BACKGROUND

Some Ras protein mutations can give rise to cancer. Over 90% of pancreatic tumors appear to be associated with some Ras protein mutations. In certain instances, when Ras protein is bound by GTP, Ras guanine nucleotide exchange factors (RasGEFs) appear to activate Ras-like (Ral) proteins by promoting Ral protein binding to GTP. Activated Ral proteins can sometimes enhance the development of cancer, including tumorigenesis and metastasis. There are four members of the RalGEF family: Ral guanine nucleotide dissociation stimulator (RalGDS), RGL1, RGL2, and RGL3.

Several compounds are known to treat cancer, but do so inadequately. For example, many attempts to develop a clinically effective Ras inhibitor have failed. There appear to be no reported inhibitors of RalGEFs.

Certain embodiments of the invention address one or more of the deficiencies described above. For example, in some embodiments of the invention, inventive compounds such as Formula (I) are disclosed. In some embodiments, RalGEF inhibitors are disclosed. 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). 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, C1-C3alkyl, C2-C3alkenyl, or C2-C3alkynyl, which C1-C3alkyl, C2-C3alkenyl, or C2-C3alkynyl is optionally substituted with one or more of halogen, hydroxy (—OH), methanoyl (—COH), carboxy (—CO2H), ethynyl (—CCH), cyano (—CN), sulfo (—SO3H), methyl, or ethyl; R2is H, halogen, hydroxy (—OH), cyano (—CN), sulfo (—SO3H), 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 (—OH), methanoyl (—COH), carboxy (—CO2H), ethynyl (—CCH), cyano (—CN), sulfo (—SO3H), methyl, or ethyl; R3is H, halogen, hydroxy (—OH), cyano (—CN), sulfo (—SO3H), 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 (—OH), methanoyl (—COH), carboxy (—CO2H), ethynyl (—CCH), cyano (—CN), sulfo (—SO3H), methyl, or ethyl; R4is H, halogen, —CN, hydroxy (—OH), 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, C1-C6alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more of halogen, oxo (═O), hydroxy (—OH), methanoyl (—COH), carboxy (—CO2H), nitro (—NO2), —NH2, —N(CH3)2, cyano (—CN), ethynyl (—CCH), propynyl, sulfo (—SO3H), morpholinyl, —CO-morpholin-4-yl, phenyl, —CONH2, —CON(CH3)2, C1-C3alkyl, C1-C3perfluoronated alkyl, or C1-C3alkoxy; R5is H, halogen, —CN, hydroxy (—OH), 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, C1-C6alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more of halogen, oxo (═O), hydroxy (—OH), methanoyl (—COH), carboxy (—CO2H), nitro (—NO2), —NH2, —N(CH3)2, cyano (—CN), ethynyl (—CCH), propynyl, sulfo (—SO3H), morpholinyl, —CO-morpholin-4-yl, —CONH2, —CON(CH3)2, C1-C3alkyl, C1-C3perfluoronated alkyl, or C1-C3alkoxy; X is a bivalent C1-C7alkyl where 1, 2, or 3 of the C1-C7alkyl carbons is optionally replaced with a hetero atom which can be the same or different if more than one carbon atom is replaced, and which C1-C7alkyl or any of the hetero atom replacements, as chemically appropriate, is optionally substituted with one or more of halogen, oxo (═O), hydroxy (—OH), methanoyl (—COH), carboxy (—CO2H), nitro (—NO2), —NH2, —N(CH3)2, cyano (—CN), ethynyl (—CCH), propynyl, sulfo (—SO3H), morpholinyl, —CO-morpholin-4-yl, —CONH2, —CON(CH3)2, C1-C3alkyl, C1-C3perfluoronated alkyl, or C1-C3alkoxy; and ring A is a monocyclic or bicyclic ring comprising 1, 2, 3, 4, or 