WO2023097190A1 - Ampk activators - Google Patents

Ampk activators Download PDF

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WO2023097190A1
WO2023097190A1 PCT/US2022/080267 US2022080267W WO2023097190A1 WO 2023097190 A1 WO2023097190 A1 WO 2023097190A1 US 2022080267 W US2022080267 W US 2022080267W WO 2023097190 A1 WO2023097190 A1 WO 2023097190A1
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alkyl
compound
independently selected
optionally substituted
salt
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PCT/US2022/080267
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French (fr)
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Iyassu Sebhat
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Kallyope, Inc.
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Publication of WO2023097190A1 publication Critical patent/WO2023097190A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • Adenosine 5 '-monophosphate-activated protein kinase is a serine/threonine kinase and is evolutionarily conserved from yeast to mammals. AMPK acts as an energy sensor and is activated by upstream enzymes when the cellular ratio of adenosine 5 '-monophosphate (AMP) to adenosine triphosphate (ATP) is elevated due to nutrient deprivation. Activated AMPK phosphorylates downstream substrates to promote catabolism and impede anabolism, leading to ATP production and energy restoration.
  • AMP adenosine 5 '-monophosphate-activated protein kinase
  • ATP adenosine triphosphate
  • AMPK activity can be altered due to numerous physiological factors, such as hormones, cytokines and dietary nutrients, as well as pathological conditions such as obesity, chronic inflammation and type 2 diabetes. AMPK activation can lead to lower hepatic glucose production and plasma glucose levels. Thus, AMPK is an attractive target to treat various metabolic diseases.
  • AMPK has beneficial effects for gut health, such as enhancing intestinal absorption, improving barrier function, suppressing colorectal carcinogenesis, and reducing intestinal inflammation and metabolic-related disease, and is important for the maintenance of intestinal homeostasis.
  • AMPK activation enhances paracellular junctions, nutrient transporters, autophagy and apoptosis, and suppresses inflammation and carcinogenesis in the intestine.
  • AMPK is associated with the maintenance of tight junctions in colonic epithelium and controls the progression of colitis.
  • adenosine 5 '-monophosphate-activated protein kinase (5' AMP-activated protein kinase, AMPK) activators useful for the treatment of conditions or disorders associated with AMPK.
  • the condition or disorder is associated with the gut-brain axis.
  • the condition or disorder is associated with systemic infection and inflammation from having a leaky gut barrier.
  • the AMPK activators are gut-restricted or selectively modulate AMPK located in the gut.
  • the condition is selected from the group consisting of: central nervous system (CNS) disorders including mood disorders, anxiety, depression, affective disorders, schizophrenia, malaise, cognition disorders, addiction, autism, epilepsy, neurodegenerative disorders, Alzheimer’s disease, and Parkinson’s disease, Lewy Body dementia, episodic cluster headache, migraine, pain; metabolic conditions including diabetes and its complications such as chronic kidney disease/diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, cardiovascular disease, metabolic syndrome, obesity, dyslipidemia, and nonalcoholic steatohepatitis (NASH); eating and nutritional disorders including hyperphagia, cachexia, anorexia nervosa, short bowel syndrome, intestinal failure, intestinal insufficiency and other eating disorders; inflammatory disorders and autoimmune diseases such as inflammatory bowel disease, ulcerative colitis, Crohn’s disease, checkpoint inhibitor-induced colitis, psoriasis and celiac disease; necrotizing enterocolitis; gastrointestinal injury resulting from toxic insults such
  • CNS
  • R 1 , R 2 , and R 3 are each independently selected at each occurrence from halogen, hydroxyl, C 1-4 alkyl, -CN, and Ci.4 haloalkyl; n is selected from 0, 1, 2, 3, and 4; o is selected from 0, 1, 2, 3, and 4; p is selected from 0, 1, and 2;
  • R 4 is selected from hydrogen, halogen, C 1-4 alkyl, and C 1-4 haloalkyl;
  • R 5a and R 5b are each independently selected from hydrogen, C 1-4 alkyl, and C 1-4 haloalkyl;
  • R 6 is selected from hydrogen and C 1-4 alkyl
  • D is selected from -CO2R 11 , -P(O)(OR U ) 2 , -P(O)R n (OR n ), -S(O) 2 OH, and -L-K;
  • L is selected from z -(C(R 13 ) 2 ) r -, z -O(C(R 13 ) 2 ) r -, z -(C(R 13 ) 2 ) r O-, ⁇ -N(R 12 )(C(R 13 ) 2 ) S -, ⁇ -C(O)O-, ⁇ -OC(O)-, ⁇ -C(O)N(R 12 )-, ⁇ -N(R 12 )C(O)-, ⁇ -N(R 12 )S(O) 2 -, ⁇ -S(O) 2 N(R 12 )-, and 4- to 6- membered heterocycle wherein 1 denotes the connection to K; r is selected from 1, 2, and 3; s is selected from 0, 1, 2, and 3;
  • K is selected from (i) and (ii):
  • compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, and at least one pharmaceutically acceptable excipient.
