, 206-214). The assay uses a Kinase-NanoLuc ® fusion vector expressing a kinase protein to which a luciferase tag has been added, a cell-permeant fluorescent NanoBRET™ tracer, a NanoLuc ® substrate, and an extracellular NanoLuc ® inhibitor. Upon expression of the luciferase-tagged kinase, cells will produce a strong BRET signal only in the presence of the NanoBRET™ tracer. The extracellular NanoLuc ® inhibitor ensures that the BRET signal observed emanates only from live cells. Because the BRET signal has tight distance constraints, addition of the test compound will decrease the BRET signal if the compound competes with the NanoBRET™ tracer for binding to the kinase domain. Under the appropriate tracer conditions established by the manufacturer, quantitative intracellular affinity and relative potency can then be determined using Mass Action model equations. 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)]. The IC 50 values of compounds were calculated with Prism GraphPad program. NanoBRET™ Target Engagement Assay Protocol 1. Transient Transfection of HEK-293 Cells NanoLuc® Fusion Vector DNA 1). Cultivate HEK-293 cells (70-80% confluence) appropriately prior to assay. Trypsinize and collect HEK-293 cells. 2). Prepare lipid: DNA complexes as follows: a. Prepare a 10 μg/ml solution of DNA in Opti-MEM without serum that consists of the following ratios of carrier DNA and DNA encoding NanoLuc® fusion.9.0 μg/mL of Transfection Carrier DNA, 1.0 μg/mL of NanoLuc fusion vector DNA and 1 mL of Opti- MEM without phenol red. Mix thoroughly. b. Add 30 μl of FuGENE HD Transfection Reagent into each milliliter of DNA mixture to form lipid: DNA complex. c. Mix by inversion 10 times. d. Incubate at ambient temperature for 20 minutes to allow complexes to form. 3). In a sterile, conical tube, mix 1 part of lipid:DNA complex with 20 parts of HEK-293 cells in suspension. Mix gently by inversion 5 times. 4). Dispense cells + lipid: DNA complex into a sterile tissue culture dish and incubate for 22-24 hours. 2. Addition of Test Compounds (dry plate shooting) Each test compound is delivered from the compound source plate to the wells of 384-well white NBS plate by Echo 550. 3. Preparation of Cells with NanoBRET™ Tracer Reagent 1). Remove medium from dish with transfected HEK-293 cells via aspiration, trypsinize and allow cells to dissociate from the dish. 2). Neutralize trypsin using medium containing serum and centrifuge at 200 × g for 5 minutes to pellet the cells. Adjust the cell density to 2 × 105 cells/mL in Opti-MEM without phenol red. 3). Prepare Complete 20X NanoBRET™ Tracer Reagent with Tracer Dilution Buffer. 4). Dispense one part of Complete 20X NanoBRET™ Tracer Reagent to 20 parts of cells in the tube. Mix gently by inversion 10 times. 5). Dispense cell suspension into white, 384-well NBS plates. Incubate the plate at 37 °C, 5% CO 2 for 1 hour. Note: Prepare a separate set of samples without tracer for background correction steps. 4. NanoBRET™ Assay 1). Remove plate from incubator and equilibrate to room temperature for 15 minutes. 2). Prepare 3X Complete Substrate plus Inhibitor Solution in Assay Medium (Opti- MEMR I Reduced Serum Medium, no phenol red) just before measuring BRET. 3). Add 3X Complete Substrate plus Inhibitor Solution to each well of the 384-well plate. Incubate for 2–3 minutes at room temperature. 4). Measure donor emission wavelength (460 nm) and acceptor emission wavelength (600 nm) using the Envision 2104 plate reader. 5. Determination of BRET Ratio To generate raw BRET ratio values, divide the acceptor emission value (600 nm) by the donor emission value (460 nm) for each sample. To correct for background, subtract the BRET ratio in the absence of tracer (average of no-tracer control samples) from the BRET ratio of each sample. NanoBRET™ ratio equation: BRET Ratio = (Acceptor sample ÷ Donor sample) NanoBRET™ ratio equation, including optional background correction: BRET Ratio = [(Acceptor sample ÷ Donor sample) – (Acceptor no-tracer control ÷ Donor no-tracer control)] Normalized Bret Response equation (%): (BRET Ratio of Compound Treated Sample/BRET Ratio of DMSO Control Sample)*100% 6. Determination of IC 50 Values IC 50 curves are plotted and IC 50 values are calculated using the GraphPad Prism 4 program based on a sigmoidal dose-response equation. Table 14. Biological data obtained in accordance with the protocol described in Example 15. 