Compounds, compositions, methods of using, and methods for preparing compounds

Abstract

In some embodiments of the invention, inventive compounds (e.g., Formula (I), (IA), (II), and (III), and urolithin derivatives) 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). Further embodiments include methods for making the inventive compounds. Additional embodiments of the invention are also discussed herein.

What is claimed is: 
     
         1 . A compound selected from 
       
         
           
           
               
               
           
         
       
       salts, optical isomers, geometric isomers, salts of isomers, and derivatives thereof,
 wherein
 the bond between X 1  and X 2  is a single bond or a double bond; 
 the bond between X 7  and X 8  is a single bond or a double bond; 
 X 1 , X 2 , X 7 , and X 3  are the same or different and each can be independently selected from CH, CH 2 , O, S, C—NH 2 , C—N═CH 2 , C(H)(NH 2 ), C═O, C═N—NH 2 , C═NH, C═N-cycloalkyl, C═N—S(O)H, C═NC(EtOH) 3 , C═NCH(EtOH) 2 , C═NEtOH, C(CH 3 )(OH), N, NH, C-halogen, C(H)(halogen), C-(halogen) 2 , C-cycloalkyl, C-heterocyclyl, C-aryl, C-heteroaryl, C(H)(cycloalkyl), C(H)(heterocyclyl), C(H)(aryl), or C(H)(heteroaryl), which CH, CH 2 , C—NH 2 , C—N═CH 2 , C(H)(NH 2 ), C═N—NH 2 , C═NH, C═N-cycloalkyl, C═N—S(O)H, C═NC(EtOH) 3 , C═NCH(EtOH) 2 , C═NEtOH, C(CH 3 )(OH), NH, C(H)(halogen), C-cycloalkyl, C-heterocyclyl, C-aryl, C-heteroaryl, C(H)(cycloalkyl), C(H)(heterocyclyl), C(H)(aryl), or C(H)(heteroaryl), are optionally substituted with one or more of halogen, hydroxy (—OH), methanoyl (—COH), —COCH 3 , carboxy (—CO 2 H), ethynyl (—CCH), cyano (—CN), sulfo (—SO 3 H), methyl, ethyl, perfluorinated methyl, or perfluorinated ethyl; 
 X 1  and X 2  are optionally further cyclized to form a 5 or 6 membered cycloalkyl, 5 or 6 membered heterocyclyl, 5 or 6 membered aryl, or 5 or 6 membered heteroaryl, which 5 or 6 membered cycloalkyl, 5 or 6 membered heterocyclyl, 5 or 6 membered aryl, or 5 or 6 membered heteroaryl are optionally substituted with one or more of halogen, hydroxy (—OH), methanoyl (—COH), —COCH 3 , carboxy (—CO 2 H), ethynyl (—CCH), cyano (—CN), sulfo (—SO 3 H), methyl, ethyl, perfluorinated methyl, or perfluorinated ethyl; 
 X 7  and X 3  are optionally further cyclized to form a 5 or 6 membered cycloalkyl, 5 or 6 membered heterocyclyl, 5 or 6 membered aryl, or 5 or 6 membered heteroaryl, which 5 or 6 membered cycloalkyl, 5 or 6 membered heterocyclyl, 5 or 6 membered aryl, or 5 or 6 membered heteroaryl are optionally substituted with one or more of halogen, hydroxy (—OH), methanoyl (—COH), —COCH 3 , carboxy (—CO 2 H), ethynyl (—CCH), cyano (—CN), sulfo (—SO 3 H), methyl, ethyl, perfluorinated methyl, or perfluorinated ethyl; 
 R 1 , R 2 , R 3 , R 4 , and R 5  are the same or different and each is independently selected from H, OH, halogen, methanoyl (—COH), —OCF 3 , —COCH 3 , carbonyl, carboxy (—CO 2 H), ethynyl (—CCH), cyano (—CN), amine, —NO 2 , sulfo (—SO 3 H), C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, C 1 -C 3  alkoxy, methyl, ethyl, perfluorinated methyl, perfluorinated ethyl, cycloalkyl, or heterocyclyl, which H, OH, methanoyl (—COH), —COCH 3 , carbonyl, carboxy (—CO 2 H), ethynyl (—CCH), sulfo (—SO 3 H), C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, C 1 -C 3  alkoxy, methyl, ethyl, cycloalkyl, or heterocyclyl are optionally substituted with one or more of halogen, hydroxy (—OH), methanoyl (—COH), —COCH 3 , carboxy (—CO 2 H), ethynyl (—CCH), cyano (—CN), sulfo (—SO 3 H), methyl, ethyl, perfluorinated methyl, or perfluorinated ethyl; and 
 X 3 , X 4 , X 5 , and X 6  are the same or different and each is independently selected from CH or N, which CH is optionally substituted with one or more of halogen, hydroxy (—OH), methanoyl (—COH), —COCH 3 , carboxy (—CO 2 H), ethynyl (—CCH), cyano (—CN), sulfo (—SO 3 H), methyl, ethyl, perfluorinated methyl, or perfluorinated ethyl. 
 
