BACKGROUND

Several compounds are known to treat cancer, but do so inadequately. Some known compounds, such as Quizartinib and Cremolanib, can be used to treat Acute Myeloid Leukemia (AML). Some of these treatments do not result in complete remission or partial remission. In some instances, treatment can result in mutations that are resistant to inhibitors. Several compounds are known to treat blood disorders (e.g., Myelodysplastic syndromes (MDS)), but do so inadequately. Certain embodiments of the invention can address one or more of these deficiencies.

Some embodiments of the invention include inventive compounds (e.g., compounds of Formula (I)). Other embodiments include compositions (e.g., pharmaceutical compositions) comprising the inventive compound. Still other embodiments of the invention include compositions (e.g., pharmaceutical compositions) for treating, for example, certain diseases using the inventive compounds. Some embodiments include methods of using the inventive compound (e.g., in compositions or in pharmaceutical compositions) for administering and treating (e.g., diseases such as cancer or blood disorders). Further embodiments include methods for making the inventive compounds. Additional embodiments of the invention are also discussed herein.

SUMMARY

Some embodiments of the present invention include a compound selected from Formula (I)


salts, optical isomers, geometric isomers, salts of isomers, and derivatives thereof. In some embodiments, R1is H, halogen, hydroxy, C1-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, or C1-C6alkoxy, which C1-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, or C1-C6alkoxy is optionally substituted with one or more of halogen, hydroxy, methanoyl (—COH), carboxy (—CO2H), nitro (—NO2), cyano (—CN), ethynyl (—CCH), sulfo (—SO3H), methyl, ethyl, or morpholinyl; R2is H, halogen, hydroxy, —CN, methanoyl (—COH), carboxy (—CO2H), C1-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, C1-C6alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, which methanoyl (—COH), carboxy (—CO2H), C1-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, C2-C6alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more of halogen, hydroxy, methanoyl (—COH), carboxy (—CO2H), nitro (—NO2), —NH2, —N(CH3)2, cyano (—CN), ethynyl (—CCH), propynyl, sulfo (—SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, —CO-morpholin-4-yl, —CONH2, —CON(CH3)2, C1-C3alkyl, C1-C3perfluoronated alkyl, or C1-C3alkoxy; R3is H, halogen, hydroxy, C1-C3alkyl, C2-C3alkenyl, C2-C3alkynyl, or C1-C2alkoxy, which C1-C3alkyl, C2-C3alkenyl, C2-C3alkynyl, or C1-C2alkoxy is optionally substituted with one or more of halogen, hydroxy, methanoyl (—COH), carboxy (—CO2H), cyano (—CN), ethynyl (—CCH), sulfo (—SO3H), methyl, or ethyl; R4is H, halogen, hydroxy, methanoyl (—COH), carboxy (—CO2H), nitro (—NO2), cyano (—CN), sulfo (—SO3H), C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, or C1-C3alkoxy, which C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, or C1-C3alkoxy is optionally substituted with one or more of halogen, hydroxy, methanoyl (—COH), carboxy (—CO2H), nitro (—NO2), cyano (—CN), ethynyl (—CCH), sulfo (—SO3H), methyl, or ethyl; R5is H, halogen, hydroxy, methanoyl (—COH), carboxy (—CO2H), nitro (—NO2), cyano (—CN), sulfo (—SO3H), C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, or C1-C3alkoxy, which C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, or C1-C3alkoxy is optionally substituted with one or more of halogen, hydroxy, methanoyl (—COH), carboxy (—CO2H), nitro (—NO2), cyano (—CN), ethynyl (—CCH), sulfo (—SO3H), methyl, or ethyl; R6is H, halogen, hydroxy, methanoyl (—COH), carboxy (—CO2H), nitro (—NO2), cyano (—CN), sulfo (—SO3H), C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, or C1-C3alkoxy, which C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, or C1-C3alkoxy is optionally substituted with one or more of halogen, hydroxy, methanoyl (—COH), carboxy (—CO2H), nitro (—NO2), cyano (—CN), ethynyl (—CCH), sulfo (—SO3H), methyl, or ethyl; Y is