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. Because THP-1 cells do not contain activated FLT3 receptors, measurement of the ability of a FLT3/IRAK1/IRAK4 inhibitor compound to inhibit the NF-kB production reflects the ability to inhibit signaling downstream of blocking signaling through the IRAK1/4 complex, and is not a composite measurement of activity that includes FLT3 kinase inhibition. THP-1-Blue NF-κB cells (InvivoGen) carrying a stable integrated NF-κB-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 μM or 3 μM) with a final volume of 200 μL for 24 hours at 37 °C. After 24 hours, the cells were centrifuged and 20 μL supernatant was incubated with 180 μL QUANTI-Blue reagent at 37 °C for 30 – 60 minutes. The levels of NF-κB-induced was measured in a microplate reader at 620 nm. Table 15. Biological data obtained in accordance with the protocol described in Example 16. Example 17 Biological Data for Exemplary Compounds Cellular potency data were obtained for various exemplary compounds prepared according to Examples 1-8 using the MOLM14 D835Y and MOLM14 F691L cell viability assay protocols described below. Both cell lines have activated FLT3 receptors, each of which carry additional resistance mutations in the kinase domain (D835Y and F691L, respectively). Leukemias from patients harboring these kinase domain resistance mutations are resistant to FLT3 inhibitors that do not inhibit the mutant kinase. Because the activated FLT3 receptor drives a mitogenic response, and because there can be a discrepancy between activity in the biochemical kinase assay and in the context of a whole cell (Vasta, J.D. et al., (2018) Cell Chem. Biol.25, 206-214), demonstration of antiproliferative activity in these cell lines with compounds known to inhibit the D835Y or F691L kinases in biochemical assays provides a more relevant cellular context for demonstration of activity. MOLM14 D835Y and MOLM14 F691L cells were grown in RPMI-1640 media supplemented with 20% fetal bovine serum (FBS). For viability/cytotoxicity assessments, cells were seeded into 1536-well white polystyrene tissue culture-treated Greiner plates using a Multidrop Combi dispenser (ThermoFisher), in final volume 5 μL of growth media per well, at a density of 1000 cells per well. After cell addition, 23 nL of test compound were transferred into individual wells (22 doses tested for each test compound, with a 1:2 dilution series starting at 10 μM) via a 1536 pin-tool. Bortezomib (final concentration 2.3 μM) was used as a positive control for cell cytotoxicity. Plates were incubated for 48 hours at standard incubator conditions covered by a stainless steel gasketed lid to prevent evaporation.48 hours post compound addition, 3 μL of Cell Titer Glo (Promega) were added to each well and plates were incubated at room temperature for 15 minutes with the stainless-steel lid in place. Luminescence readings were taken using a Viewlux imager (PerkinElmer) with a 2 second exposure time per plate. Table 16. Biological data obtained in accordance with the protocol described in Example 17. 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. Unlike kinase binding assays that measure competition for ATP, the HotSpot Kinase Assay is a functional assay that measures catalytic activity; as such it measures relative functional potency regardless of the mechanism of enzyme inhibition. This assay uses the form of the various enzymes that are easiest to express, which may not necessarily be the form of the enzyme that exist in the cell. 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. 4) Compounds were delivered in 100% DMSO into the kinase reaction mixture by Acoustic technology (Echo550; nanoliter range), followed by incubation for 20 min at room temp. 5) 33 P-ATP was delivered into the reaction mixture to initiate the reaction. 6) The mixture was incubated for 2 hours at room temperature. 7) Kinase activity was detected by P81 filter-binding method. The data obtained are shown in Table 17. Table 17. Biological data obtained in accordance with the protocol described in Example 18. Example 19 Biological Data for Exemplary Compounds Kinase binding data were obtained for various exemplary compounds prepared according to Examples 9-12 using the DiscoverX KINOMEscan ® active site-directed competition binding site-directed assay protocol described below. Unlike other kinase competitive binding site assays, KINOMEscan ® assays do not require ATP. As a result, 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 μM 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 data obtained is shown in Tables 18 and 19. Table 18. Biological data obtained in accordance with the protocol described in Example 19. Table 19. Biological data obtained in accordance with the protocol described in Example 19. Example 20 Biological Data for Exemplary Compounds Kinase cellular potency data were obtained for various exemplary compounds prepared according to Examples 9-12, using the Reaction Biology NanoBRET assay protocol described below. The NanoBRET