 
     
     
         2 . The compound of  claim 1 , wherein X 1 , X 2 , X 7 , and X 8  are the same or different and each can be independently selected from CH 2 , O, C(H)(NH 2 ), C═O, C═N—NH 2 , C═NH, C═N-cycloalkyl, C═N-adamantane, C═NC(EtOH) 3 , C═NCH(EtOH) 2 , C═NEtOH, C(CH 3 )(OH), or C(H)(cycloalkyl). 
     
     
         3 . The compound of  claim 1  or  claim 2 , wherein X 1  and X 2  are the same, X 7  and X 3  is the same, X 1  and X 7  is the same, X 2  and X 3  is the same, or a combination thereof. 
     
     
         4 . The compound of any of  claims 1 - 3 , wherein X 3 , X 4 , X 5 , and X 6  are the same or different and each is independently selected from CH or N. 
     
     
         5 . The compound of any of  claims 1 - 4 , wherein R 1 , R 2 , R 3 , R 4 , and R 5  are the same or different and each is independently selected from H, OH, halogen, methanoyl (—COH), —OCF 3 , —COCH 3 , carbonyl, carboxy (—CO 2 H), cyano (—CN), amine, —NO 2 , methoxy, ethoxy, methyl, ethyl, perfluorinated methyl, perfluorinated ethyl, cycloalkyl, bicycloalkyl, heterocyclyl, or imidazolyl. 
     
     
         6 . The compound of any of  claims 1 - 5 , wherein the compound is selected from Formula (IA) 
       
         
           
           
               
               
           
         
       
       salts, optical isomers, geometric isomers, salts of isomers, and derivatives thereof. 
     
     
         7 . The compound of any of  claims 1 - 6 , wherein X 1  and X 2  are the same or different and each is independently selected from CH 2 , O, C(H)(NH 2 ), C═O, C═N—NH 2 , C═NH, C═N-cycloalkyl, C═NC(EtOH) 3 , C═NCH(EtOH) 2 , C═NEtOH, C(CH 3 )(OH), or C(H)(cycloalkyl), which CH 2 , C(H)(NH 2 ), C═N—NH 2 , C═NH, C═N-cycloalkyl, C═NC(EtOH) 3 , C═NCH(EtOH) 2 , C═NEtOH, C(CH 3 )(OH), or C(H)(cycloalkyl), are optionally substituted with one or more of halogen, hydroxy (—OH), methanoyl (—COH), —COCH 3 , carboxy (—CO 2 H), ethynyl (—CCH), cyano (—CN), sulfo (—SO 3 H), methyl, ethyl, perfluorinated methyl, or perfluorinated ethyl. 
     
     
         8 . The compound of any of  claims 1 - 7 , wherein X 1  and X 2  are the same or different and each is independently selected from CH 2 , O, C═O, C═NH, C═N-cycloalkyl, C═NC(EtOH) 3 , C═NCH(EtOH) 2 , C═NEtOH, C(CH 3 )(OH), or C(H)(cycloalkyl). 
     