5 double bonds and 4, 5, 6, 7, 8, 9, or 10 carbon atoms, where 1, 2, 3, 4, or 5 of the non-fusion carbon atoms, can be optionally replaced with a hetero atom (e.g., N, O, S) which can be the same or different if more than one carbon atom is replaced, which ring A carbon atoms or any of the hetero atom replacements, as chemically appropriate, can optionally be substituted with one or more of halogen, oxo (═O), hydroxy (—OH), methanoyl (—COH), carboxy (—CO2H), nitro (—NO2), —NH2, —N(CH3)2, cyano (—CN), ethynyl (—CCH), propynyl, sulfo (—SO3H), morpholinyl, —CO-morpholin-4-yl, —CONH2, —CON(CH3)2, C1-C6alkyl, C1-C6perfluoronated alkyl (e.g., trifluoromethyl or perfluoroethyl), or C1-C5alkoxy, and wherein the fusion carbon atoms are single bonded or double bonded to each other. In certain embodiments, R1is H or C1-C3alkyl, which C1-C3alkyl is optionally substituted with one or more of halogen, hydroxy (—OH), methanoyl (—COH), carboxy (—CO2H), cyano (—CN), ethynyl (—CCH), sulfo (—SO3H), methyl, or ethyl. In other embodiments, R1is H, methyl, ethyl, perfluorinated methyl, or perfluorinated ethyl. In some embodiments, R2is H, halogen, hydroxy (—OH), C1-C3alkyl, or C1-C2alkoxy, which C1-C3alkyl or C1-C2alkoxy is optionally substituted with one or more of halogen, hydroxy (—OH), methanoyl (—COH), carboxy (—CO2H), cyano (—CN), ethynyl (—CCH), sulfo (—SO3H), methyl, or ethyl. In other embodiments, R2is H, halogen, hydroxy (—OH), cyano (—CN), sulfo (—SO3H), methyl, ethyl, methoxy, perfluorinated methyl, or perfluorinated ethyl. In some embodiments, R3is H, halogen, hydroxy (—OH), C1-C3alkyl, or C1-C2alkoxy, which C1-C3alkyl or C1-C2alkoxy is optionally substituted with one or more of halogen, hydroxy (—OH), methanoyl (—COH), carboxy (—CO2H), cyano (—CN), ethynyl (—CCH), sulfo (—SO3H), methyl, or ethyl. In other embodiments, R3is H, halogen, hydroxy (—OH), cyano (—CN), sulfo (—SO3H), methyl, ethyl, methoxy, perfluorinated methyl, or perfluorinated ethyl. In some embodiments, R4is H, halogen, —CN, hydroxy (—OH), methanoyl (—COH), carboxy (—CO2H), C1-C7alkyl, C1-C6alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, which methanoyl (—COH), carboxy (—CO2H), C1-C7alkyl, C1-C6alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more of halogen, oxo (═O), hydroxy (—OH), methanoyl (—COH), carboxy (—CO2H), nitro (—NO2), —NH2, —N(CH3)2, cyano (—CN), ethynyl (—CCH), propynyl, sulfo (—SO3H), morpholinyl, —CO-morpholin-4-yl, phenyl, —CONH2, —CON(CH3)2, C1-C3alkyl, C1-C3perfluoronated alkyl, or C1-C3alkoxy. In yet other embodiments, R4is Cl, hydroxy (—OH), methyl, ethyl, C1-5alkyl, C3alkyl, —CN, ethynyl, —CONH2, —CON(CH3)2, 2-(morpholinyl)ethoxy, —CO-morpholin-4-yl, ethoxy, methoxy, 5-hydroxy pyridyl, 5-hydroxy pyrid-3-yl, indolyl, 1-indolyl, 1,2,3,4-tetrahydroisoquinolyl, 2-1,2,3,4-tetrahydroisoquinolyl, 1,2-methylenedioxyphenyl, 2,3-methylenedioxyphenyl, furyl, 2-furyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2-trifluoromethyl phenyl, 3-trifluoromethyl phenyl, 4-trifluoromethyl phenyl, 2-trifluoromethoxy phenyl, 3-trifluoromethoxy phenyl, 4-trifluoromethoxy phenyl, 3,5-dimethoxyphenyl, 3,5-diethoxyphenyl, 3,5-dimethylphenyl, 3,5-diethylphenyl, 3,5-dihydroxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5-bis-trifluoromethyl phenyl, phenyl, benzyl, pyridyl, 3-pyridyl, methylenedioxyphenyl, perfluorinated