assay measures kinase engagement in real time in the context of the intact cell. Unlike the previously described biochemical kinase assay methodologies in Examples 5 and 6, the NanoBRET assay measures the binding and activity characteristics under equilibrium conditions using full-length kinases in the presence of cellular concentrations of ATP in live, uncompromised cells. As such, the assay provides a more relevant assessment of kinase potency and selectivity that would be expected to be observed in the native cellular environment, where potency is often considerably lower than that observed in the isolated biochemical assays (Vasta, J.D. et al., (2018) Cell Chem. Biol.25, 206-214). The assay uses a Kinase-NanoLuc ® fusion vector expressing a kinase protein to which a luciferase tag has been added, a cell-permeant fluorescent NanoBRET™ tracer, a NanoLuc ® substrate, and an extracellular NanoLuc ® inhibitor. Upon expression of the luciferase-tagged kinase, cells will produce a strong BRET signal only in the presence of the NanoBRET™ tracer. The extracellular NanoLuc ® inhibitor ensures that the BRET signal observed emanates only from live cells. Because the BRET signal has tight distance constraints, addition of the test compound will decrease the BRET signal if the compound competes with the NanoBRET™ tracer for binding to the kinase domain. Under the appropriate tracer conditions established by the manufacturer, quantitative intracellular affinity and relative potency can then be determined using Mass Action model equations. 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)]. The IC 50 values of compounds were calculated with Prism GraphPad program. NanoBRET™ Target Engagement Assay Protocol 1. Transient Transfection of HEK-293 Cells NanoLuc® Fusion Vector DNA 1). Cultivate HEK-293 cells (70-80% confluence) appropriately prior to assay. Trypsinize and collect HEK-293 cells. 2). Prepare lipid: DNA complexes as follows: a. Prepare a 10 μg/ml solution of DNA in Opti-MEM without serum that consists of the following ratios of carrier DNA and DNA encoding NanoLuc® fusion.9.0 μg/mL of Transfection Carrier DNA, 1.0 μg/mL of NanoLuc fusion vector DNA and 1 mL of Opti-MEM without phenol red. Mix thoroughly. b. Add 30 μl of FuGENE HD Transfection Reagent into each milliliter of DNA mixture to form lipid: DNA complex. c. Mix by inversion 10 times. d. Incubate at ambient temperature for 20 minutes to allow complexes to form. 3). In a sterile, conical tube, mix 1 part of lipid: DNA complex with 20 parts of HEK-293 cells in suspension. Mix gently by inversion 5 times. 4). Dispense cells + lipid: DNA complex into a sterile tissue culture dish and incubate for 22-24 hours. 2. Addition of Test Compounds (dry plate shooting) Each test compound is delivered from the compound source plate to the wells of 384-well white NBS plate by Echo 550. 3. Preparation of Cells with NanoBRET™ Tracer Reagent 1). Remove medium from dish with transfected HEK-293 cells via aspiration, trypsinize and allow cells to dissociate from the dish. 2). Neutralize trypsin using medium containing serum and centrifuge at 200 × g for 5 minutes to pellet the cells. Adjust the cell density to 2 × 10 5 cells/mL in Opti-MEM without phenol red. 3). Prepare Complete 20X NanoBRET™ Tracer Reagent with Tracer Dilution Buffer. 4). Dispense one part of Complete 20X NanoBRET™ Tracer Reagent to 20 parts of cells in the tube. Mix gently by inversion 10 times. 5). Dispense cell suspension into white, 384-well NBS plates. Incubate the plate at 37 °C, 5% CO2 for 1 hour. Note: Prepare a separate set of samples without tracer for background correction steps. 4. NanoBRET™ Assay 1). Remove plate from incubator and equilibrate to room temperature for 15 minutes. 2). Prepare 3X Complete Substrate plus Inhibitor Solution in Assay Medium (Opti- MEMR I Reduced Serum Medium, no phenol red) just before measuring BRET. 3). Add 3X Complete Substrate plus Inhibitor Solution to each well of the 384-well plate. Incubate for 2–3 minutes at room temperature. 4). Measure donor emission wavelength (460 nm) and acceptor emission wavelength (600 nm) using the Envision 2104 plate reader. 5. Determination of BRET Ratio To generate raw BRET ratio values, divide the acceptor emission value (600 nm) by the donor emission value (460 nm) for each sample. To correct for background, subtract the BRET ratio in the absence of tracer (average of no-tracer control samples) from the BRET ratio of each sample. NanoBRET™ ratio equation: BRET Ratio = (Acceptor sample ÷ Donor sample) NanoBRET™ ratio equation, including optional background correction: BRET Ratio = [(Acceptor sample ÷ Donor sample) – (Acceptor no-tracer control ÷ Donor no-tracer control)] Normalized Bret Response equation (%): (BRET Ratio of Compound Treated Sample/BRET Ratio of DMSO Control Sample) *100% 6. Determination of IC 50 Values IC 50 curves are plotted and IC 50 values are calculated using the GraphPad Prism 4 program based on a sigmoidal dose-response equation. The results are shown in Table 20. Table 20. Biological data obtained in accordance with the protocol described in Example 20. 