     
         9 . The compound of any of  claims 1 - 8 , wherein R 1  and R 2  are the same or different and each is independently selected from H, OH, halogen, methanoyl (—COH), —OCF 3 , —COCH 3 , carbonyl, carboxy (—CO 2 H), ethynyl (—CCH), cyano (—CN), amine, —NO 2 , sulfo (—SO 3 H), C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, C 1 -C 3  alkoxy, methyl, ethyl, perfluorinated methyl, perfluorinated ethyl, which H, OH, methanoyl (—COH), —COCH 3 , carbonyl, carboxy (—CO 2 H), ethynyl (—CCH), sulfo (—SO 3 H), C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, C 1 -C 3  alkoxy, methyl, or ethyl, are optionally substituted with one or more of halogen, hydroxy (—OH), methanoyl (—COH), —COCH 3 , carboxy (—CO 2 H), ethynyl (—CCH), cyano (—CN), sulfo (—SO 3 H), methyl, ethyl, perfluorinated methyl, or perfluorinated ethyl. 
     
     
         10 . The compound of any of  claims 1 - 9 , wherein R 1  and R 2  are the same or different and each is independently selected from H, OH, halogen, methanoyl (—COH), —OCF 3 , —COCH 3 , carbonyl, carboxy (—CO 2 H), cyano (—CN), amine, —NO 2 , methoxy, ethoxy, methyl, ethyl, perfluorinated methyl, or perfluorinated ethyl. 
     
     
         11 . The compound of any of  claims 1 - 10 , the compound (a) is not I-1, I-3, I-5, I-7, I-20, I-26, I-27, I-28, I-33, I-53, I-54, I-55, I-56, I-57, I-59, I-94, I-98, II-99, II-100, II-101, II-102, II-103, II-118, II-119, II-120, II-121, and II-122, (b) is a compound selected from Table 1, or (c) both. 
     
     
         12 . A urolithin derivative having a chemical group substitution of the urolithin cyclic ester resulting in improved potency of the derivative as compared to urolithin A, or improved stability of the derivative at acidic pH and/or in presence of esterase and/or protease as compared to urolithin A. 
     
     
         13 . The urolithin derivative of  claim 12 , wherein the urolithin cyclic ester is replaced with a cyclic ether. 
     
     
         14 . The urolithin derivative of  claim 13 , wherein the urolithin cyclic ether comprises one or more substituents. 
     
     
         15 . The urolithin derivative of  claim 14 , wherein the cyclic ether substituents are independently selected from halo, amine, substituted amine, hydroxyl, and a C5 or C6 heterocycle having one or two heteroatoms independently selected from O, N, or S. 
     
     
         16 . The urolithin derivative of  claim 12 , wherein the urolithin cyclic ester is replaced with a carbocycle having adjacent carbonyl groups. 
     
     
         17 . The urolithin derivative of  claim 12 , wherein the urolithin cyclic ester is replaced with a cyclic alkenyl group, which is optionally aromatic, and optionally substituted. 
     
     
         18 . The urolithin derivative of  claim 17 , wherein the cyclic alkenyl group has one or more substituents. 
     
     
         19 . The urolithin derivative of  claim 18 , wherein the cyclic alkenyl group substituents are independently selected from ketone, optionally substituted imine, optionally substituted amine, halo, and hydroxyl. 
     
     
         20 . The urolithin derivative of  claim 12 , wherein the urolithin cyclic ester is replaced with a cyclic amide. 
     
     
         21 . The urolithin derivative of  claim 12 , wherein the urolithin cyclic ester is replaced with a non-cyclic bridge. 
     
     
         22 . The urolithin derivative of any one of  claims 12  to  21 , wherein the urolithin aromatic groups have one or more substituents. 
     
     
         23 . The urolithin derivative of  claim 22 , wherein the aromatic groups are phenyl groups which are optionally substituted. 
     
     
         24 . The urolithin derivative of  claim 22  or  23 , wherein the one or more aromatic substituents are independently selected from hydroxyl, alkoxy, halo, amine, a 5 or 6 membered carbocyclic or heterocyclic ring, nitro, nitrile, alkyl, alkyl ether, and haloalkyl. 
     
     
         25 . The urolithin derivative of any one of  claims 12  to  24 , wherein one or more urolithin aromatic rings are heterocyclic. 
     
     
         26 . The urolithin derivative of  claim 25 , wherein the heteroatoms of the heterocyclic ring are independently selected from N, O, and S. 
     