methyl, or perfluorinated ethyl. In other embodiments, R4is methyl, ethyl, C3alkyl, n-propyl, isopropyl, ethoxy, methoxy, 5-hydroxy pyridyl, 5-hydroxy pyrid-3-yl, indolyl, 1-indolyl, 1,2,3,4-tetrahydroisoquinolyl, 2-1,2,3,4-tetrahydroisoquinolyl, furyl, 2-furyl), 1,2-methylenedioxyphenyl, 2,3-methylenedioxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2-trifluoromethyl phenyl, 3-trifluoromethyl phenyl, 4-trifluoromethyl phenyl, 2-trifluoromethoxy phenyl, 3-trifluoromethoxy phenyl, 4-trifluoromethoxy phenyl, 3,5-dimethoxyphenyl, 3,5-diethoxyphenyl, 3,5-dimethylphenyl, 3,5-diethylphenyl, 3,5-dihydroxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5-bis-trifluoromethyl phenyl, phenyl, benzyl, pyridyl, 3-pyridyl, methylenedioxyphenyl, perfluorinated methyl, or perfluorinated ethyl. In some embodiments, R5is H, halogen, —CN, hydroxy (—OH), methanoyl (—COH), carboxy (—CO2H), C1-C7alkyl, C1-C6alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, which methanoyl (—COH), carboxy (—CO2H), C1-C7alkyl, C1-C6alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more of halogen, oxo (═O), hydroxy (—OH), methanoyl (—COH), carboxy (—CO2H), nitro (—NO2), —NH2, —N(CH3)2, cyano (—CN), ethynyl (—CCH), propynyl, sulfo (—SO3H), morpholinyl, —CO-morpholin-4-yl, —CONH2, —CON(CH3)2, C1-C3alkyl, C1-C3perfluoronated alkyl, or C1-C3alkoxy. In other embodiments, R5is phenyl, 5-hydroxy pyridyl, 5-hydroxy pyrid-3-yl, 6-hydroxy pyridyl, 6-hydroxy pyrid-3-yl, 4-hydroxy pyridyl, 4-hydroxy pyrid-3-yl, indolyl, 1-indolyl, 1,2,3,4-tetrahydroisoquinolyl, 2-1,2,3,4-tetrahydroisoquinolyl, 1,2-methylenedioxyphenyl, 2,3-methylenedioxyphenyl, —CO-morpholin-4-yl, —CON(CH3)2, Cl, hydroxy (—OH), methyl, C1-5alkyl, C3alkyl, n-propyl, isopropyl, —CN, ethynyl, —CONH2, —CON(CH3)2, 2-(morpholinyl)ethoxy, ethoxy, methoxy, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2-trifluoromethyl phenyl, 3-trifluoromethyl phenyl, 4-trifluoromethyl phenyl, 3,5-dimethoxyphenyl, 3,5-diethoxyphenyl, 3,5-dimethylphenyl, 3,5-diethylphenyl, 3,5-dihydroxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5-bis-trifluoromethyl phenyl, perfluorinated methyl, or perfluorinated ethyl. In still other embodiments, R5is phenyl, 5-hydroxy pyridyl, 5-hydroxy pyrid-3-yl, indolyl, 1-indolyl, 1,2,3,4-tetrahydroisoquinolyl, 2-1,2,3,4-tetrahydroisoquinolyl, 1,2-methylenedioxyphenyl, 2,3-methylenedioxyphenyl, methyl, C3alkyl, n-propyl, isopropyl, ethoxy, methoxy, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2-trifluoromethyl phenyl, 3-trifluoromethyl phenyl, 4-trifluoromethyl phenyl, 3,5-dimethoxyphenyl, 3,5-diethoxyphenyl, 3,5-dimethylphenyl, 3,5-diethylphenyl, 3,5-dihydroxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5-bis-trifluoromethyl phenyl, perfluorinated methyl, or perfluorinated ethyl. In yet other embodiments, R5is phenyl, 5-hydroxy pyridyl, 5-hydroxy pyrid-3-yl, indolyl, 1-indolyl, 1,2,3,4-tetrahydroisoquinolyl, 2-1,2,3,4-tetrahydroisoquinolyl, 1,2-methylenedioxyphenyl, 2,3-methylenedioxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2-trifluoromethyl phenyl, 3-trifluoromethyl phenyl, 4-trifluoromethyl phenyl, 3,5-dimethoxyphenyl, 3,5-diethoxyphenyl, 3,5-dimethylphenyl, 3,5-diethylphenyl, 3,5-dihydroxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, or 3,5-bis-trifluoromethyl phenyl. In some embodiments, X is