R7is


R8; R8is H, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, methanoyl (—COH), ethanoyl (—COCH3), benzoyl (—COC6H5), toluoyl, carboxy (—CO2H), nitro (—NO2), cyano (—CN), or —COCH2CN; n is 0, 1, 2, 3, 4, or 5; m is 0, 1, 2, 3, 4, or 5; and n+m is at least 1. In some embodiments, R1is H, halogen, hydroxy, C1-C7alkyl, or C1-C6alkoxy, which C1-C7alkyl or C1-C6alkoxy is optionally substituted with one or more of halogen, hydroxy, methanoyl (—COH), carboxy (—CO2H), nitro (—NO2), cyano (—CN), ethynyl (—CCH), sulfo (—SO3H), methyl, or ethyl, or morpholinyl. In other embodiments, R1is Cl, methyl, 2-(morpholinyl)ethoxy, or —OCH3. In yet other embodiments, R1is not H. In some embodiments, R2is H, halogen, hydroxy, —CN, methanoyl (—COH), carboxy (—CO2H), C1-C7alkyl, C1-C6alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, which methanoyl (—COH), carboxy (—CO2H), C1-C7alkyl, C2-C6alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more of halogen, hydroxy, methanoyl (—COH), carboxy (—CO2H), nitro (—NO2), —NH2, —N(CH3)2, cyano (—CN), ethynyl (—CCH), propynyl, sulfo (—SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, —CO-morpholin-4-yl, —CONH2, —CON(CH3)2, C1-C3alkyl, C1-C3perfluoronated alkyl, or C1-C3alkoxy. In certain embodiments, R2is —CO-morpholin-4-yl, —CON(CH3)2, Cl, methyl, —CN, ethynyl, —CONH2, —CON(CH3)2, 2-(morpholinyl)ethoxy, ethoxy, methoxy, 1H-pyrazol-4-yl, 1-methyl-pyrazol-4-yl, 1-(morpholin-4-yl)-pyrazol-4-yl, pyridin-3-yl, 2-methoxy-pyridin-5-yl, pyridin-4-yl, 3,5-dimethylisoxazol-4-yl, 1H-pyrrol-3-yl, 3,5-(di-methyl)-pyrazolyl, pyrazol-3-yl, 5-tetrazolyl, 1H-pyrazol-4-yl, 4-ethyl-piperazin-1-yl, perfluorinated methyl, or perfluorinated ethyl. In still other embodiments, R2is not H. In certain embodiments, R3is H, halogen, hydroxy, C1-C3alkyl, or C1-C2alkoxy, which C1-C3alkyl or C1-C2alkoxy can optionally be substituted with one or more of halogen, hydroxy, methanoyl (—COH), carboxy (—CO2H), cyano (—CN), ethynyl (—CCH), sulfo (—SO3H), methyl, or ethyl. In other embodiments, R3is H, methoxy, which methoxy is optional substituted with one, two, or three halogen. In still other embodiments, R3is H or methoxy. In some embodiments, R4is H, halogen, hydroxy, methanoyl (—COH), carboxy (—CO2H), nitro (—NO2), cyano (—CN), sulfo (—SO3H), C1-C4alkyl, or C1-C3alkoxy, which C1-C4alkyl or C1-C3alkoxy is optionally substituted with one or more of halogen, hydroxy, methanoyl (—COH), carboxy (—CO2H), nitro (—NO2), cyano (—CN), ethynyl (—CCH), sulfo (—SO3H), methyl, or ethyl. In other embodiments, R4is F, Cl, Br, methyl, perfluorinated methyl, or methoxy. In some embodiments, R5is H, halogen, hydroxy, methanoyl (—COH), carboxy (—CO2H), nitro (—NO2), cyano (—CN), sulfo (—SO3H), C1-C4alkyl, or C1-C3alkoxy, which C1-C4alkyl or C1-C3alkoxy is optionally substituted with one or more of halogen, hydroxy, methanoyl (—COH), carboxy (—CO2H), nitro (—NO2), cyano (—CN), ethynyl (—CCH), sulfo (—SO3H), methyl, or ethyl. In other embodiments, R5is F, Cl, Br, methyl, ethyl, or methoxy. In some embodiments, R6is H, halogen, hydroxy, methanoyl (—COH), carboxy (—CO2H), nitro (—NO2), cyano (—CN), sulfo (—SO3H), C1-C4alkyl, or C1-C3alkoxy, which C1-C4alkyl or C1-C3alkoxy can optionally be substituted with one or more of halogen, hydroxy, methanoyl (—COH), carboxy (—CO2H), nitro (—NO2), cyano (—CN), ethynyl (—CCH), sulfo (—SO3H), methyl, or ethyl. In other embodiments, R6is F, Cl, Br, methyl, perfluorinated methyl, or methoxy. In some embodiments, Y is