     
         27 . The urolithin derivative of any one of  claims 12  to  26 , wherein substituents of each aromatic ring together form a second bridging ring. 
     
     
         28 . The urolithin derivative of  claim 27 , wherein the second bridging ring is identical in structure to a first bridging ring. 
     
     
         29 . The urolithin derivative of  claim 27 , wherein the second bridging ring is different in structure to the first bridging ring. 
     
     
         30 . A composition comprising a compound of any of  claims 1 - 29 . 
     
     
         31 . The composition of  claim 30 , wherein the amount of the compound is from about 0.0001% (by weight total composition) to about 99%. 
     
     
         32 . The composition of  claim 30  or  claim 31 , further comprising a formulary ingredient, an adjuvant, or a carrier. 
     
     
         33 . The composition of any of  claims 30 - 32 , further comprising 5-florouracil. 
     
     
         34 . A pharmaceutical composition comprising a compound of any of  claims 1 - 29 . 
     
     
         35 . The pharmaceutical composition of  claim 34 , wherein the amount of the compound is from about 0.0001% (by weight total composition) to about 50%. 
     
     
         36 . The pharmaceutical composition of  claim 34  or  claim 35 , further comprising a formulary ingredient, an adjuvant, or a carrier. 
     
     
         37 . The pharmaceutical composition of any of  claims 34 - 36 , further comprising 5-florouracil. 
     
     
         38 . A method for providing an animal with a compound comprising one or more administrations of one or more compositions comprising the compound of any of  claims 1 - 29 , wherein the compositions may be the same or different if there is more than one administration. 
     
     
         39 . The method of  claim 38 , wherein at least one of the one or more compositions further comprises a formulary ingredient. 
     
     
         40 . The method of  claim 38  or  claim 39 , wherein at least one of the one or more compositions comprises the composition of any of  claims 30 - 33  or the pharmaceutical composition of any of  claims 34 - 37 . 
     
     
         41 . The method of any of  claims 38 - 40 , wherein at least one of the one or more administrations comprises parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration. 
     
     
         42 . The method of any of  claims 38 - 41 , wherein if there is more than one administration at least one composition used for at least one administration is different from the composition of at least one other administration. 
     
     
         43 . The method of any of  claims 38 - 42 , wherein 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 50 mg/kg animal body weight. 
     
     
         44 . The method of any of  claims 38 - 43 , wherein the animal is a human, a rodent, or a primate. 
     
     
         45 . A method for treating an animal for a disease, comprising one or more administrations of one or more compositions comprising the compound of any of  claims 1 - 29 , wherein the compositions may be the same or different if there is more than one administration. 
     
     
         46 . The method of  claim 45 , wherein at least one of the one or more compositions further comprises a formulary ingredient. 
     
     
         47 . The method of  claim 45  or  claim 46 , wherein at least one of the one or more compositions comprises the composition of any of  claims 30 - 33  or the pharmaceutical composition of any of  claims 34 - 37 . 
     
     
         48 . The method of any of  claims 45 - 47 , wherein at least one of the one or more administrations comprises parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration. 
     
     
         49 . The method of any of  claims 45 - 48 , wherein if there is more than one administration at least one composition used for at least one administration is different from the composition of at least one other administration. 
     
     
         50 . The method of any of  claims 45 - 49 , wherein 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. 
     
     
         51 . The method of any of  claims 45 - 50 , wherein the animal is a human, a rodent, or a primate. 
     
     
         52 . The method of any of  claims 45 - 51 , wherein the animal is in need of the treatment. 
     