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. Because THP-1 cells do not contain activated FLT3 receptors, measurement of the ability of a FLT3/IRAK1/IRAK4 inhibitor compound to inhibit the NF-kB production reflects the ability to inhibit signaling downstream of blocking signaling through the IRAK1/4 complex and is not a composite measurement of activity that includes FLT3 kinase inhibition. THP-1-Blue NF-κB cells (InvivoGen) carrying a stable integrated NF-κB-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. After 24 hours, the cells were centrifuged and 20 mL supernatant was incubated with 180 mL QUANTI-Blue reagent at 37 °C for 30 – 60 minutes. The levels of NF-κB-induced gene expression were measured in a microplate reader at 620 nm. The data obtained is shown in Table 21. Table 21. Biological data obtained in accordance with the protocol described in Example 21. Example 22 Biological Data for Exemplary Compounds Cellular potency data were obtained for various exemplary compounds prepared according to Examples 9-12, using the MOLM14 D835Y cell viability assay protocols described below. This cell line has activated FLT3 receptors, which carries an additional resistance mutation in the kinase domain at D835Y. Leukemias from patients harboring this kinase domain resistance mutation are resistant to FLT3 inhibitors that do not inhibit the mutant kinase. Because the activated FLT3 receptor drives a mitogenic response, and because there can be a discrepancy between activity in the biochemical kinase assay and in the context of a whole cell (Vasta, J.D. et al., (2018) Cell Chem. Biol.25, 206-214), demonstration of antiproliferative activity in this cell line with compounds known to inhibit the D835Y kinase in biochemical assays provides a more relevant cellular context for demonstration of activity. MOLM14 D835Y cells were grown in RPMI-1640 media supplemented with 20% fetal bovine serum (FBS). For viability/cytotoxicity assessments, cells were seeded into 1536-well white polystyrene tissue culture-treated Greiner plates using a Multidrop Combi dispenser (ThermoFisher), in final volume 5 mL 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 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. 48 hours post compound addition, 3 mL of Cell Titer Glo (Promega) were added to each well and plates were incubated at room temperature for 15 minutes with the stainless-steel lid in place. Luminescence readings were taken using a Viewlux imager (PerkinElmer) with a 2 second exposure time per plate. The data obtained in shown in Table 22. Table 22. Biological data obtained in accordance with the protocol described in Example 22. Example 23 Combination Drug Screening for Exemplary Compounds Combination drug therapy has the potential to produce enhanced effects with lower side effects not obtained using either agent alone, or beyond the additive effect of the different concentrations of the two different agents. To determine whether enhanced effects are observed in different drug combinations, combination drug screening was performed as previously described (Mathews-Griner, L. A. et al., Proc. Nat. Acad. Sci., 2014, 111: 2349-2354; Lin, G. L. et al., Sci. Trans. Med., 2019, 11:eaaw0064). Briefly, 10 nL of compounds were acoustically dispensed into 1536-well white polystyrene tissue culture-treated plates with an Echo 550 acoustic liquid handler (Labcyte). Cells were then added to compound-containing plates at a density of 500-cells/well in 5 μL of medium. A 10-point custom concentration range was used for all listed drugs in a 10 x 10 matrix. Plates were incubated for 48 hours at standard incubator conditions covered by a stainless steel gasketed lid to prevent evaporation. 