This disclosure is directed, at least in part, to AMPK activators useful for the treatment of conditions or disorders associated with AMPK. In some embodiments, the condition or disorder is associated with the gut-brain axis. In some embodiments, condition or disorder is associated with systemic inf
This disclosure is directed, at least in part, to AMPK activators useful for the treatment of conditions or disorders associated with AMPK. In some embodiments, the condition or disorder is associated with the gut-brain axis. In some embodiments, condition or disorder is associated with systemic infection and inflammation from having a leaky gut barrier. In some embodiments, the AMPK activators are gut-restricted compounds. In some embodiments, the AMPK activators are agonists or partial agonists.
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1. A compound of Formula (III): or a pharmaceutically acceptable salt thereof, wherein:R2 is halogen, —CN, C1-C4 alkyl, or C1-C4 fluoroalkyl;G is —C(O)OR7, —P(O)(R8)OR7, —P(O)(OR7)2, or —S(O)2OR7; each R7 is independently hydrogen or C1-C4 alkyl;R8 is C1-C4 alkyl;A is phenyl which is substituted wit
1. A compound of Formula (III): or a pharmaceutically acceptable salt thereof, wherein:R2 is halogen, —CN, C1-C4 alkyl, or C1-C4 fluoroalkyl;G is —C(O)OR7, —P(O)(R8)OR7, —P(O)(OR7)2, or —S(O)2OR7; each R7 is independently hydrogen or C1-C4 alkyl;R8 is C1-C4 alkyl;A is phenyl which is substituted with 1, 2, or 3 R12 groups;each R12 is independently —CN, —OH, —OR13, —NR14R14, —C(═O)OR14, —C(═O)NR14R14, OSO2OR14, C1-C6 alkyl, C1-C6 fluoroalkyl, or monocyclic heteroaryl;each R13 is independently C1-C6 alkyl; andeach R14 is independently hydrogen or C1-C6 alkyl. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: R2 is —F, —Cl, or —CN. 3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: R3 and R4 are each independently hydrogen or methyl. 4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: G is —C(O)OH, —P(O)(Me)OH, —P(O)(OEt)(OH), —P(O)(OH)2, or —S(O)2OH. 5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: G is —C(O)OH. 6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: R2 is —Cl;R3 and R4 are each hydrogen; andG is —C(O)OH, —P(O)(Me)OH, —P(O)(OEt)(OH), or —P(O)(OH)2. 7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein: G is —C(O)OH. 8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: each R12 is independently —F, —Cl, —Br, —CN, —OH, —OMe, —NH2, —C(═O)OH, —C(═O)NH2, —CH3, —CH2CH3, —CH2CH2CH3, —CH(CH3)2, —CH2CH2CH2CH3, —CH2CH(CH3)2, —CH(CH3)(CH2CH3), —CH2CH2C(CH3)3, —CF3, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, or tetrazolyl. 9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: each R12 is independently —OH, —OSO2OH, —CH2CH2C(CH3)3, or triazolyl. 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: A is phenyl which is substituted with a —OH group and is optionally substituted with one other group selected from —CH2CH2C(CH3)3 and triazolyl. 11. The compound of claim 1, having the structure of Formula (IV): or a pharmaceutically acceptable salt thereof. 12. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein: R2 is —F, —Cl, or —CN;R3 and R4 are each independently hydrogen or methyl; andG is —C(O)OH, —P(O)(Me)OH, —P(O)(OEt)(OH), —P(O)(OH)2, or —S(O)2OH. 13. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein: G is —C(O)OH. 14. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein: R2 is —Cl;R3 and R4 are each hydrogen; andG is —C(O)OH, —P(O)(Me)OH, —P(O)(OEt)(OH), or —P(O)(OH)2. 15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein: G is —C(O)OH. 16. The compound of claim 1, selected from: or a pharmaceutically acceptable salt thereof. 17. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. 18. A method of treating an adenosine 5′-monophosphate-activated protein kinase (AMPK) associated condition or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof; wherein the condition or disorder is short bowel syndrome, intestinal failure, intestinal insufficiency, metabolic syndrome, obesity, type 2 diabetes, coronary artery disease, fatty liver, nonalcoholic steatohepatitis (NASH), cirrhosis, hepatic encephalopathy, fibrotic disorders including scleroderma, inflammatory bowel disease including Crohn's disease and ulcerative colitis, psoriasis, celiac disease, necrotizing enterocolitis, gastrointestinal injury resulting from toxic insults such as radiation or chemotherapy, environmental enteric dysfunction, allergy including food allergy, celiac sprue, and childhood allergy, irritable bowel syndrome, spontaneous bacterial peritonitis, ischemic colitis, sclerosing cholangitis, Alzheimer's disease, Parkinson's disease, colorectal cancer, depression, autism, or a combination thereof. 19. A method of treating gastrointestinal injury resulting from toxic insult, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof. 20. The method of claim 19, wherein the toxic insult is from radiation, chemotherapy, or a combination thereof.
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