     
         53 . The method of any of  claims 45 - 52 , wherein the method is for treating alcoholic liver disease (ALD), non-alcoholic steatohepatitis (NASH), intestinal permeability, leaky gut, metal induced gut leakiness, stress induced gut leakiness, radiation induced gut permeability, colitis, local inflammation, inflammation in the brain, inflammation in the mouth, inflammation in the esophagus, inflammation in the stomach, inflammation in the small intestine, systemic inflammation, inflammatory bowel disease, ulcerative colitis, Crohn's disease, infection-induced inflammatory disease, sepsis, sepsis-induced kidney injury, sepsis-induced lung injury, scleroderma, vasculitis, drug-induced vasculitis, neuroinflammatory disorders, Alzheimer's Disease, Parkinson's Disease, anxiety, depression, metabolic stress, cardiovascular disease, sarcopenia, muscle degenerative disease, Duchenne muscular dystrophy, nonalcoholic fatty liver disease, drug-induced liver injury, alpha-antitrypsin deficiency, ischemia/reperfusion injury, obesity, metabolic syndrome, type II diabetes mellitus, hyperlipidemia, osteoarthritis, neurodegenerative disease, amyotrophic lateral sclerosis (ALS), cancer, cancerous tumors, breast cancer, colon cancer, cognitive disorder, stress, mood disorder, or fibrosis. 
     
     
         54 . The method of any of  claims 45 - 53 , wherein the method is for treating alcoholic liver disease (ALD), non-alcoholic steatohepatitis (NASH), colitis, intestinal permeability, leaky gut, metal induced gut leakiness, stress induced gut leakiness, radiation induced gut permeability, local inflammation, systemic inflammation, inflammatory bowel disease, ulcerative colitis, Crohn's disease, infection-induced inflammatory disease, sepsis, sepsis-induced kidney injury, sepsis-induced lung injury, scleroderma, vasculitis, drug-induced vasculitis, neuroinflammatory disorders, Alzheimer's Disease, Parkinson's Disease, cancer, cancerous tumors, breast cancer, colon cancer, or fibrosis. 
     
     
         55 . The method of any of  claims 45 - 54 , wherein the method is for treating alcoholic liver disease (ALD), non-alcoholic steatohepatitis (NASH), intestinal permeability, leaky gut, metal induced gut leakiness, stress induced gut leakiness, radiation induced gut permeability, local inflammation, systemic inflammation, inflammatory bowel disease, ulcerative colitis, Crohn's disease, sepsis, Alzheimer's Disease, Parkinson's Disease, cancer, cancerous tumors, breast cancer colon cancer, or fibrosis. 
     
     
         56 . The method of any of  claims 45 - 55 , wherein the method is for treating vasculitis, drug-induced vasculitis, scleroderma, internal vascular bleeding, drug-induced internal bleeding, atopic dermatitis, perfusion-related injury, perfusion related inflammation, diabetic retinopathy, celiac disease, Non-Alcoholic SteatoHepatitis (NASH), Alcoholic SteatoHepatitis (ASH), metabolic stress, cardiovascular disease, sarcopenia, muscle degenerative disease, Duchenne muscular dystrophy, alcoholic liver disease, nonalcoholic fatty liver disease, drug-induced liver injury, chronic kidney disease, alpha-antitrypsin deficiency, ischemia/reperfusion injury, inflammation, inflammatory bowel disease, Crohn's disease, obesity, metabolic syndrome, type II diabetes mellitus, hyperlipidemia, osteoarthritis, neurodegenerative disease, neuroinflammatory disorder, Alzheimer's disease, Parkinson's disease, multiple sclerosis, myotrophic lateral sclerosis (ALS), pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), acute lung injury, blood transfusion related acute lung injury, acute respiratory distress syndrome, asthma, cancer, cognitive disorder, stress, or mood disorder. 
     
     
         57 . The method of any of  claims 45 - 56 , wherein the method is for treating cancer and the cancer is 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. 
     
     
         58 . A method of inducing the expression of tight junction proteins in a tissue, comprising administering an effective amount of a pharmaceutical composition comprising a urolithin structural analogue to a subject in need. 
     
     
         59 . A method of inducing the expression of tight junction proteins in a tissue, comprising administering an effective amount of the composition of any one of  claims 30  to  32  to a subject in need. 
     
     
         60 . The method of  claim 58  or  59 , wherein the subject exhibits symptoms of gastrointestinal permeability or inflammation, and the composition is administered to the small and/or large intestine. 
     
     
         61 . The method of  claim 60 , wherein the subject has an inflammatory bowel disease. 
     
     
         62 . The method of  claim 61 , wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis. 
     
     
         63 . The method of  claim 60 , wherein the subject has celiac disease. 
     