In other embodiments, Y is


In some embodiments, R7is piperid-2-yl, piperid-3-yl, piperid-4-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, or azetidyl. In certain embodiments, R8is H, ethanoyl (—COCH3), benzoyl (—COC6H5), ethynyl (—CCH), or —COCH2CN. In some instances, n is 1, 2, or 3. In other instances, m is 1, 2, or 3.

In some embodiments, the compound is I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22, I-23, I-24, I-25, I-26, I-27, I-28, I-29, I-30, I-31, I-32, I-33, I-34, I-35, I-36, I-37, I-38, I-39, I-40, I-41, I-42, I-43, I-44, I-45, I-46, I-47, I-48, I-49, I-50, I-51, I-52, I-53, I-54, I-55, I-56, I-57, I-58, I-59, I-60, I-61, I-62, I-63, I-64, I-65, I-66, I-67, or I-68. In other embodiments, the compound is I-20, I-21, I-22, I-23, I-24, I-25, I-26, I-27, I-28, I-29, I-30, I-31, I-32, I-33, I-34, I-35, I-36, I-37, I-38, I-39, I-40, I-41, I-42, I-43, I-44, I-45, I-46, I-47, I-48, I-49, I-50, I-51, I-52, I-53, I-54, I-55, I-56, I-57, I-58, I-59, I-60, I-61, I-62, I-63, I-64, I-65, I-66, I-67, or I-68. In yet other embodiments, the compound is I-2, I-15, I-20, I-22, I-24, I-26, I-27, I-42, I-53, or I-54. In still other embodiments, the compound is I-2, I-15, I-20, I-22, I-24, I-26, I-27, I-42, I-43, I-44, I-53, or I-54. In some instances, the compound is I-20, I-22, I-24, I-26, I-27, I-42, I-53, or I-54. In yet other instances, the compound is I-20, I-22, I-24, I-26, I-27, I-42, I-43, I-44, I-53, or I-54.

In some embodiments, if Y is —NH—; R1is H; R3is H; R4is H; R5is H; R6is H; and R8is H, then (a) R2is not H, Cl, methoxy, or CN, and (b) R7is not


In other embodiments, if Y is —NH—; R1is H; R3is H; R4is H; R5is H; R6is H; and R8is H, then (a) R2is not H, Cl, F, Br, I, methoxy, ethoxy, or CN, and (b) R7is not


In still other embodiments, if Y is —NH—; R1is H; R3is H; R4is H; R5is H; R6is H; and R8is H, then (a) R2can be hydroxy, methanoyl (—COH), carboxy (—CO2H), C1-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, C3-C6alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, which methanoyl (—COH), carboxy (—CO2H), C1-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, C3-C6alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl can optionally be substituted with one or more of halogen, hydroxy, methanoyl (—COH), carboxy (—CO2H), nitro (—NO2), —NH2, —N(CH3)2, cyano (—CN), ethynyl (—CCH), propynyl, sulfo (—SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, —CO-morpholin-4-yl, —CONH2, —CON(CH3)2, C1-C3alkyl, C1-C3perfluoronated alkyl, or C1-C3alkoxy, and (b) R7is not


In yet other embodiments, if Y is —NH—; R1is H; R3is H; R4is H; R5is H; R6is H; and R8is H, then (a) R2can be hydroxy, methanoyl (—COH), carboxy (—CO2H), C1-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, C5-C6alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, which methanoyl (—COH), carboxy (—CO2H), C1-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, C5-C6alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl can optionally be substituted with one or more of halogen, hydroxy, methanoyl (—COH), carboxy (—CO2H), nitro (—NO2), —NH2, —N(CH3)2, cyano (—CN), ethynyl (—CCH), propynyl, sulfo (—SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, —CO-morpholin-4-yl, —CONH2, —CON(CH3)2, C1-C3alkyl, C1-C3perfluoronated alkyl, or C1-C3alkoxy, and (b) R7is not


In certain embodiments, one or more of compounds I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, or I-19 are not included in Formula (I). In still other embodiments, compounds I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, and I-19 are not included in Formula (I).