48 hours post compound addition, 3 μL of Cell Titer Glo (Promega) were added to each well and plates were incubated at room temperature for 15 minutes with the stainless-steel lid in place. Luminescence readings were taken using a Viewlux imager (PerkinElmer) with a 2 second exposure time per plate. Each compound was studied in combination with venetoclax at two concentration ranges of compound and venetoclax, respectively (for a total of 4 combination dose-response curves). The dose combinations that yielded the optimal synergy score, measured as excess HSA, which are reported in Tables 23 and 24 for the FLT3 mutant cell line MOLM14 (D835Y) and the FLT3 WT cell line THP1, respectively. The results demonstrate that synergy is seen in both the FLT3 mutant setting (MOLM14 (D835Ycells)) and the FLT3 WT setting (THP1 cells). Table 23 provides combination outcomes for representative compounds with venetoclax in the Cell Titer Glo assay in MOLM14 (D835Y) cells (a FLT3 mutant cell line) 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. Table 23. Excess HSA scores for a combination therapy of compounds of the disclosure with venetoclax compared to gilteritinib hemifumarate obtained in MOLM14 (D835Y) cells in a 10 x 10 dataset 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. Furthermore, in the FLT3 mutant 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. C. et al., Drug Discovery Today, 2019, 24(12):2286-2298. While there are other methods of quantitating drug interactions, excess HSA method is preferred because it does not require making assumptions about similarities in the mechanism of action of the drugs involved or the shape of the dose-response curves being compared and does not place arbitrary requirements on the computational algorithm that the two drugs produce similar efficacy in the given system. However, different methodologies may yield different numerical scores, and different definitions of what constitutes a deviation from mere additivity vs true drug synergy. The large negative excess HSA values provided in Tables 23 and 24 illustrate that multiple members of this structural class synergize with venetoclax. The degree to which combination therapy has to potential to produce enhanced effects with lower side effects not obtained using either agent alone, or beyond the additive effect of the different concentrations of the two different agents depends on the nature of the drugs used in the combination, and the specific doses/concentrations at which they are ultimately used in the therapeutic regimen. A negative excess HSA score illustrates that the drug combination is better than either drug alone (at the concentrations being studied). Hence, the drug combinations that are noteworthy as having more profound synergistic effects are those with greater negative excess HSA scores. However, the utility in certain drug combinations vs. others should not be distinguished based on cutoffs between excess HSA scores, because the score itself is only a relative indicator that is completely dependent on experimental design and is not an absolute number. Furthermore, the concept of what constitutes clinically meaningful drug synergy is something that is still being debated, not only between pharmacologists and physicians, but amongst pharmacologists themselves. The data in Tables 23 and 24 illustrate that the nature of the combined effect is dependent on the characteristics of each individual compound as well as the characteristics of the cell line itself and the concentration ranges in which the synergy is evaluated. It is noted that terms like “preferably,” “commonly,” and “typically” are not used herein to limit the scope of the claimed disclosure or to imply that certain features are critical, essential, or even important to the structure or function of the claimed disclosure. Rather, these terms are merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment of the present disclosure. The various methods and techniques described above provide a number of ways to carry out the disclosure. Of course, it is to be understood that not necessarily all objectives or advantages described can be achieved in accordance with any particular embodiment described herein. Thus, for example, those skilled in the art will recognize that the methods can be performed in a manner that achieves or optimizes one advantage or group of advantages as taught herein without necessarily achieving other objectives or advantages as taught or suggested herein. A variety of alternatives are mentioned herein. It is to be understood that some preferred embodiments specifically include one, another, or several features, while others specifically exclude one, another, or several features, while still others mitigate a particular feature by inclusion of one, another, or several advantageous features. Furthermore, the skilled artisan will recognize the applicability of various features from different embodiments. Similarly, the various elements, features and steps discussed above, as well as other known equivalents for each such element, feature or step, can be employed in various combinations by one of ordinary skill in this art to perform methods in accordance with the principles described herein. Among the various elements, features, and steps some will be specifically included