     
         64 . The method of  claim 61 , wherein the inflammatory bowel disease comprises colonic inflammation. 
     
     
         65 . The method of  claim 58  or  59 , wherein the composition is administered systemically in an amount effect to improve endothelial or vascular barrier integrity in organs. 
     
     
         66 . The method of  claim 65 , wherein the organs are one or more selected from liver, kidneys, pancreas, heart, lungs, skin, muscle, fat, brain, eyes, bone, and intestine. 
     
     
         67 . The method of  claim 66 , wherein the subject has a condition selected from vasculitis, drug-induced vasculitis, scleroderma, internal vascular bleeding, drug-induced internal bleeding, atopic dermatitis, perfusion-related injury, perfusion related inflammation, and diabetic retinopathy. 
     
     
         68 . A method of treating systemic inflammation comprising administering to a patient in need thereof an effective amount of a composition of  claim 30 . 
     
     
         69 . The method of  claim 68 , wherein the composition is administered enterally or parenterally. 
     
     
         70 . The method of  claim 69 , wherein the subject has or is at risk of sepsis or an infection-induced inflammatory disease. 
     
     
         71 . The method of  claim 69 , wherein the subject has or is at risk of alcoholic liver disease (ALD). 
     
     
         72 . The method of  claim 69 , wherein the subject has or is at risk of Non-Alcoholic SteatoHepatitis (NASH) or Alcoholic SteatoHepatitis (ASH). 
     
     
         73 . The method of  claim 68 , wherein the subject has inflammation of one or more organs or tissues selected from liver, kidneys, pancreas, heart, lungs, skin, muscle, fat, brain, eyes, bone, marrow, intestine, and cartilage. 
     
     
         74 . A method for treating neuroinflammatory disorder comprising administering to a patient in need thereof an effective amount of a composition of  claim 30 . 
     
     
         75 . The method of  claim 74 , wherein the neuroinflammatory disorder is Alzheimer's Disease. 
     
     
         76 . The method of  claim 74 , wherein the neuroinflammatory disorder is Parkinson's Disease. 
     
     
         77 . The method of  claim 74 , wherein the neuroinflammatory disorder is a neurodegenerative disease, which is optionally multiple sclerosis. 
     
     
         78 . A method for treating anxiety or depression, comprising administering an effective amount of the composition of  claim 30  to a subject in need, in an amount effective to inhibit monoamine oxidase enzymes in the subject. 
     
     
         79 . The method of  claim 78 , wherein the composition is administered systemically or locally to the brain. 
     
     
         80 . The method of  claim 79 , wherein the composition is administered enterally, parenterally, or intranasally. 
     
     
         81 . A method of enhancing airway barrier integrity in lungs comprising administering to a subject in need thereof an effective amount of a composition of  claim 30 . 
     
     
         82 . The method of  claim 81 , wherein the subject has pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), acute lung injury, blood transfusion related acute lung injury, acute respiratory distress syndrome, or asthma. 
     
     
         83 . A method of improving or increasing autophagy in a subject, comprising administering to a subject in need thereof an effective amount of the composition of  claim 30 . 
     
     
         84 . The method of  claim 83 , wherein autophagy is improved or increased in a tissue or organ of the subject selected from brain, eye, skin, bone, marrow, cartilage, heart, lung, stomach, intestine, liver, pancreas, kidney, muscle, and fat. 
     
     
         85 . The method of  claim 84 , wherein autophagy is improved or increased in cells of the subject selected from adult stem cells, differentiated cells, blood cells, hematopoietic cells, endothelial cells, epithelial cells, exocrine cells, endocrine cells, connective tissue cells, adipose cells, bone cells, smooth muscle cells, striated muscle cells, nerve cells, sensory cells, cardiac cells, hepatic cells, gastric cells, intestinal cells, pulmonary cells, kidney cells, and germ cells. 
     
     
         86 . The method of any one of  claims 83 - 84 , wherein the subject has a disease or condition selected from metabolic stress, cardiovascular disease, sarcopenia, muscle degenerative disease, Duchenne muscular dystrophy, alcoholic liver disease, nonalcoholic fatty liver disease, drug-induced liver injury, chronic kidney disease, alpha-antitrypsin deficiency, ischemia/reperfusion injury, inflammation, inflammatory bowel disease, Crohn's disease, obesity, metabolic syndrome, type II diabetes mellitus, hyperlipidemia, osteoarthritis, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), cancer, cognitive disorder, stress, and mood disorder, whereby the administering treats or ameliorates the disease or condition. 
     