In yet other embodiments, X is


In some embodiments, ring A is



In other embodiments, ring A is


In some embodiments, Formula (I) 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, or I-54. In other embodiments, R1is not H, R2is not H, R3is not H, R4is not 3-methoxyphenyl, R5is not 3-methoxyphenyl, X is not


or ring A is not


In certain embodiments, compound I-1 is excluded from 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 some 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 herein (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 a composition as disclosed herein or a pharmaceutical composition as 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 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 certain 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 yet still other 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 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 some embodiments, 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 a composition as disclosed herein or a pharmaceutical composition as disclosed herein. In yet 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 still 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 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 some embodiments, the animal is a human, a rodent, or a primate. In certain embodiments, the animal is in need of the treatment. In other embodiments, the method is for treating cancer. In yet other embodiments, the method is for treating pancreatic cancer, pancreatic ductal adenocarcinoma, lung cancer, liver cancer, colorectal cancer, colon cancer, rectal cancer, melanoma, cutaneous malignant melanoma, melanoma tumorigenesis, bladder cancer, prostate cancer, malignant nerve sheath tumors, multiple myeloma, breast cancer, squamous cell carcinoma, head and neck squamous cell carcinoma, lymphoma, leukemia, bone marrow cancer, non-Hodgkin lymphoma, diffuse large B-cell lymphoma, glioblastoma multiforme, endometrial cancer, kidney cancer, basal cell carcinoma, thyroid cancer, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia, rhabdomyosarcoma, meningioma, gastric cancer, Glioma, oral cancer, nasopharyngeal carcinoma, stomach cancer, uterine cancer, medulloblastoma, cancers that can result in metastasis, cancers resulting from metastasis, or cancerous tumors thereof. In yet other embodiments, the method is for treating pancreatic cancer, pancreatic ductal adenocarcinoma, lung cancer, liver cancer, colorectal cancer, colon cancer, rectal cancer, melanoma, cutaneous malignant melanoma, melanoma tumorigenesis, bladder cancer, malignant nerve sheath tumors, multiple myeloma, breast cancer, squamous cell carcinoma, head and neck squamous cell carcinoma, ovarian cancer, prostate cancer, medulloblastoma, cancers that can result in metastasis, cancers resulting from metastasis, or cancerous tumors thereof. In certain embodiments, the method is for treating pancreatic cancer, pancreatic ductal adenocarcinoma, lung cancer, liver cancer, ovarian cancer, prostate cancer, medulloblastoma, cancers that can result in metastasis, cancer resulting from metastasis of pancreatic cancer, lung cancer resulting from metastasis, or cancerous tumors thereof.

Some embodiments of the invention include a method for preparing a compound as 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 suitable compound to convert an oxo to a halogen to result in a mixture comprising a compound of Formula (V);(c) reacting a compound of Formula (V) with a compound of Formula (VI); and;(d) recovering Formula (I),
where Formula (II) is


and R11is a halogen or —CH2-halogen;

Formula (III) is R5—X—H (III);

Formula (IV) is



Formula (V) is


and

Formula (VI) is


In some embodiments, R11is —CH2-halogen, —CH2Br, or —CH2Cl. In other embodiments, the suitable compound to convert an oxo to a halogen is POCl3or POBr3.

Other embodiments of the invention are also discussed herein.