Some embodiments of the invention include a composition comprising a compound, as disclosed herein (e.g., Formula (I)). In certain embodiments, the amount of the compound is from about 0.0001% (by weight total composition) to about 99%. In other embodiments, the composition further comprises a formulary ingredient, an adjuvant, or a carrier.

Some embodiments of the invention include a pharmaceutical composition comprising a compound, as disclosed herein (e.g., Formula (I)). In certain embodiments, the amount of the compound is from about 0.0001% (by weight total composition) to about 50%. In other embodiments, the pharmaceutical composition further comprises a formulary ingredient, an adjuvant, or a carrier.

Some embodiments of the invention include a method for providing an animal with a compound comprising one or more administrations of one or more compositions comprising a compound as disclosed here (e.g., Formula (I)), where the compositions may be the same or different if there is more than one administration. In other embodiments, at least one of the one or more compositions further comprises a formulary ingredient. In certain embodiments, at least one of the one or more compositions comprises any composition disclosed herein or any pharmaceutical composition disclosed herein. In still other embodiments, at least one of the one or more administrations comprises parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration. 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 other embodiments, the compound of at least one of the one or more compositions is administered to the animal in an amount of from about 0.01 mg/kg animal body weight to about 15 mg/kg animal body weight. In certain embodiments, the animal is a human, a rodent, or a primate.

Some embodiments, of the invention include a method for treating an animal for a disease, comprising one or more administrations of one or more compositions comprising any compound disclosed herein (e.g., Formula (I)), wherein the compositions may be the same or different if there is more than one administration. In some instances, at least one of the one or more compositions further comprises a formulary ingredient. In other embodiments, at least one of the one or more compositions comprises any composition disclosed herein or any pharmaceutical composition disclosed herein. In certain embodiments, at least one of the one or more administrations comprises parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration. In other 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 still other embodiments, the compound of at least one of the one or more compositions is administered to the animal in an amount of from about 0.005 mg/kg animal body weight to about 50 mg/kg animal body weight. In yet other embodiments, the animal is a human, a rodent, or a primate. In certain embodiments, the animal is in need of the treatment. In some embodiments, the method is for treating a blood disorder, MDS, cancer, or AML. In other embodiments, the method is for treating acute myeloid leukemia, lymphoma, leukemia, bone marrow cancer, non-Hodgkin lymphoma, or Waldenstrom's macroglobulinemia. In yet other embodiments, the method is for treating MDS, MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2. In certain embodiments, the animal is susceptible to ADL or MDS. In other embodiments, the method prevents or ameliorates future ADL or MDS. In some embodiments, the method occurs 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 cancer.

Some embodiments of the invention include a method for preparing any compound disclosed herein (e.g., Formula (I)) comprising,

(a) reacting a compound of Formula (II) with a compound of Formula (III) to result in a mixture comprising a compound of Formula (IV);

(b) reacting a compound of Formula (IV) with a compound of Formula (V) to result in a mixture comprising a compound of Formula (VI);

(c) optionally reacting a compound of Formula (VI) with a compound of Formula (VII) to result in a mixture comprising a compound of Formula (VIII);

(d) removing one or more protecting groups from a compound of Formula (VI) or from a compound of Formula (VIII); and

(e) recovering Formula (I),

where Formula (II) is


Formula (III) is


Formula (IV) is


Formula (IV) is


Formula (IV) is


Formula (VII) is R2Bpin (VII); and
Formula (VIII) is


In some embodiments, R1is an C1-C6alkoxy and the method further comprises (i) the step of reacting Formula (IV) to convert the C1-C6alkoxy at R1to hydroxy and (ii) the step of reacting the product of (i) to convert the hydroxy at R1to a morpholino-C1-C6-alkoxy; and steps (i) and (ii) occur after step (a) and before step (b). In other embodiments, in step (b), Y is not O. In yet other embodiments, in step (b), Y is O. In some embodiments, during step (d), at least one of the one or more protecting groups removed is -Boc. In still other embodiments, R2is a halogen and the method further comprises the step of reacting Formula (I) to convert the halogen at R2to C2-C7alkynyl, after step (d).

Other embodiments of the invention are also discussed herein.