     
         87 . A method of increasing longevity in a subject, comprising administering to a subject a regimen of the composition of  claim 30  effective to increase longevity in an animal. 
     
     
         88 . The method of any one of  claims 58  to  87 , wherein the subject is a vertebrate animal. 
     
     
         89 . The method of  claim 88 , wherein the subject is a mammal, which is optionally a primate. 
     
     
         90 . The method of  claim 89 , wherein the subject is a human. 
     
     
         91 . The method of  claim 88 , wherein the subject is a veterinary patient. 
     
     
         92 . A method of increasing autophagy in a cell, comprising contacting a cell with an effective amount of a compound of any one of  claims 1  to  29 . 
     
     
         93 . The method of  claim 92 , wherein the autophagy is mitophagy. 
     
     
         94 . The method of  claim 92 , wherein the cell is selected from: embryonic stem cells, induced pluripotent stem cells, adult stem cells, differentiated cells, blood cells, hematopoietic cells, epithelial cells, exocrine cells, endocrine cells, connective tissue cells, adipose cells, bone cells, smooth muscle cells, striated muscle cells, nerve cells, sensory cells, cardiac cells, hepatic cells, gastric cells, intestinal cells, pulmonary cells, kidney cells, and germ cells. 
     
     
         95 . A method of increasing longevity of eukaryotic cells in vitro, comprising contacting the cells with the compound of any one of  claims 1  to  29  effective to increase longevity of the cells. 
     
     
         96 . The method of  claim 95 , wherein the eukaryotic cells are eukaryotic cells in primary culture. 
     
     
         97 . The method of  claim 95  or  96 , wherein the eukaryotic cells are part of a cell line. 
     
     
         98 . The method of any one of the claims of  95 - 97 , wherein, the eukaryotic cells are cells selected from: embryonic stem cells, induced pluripotent stem cells, adult stem cells, differentiated cells, blood cells, hematopoietic cells, epithelial cells, exocrine cells, endocrine cells, connective tissue cells, adipose cells, bone cells, smooth muscle cells, striated muscle cells, nerve cells, sensory cells, cardiac cells, hepatic cells, gastric cells, intestinal cells, pulmonary cells, kidney cells, and germ cells. 
     
     
         99 . The method of  claim 98 , wherein the eukaryotic cells are cells selected from: embryonic stem cells, induced pluripotent stem cells, and adult stem cells. 
     
     
         100 . A method for preparing a compound of Formula (I) of any of  claims 1 - 11  comprising
 (a) reacting a compound of Formula (V) with a compound of Formula (VI) to result in a mixture comprising a compound of Formula (VII); 
 (b) reacting the compound of Formula (VII) with a suitable compound to result in a mixture comprising a compound of Formula (I); 
 (c) optionally further reacting the compound of Formula (I) to result in a different compound of Formula (I) so that the identity of one or more of R 1 , R 2 , R 3 , R 4 , R 5 , X 1  or X 2  is changed by the further reacting; and 
 (d) recovering Formula (I), 
 
       wherein Formula (V) is 
       
         
           
           
               
               
           
         
         Formula (VI) is 
       
       
         
           
           
               
               
           
         
       
       where R 20  is a halogen or 
       
         
           
           
               
               
           
         
         and Formula (VII) is 
       
       
         
           
           
               
               
           
         
       
     
     
         101 . The method of  claim 100 , wherein the suitable compound in step b comprises Ti(IV)chloride, molybdenum(V)chloride, or a combination thereof. 
     
     
         102 . The method of  claim 100  or  claim 101 , wherein Formula (I) is Formula (IA), I-1, or I-2. 
     
     
         103 . The method of any of  claims 100 - 102 , wherein R 20  is Cl or 
       
         
           
           
               
               
           
         
       
     
     
         104 . The method of any of  claims 100 - 103 , wherein Formula (V) is