and others specifically excluded in diverse embodiments. Although the application has been disclosed in the context of certain embodiments and examples, it will be understood by those skilled in the art that the embodiments of the disclosure extend beyond the specifically disclosed embodiments to other alternative embodiments and/or uses and modifications and equivalents thereof. In some embodiments, the numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth, used to describe and claim certain embodiments of the application are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the application are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. In some embodiments, the terms “a” and “an” and “the” and similar references used in the context of describing a particular embodiment of the application (especially in the context of certain of the following claims) can be construed to cover both the singular and the plural. The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (for example, “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the application and does not pose a limitation on the scope of the application otherwise claimed. As used in the disclosure or claims, “another” means at least a second or more, unless otherwise specified. As used in the disclosure, the phrases “such as,” “for example,” and “e.g.” mean “for example, but not limited to” in that the list following the term (“such as,” “for example,” or “e.g.”) provides some examples but the list is not necessarily a fully inclusive list. The word “comprising” means that the items following the word “comprising” may include additional unrecited elements or steps; that is, “comprising” does not exclude additional unrecited steps or elements. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the application. In certain instances, sequences disclosed herein are included in publicly available databases, such as GENBANK ® and SWISSPROT. Unless otherwise indicated or apparent the references to such publicly available databases are references to the most recent version of the database as of the filing date of this Application. Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and claims are approximations that can vary depending upon the desired properties sought to be obtained by the presently- disclosed subject matter. As used herein, the term “about,” when referring to a value or to an amount of mass, weight, time, volume, concentration or percentage is meant to encompass variations of in some embodiments ±20%, in some embodiments ±10%, in some embodiments ±5%, in some embodiments ±1%, in some embodiments ±0.5%, and in some embodiments ±0.1% from the specified amount, as such variations are appropriate to perform the disclosed method. Preferred embodiments of this application are described herein. Variations on those preferred embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. It is contemplated that skilled artisans can employ such variations as appropriate, and the application can be practiced otherwise than specifically described herein. Accordingly, many embodiments of this application include all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the application unless otherwise indicated herein or otherwise clearly contradicted by context. All patents, patent applications, publications of patent applications, and other material, such as articles, books, specifications, publications, documents, things, and/or the like, referenced herein are hereby incorporated herein by this reference in their entirety for all purposes, excepting any prosecution file history associated with same, any of same that is inconsistent with or in conflict with the present document, or any of same that may have a limiting affect as to the broadest scope of the claims now or later associated with the present document. By way of example, should there be any inconsistency or conflict between the description, definition, and/or the use of a term associated with any of the incorporated material and that associated with the present document, the description, definition, and/or the use of the term in the present document shall prevail. In closing, it is to be understood that the embodiments of the application disclosed herein are illustrative of the principles of the embodiments of the disclosure. Other modifications that can be employed can be within the scope of the application. Thus, by way of example, but not of limitation, alternative configurations of the embodiments of the application can be utilized in accordance with the teachings herein. Accordingly, embodiments of the present application are not limited to that precisely as shown and described.
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