  • AMPK adenosine 5'- monophosphate-activated protein kinase
  • the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.
  • the condition or disorder involves the gut-brain axis.
  • the condition or disorder is a nutritional disorder.
  • the condition or disorder is short bowel syndrome, intestinal failure, or intestinal insufficiency.
  • the condition or disorder is associated with systemic infection and inflammation from having a leaky gut barrier.
  • the condition or disorder is 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, ulcerative colitis, and checkpoint inhibitor-induced 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, graft vs.
  • 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, ulcerative colitis, and checkpoint inhibitor-induced colitis, psoriasis, cel
  • irritable bowel syndrome spontaneous bacterial peritonitis, ischemic colitis, sclerosing cholangitis, Alzheimer’s disease, Parkinson’s disease, cancer including colorectal cancer, depression, autism, or a combination thereof.
  • the toxic insult is from radiation, chemotherapy, or a combination thereof.
  • the toxic insult is radiation-induced.
  • the toxic insult is chemotherapy-induced.
  • a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof for the treatment of an adenosine 5 '-monophosphate-activated protein kinase (AMPK) associated condition or disorder in a subject in need thereof.
  • AMPK adenosine 5 '-monophosphate-activated protein kinase
  • the condition or disorder involves the gut-brain axis.
  • the condition or disorder is a nutritional disorder.
  • the condition or disorder is short bowel syndrome, intestinal failure, or intestinal insufficiency.
  • the condition or disorder is associated with systemic infection and inflammation from having a leaky gut barrier.
  • the condition or disorder is 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, ulcerative colitis, and checkpoint inhibitor-induced 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, graft vs.
  • 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, ulcerative colitis, and checkpoint inhibitor-induced colitis, psoriasis, cel
  • irritable bowel syndrome spontaneous bacterial peritonitis, ischemic colitis, sclerosing cholangitis, Alzheimer’s disease, Parkinson’s disease, cancer including colorectal cancer, depression, autism, or a combination thereof.
  • a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof for the treatment of gastrointestinal injury resulting from toxic insult in a subject in need thereof.
  • the toxic insult is from radiation, chemotherapy, or a combination thereof.
  • the toxic insult is radiation-induced.
  • the toxic insult is chemotherapy induced.
  • a compound disclosed herein or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, for the preparation of a medicament for the treatment of the diseases disclosed herein.
  • AMPK activators useful for the treatment of conditions or disorders involving the gut-brain axis.
  • the AMPK activators are gut-restricted compounds.
  • the AMPK activators are agonists, super agonists, full agonists, or partial agonists.
  • Compounds disclosed herein directly activate AMPK in the intestine without systemic engagement. The preferred compounds are more potent, efficacious at lower doses, and have decreased systemic exposure compared to other previously-known AMPK activators.
  • Ci-C x includes C1-C2, C1-C3 . . . Ci-C x .
  • a group designated as “C1-C4” indicates that there are one to four carbon atoms in the moiety, i.e., groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms.
  • C1-C4 alkyl indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, Ao-propyl, //-butyl, isobutyl, sec-butyl, and /-butyl.
  • Alkyl refers to an optionally substituted straight-chain, or optionally substituted branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, or more preferably, from one to six carbon atoms, wherein an sp 3 -hybridized carbon of the alkyl residue is attached to the rest of the molecule by a single bond.
  • Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2-methyl- 1 -butyl, 3 -methyl- 1 -butyl, 2-methyl-3 -butyl, 2,2-dimethyl-l -propyl, 2-methyl-l -pentyl, 3- m ethyl- 1 -pentyl, 4-methyl-l -pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l -butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and
  • a numerical range such as “Ci-Ce alkyl” means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
  • the alkyl is a Ci-Cio alkyl, a C1-C9 alkyl, a Ci-C 8 alkyl, a C1-C7 alkyl, a Ci-C 6 alkyl, a Ci-C 5 alkyl, a C1-C4 alkyl, a C1-C3 alkyl, a C1-C2 alkyl, or a Ci alkyl.
  • an alkyl group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , - SR a , -OC(O)R a , -OC(O)-OR f , -N(R a ) 2 , -N + (R a ) 3 , -C(O)R a , -C(O)OR a , -C(O)N(R a ) 2 , - N(R a )C(O)OR f , -OC(O)-N(R a ) 2 , -N(R a )C(O)R a , -N(R a )S(O) t R f (where t is 1 or 2), -S
  • Alkenyl refers to an optionally substituted straight-chain, or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms, wherein an sp 2 -hybridized carbon or an sp 3 -hybridized carbon of the alkenyl residue is attached to the rest of the molecule by a single bond.
  • C 2 -Ce alkenyl means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated.
  • the alkenyl is a C 2 -Cio alkenyl, a C 2 -C9 alkenyl, a C 2 -Cs alkenyl, a C 2 -C? alkenyl, a C 2 -Ce alkenyl, a C 2 -Cs alkenyl, a C 2 -C 4 alkenyl, a C 2 -C 3 alkenyl, or a C 2 alkenyl.
  • an alkenyl group is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an alkenyl group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R f , -OC(O)-OR f , -N(R a ) 2 , -N + (R a ) 3 , -C(O)R a , -C(O)OR a , -C(O)N(R a ) 2 , - N(R a )C(O)OR f , -OC(O)-N(R a ) 2 , -N(R a )C(O)R f , -N(R a )S(O) t R f (where t is 1 or 2), -
  • Alkynyl refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms, wherein an sp-hybridized carbon or an sp 3 -hybridized carbon of the alkynyl residue is attached to the rest of the molecule by a single bond. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like.
  • C2-C6 alkynyl means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated.
  • the alkynyl is a C2-C10 alkynyl, a C2-C9 alkynyl, a C 2 -Cs alkynyl, a C2-C7 alkynyl, a C2-C6 alkynyl, a C2-C5 alkynyl, a C2-C4 alkynyl, a C2-C3 alkynyl, or a C2 alkynyl.
  • an alkynyl group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)R a , -OC(O)-OR f , - N(R a ) 2 , -N + (R a ) 3 , -C(O)R a , -C(O)OR a , -C(O)N(R a ) 2 , -N(R a )C(O)OR f , -OC(O)-N(R a ) 2 , - N(R a )C(O)R f , -N(R a )S(O)tR f (where t is 1 or 2), -S
  • Alkylene or “alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, ⁇ -butylene, and the like.
  • the alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • the points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain.
  • an alkylene group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)R a , -OC(O)-OR f , -N(R a ) 2 , -N + (R a ) 3 , -C(O)R a , -C(O)OR a , -C(O)N(R a ) 2 , -N(R a )C(O)OR f , -OC(O)-N(R a ) 2 , -N(R a )C(O)R f , -N(R a )S(O) t R f (where t is 1 or 2), -S(
  • alkenylene or “alkenylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms.
  • the alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • an alkenylene group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R f , -OC(O)-OR f , -N(R a ) 2 , -N + (R a ) 3 , -C(O)R a , -C(O)OR a , - C(O)N(R a ) 2 , -N(R a )C(O)OR f , -OC(O)-N(R a ) 2 , -N(R a )C(O)R f , -N(R a )S(O) t R f (where t is 1 or 2), -
  • Alkynylene or “alkynylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms.
  • the alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • an alkynylene group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, - OR a , -SR a , -OC(O)R a , -OC(O)-OR f , -N(R a ) 2 , -N + (R a ) 3 , -C(O)R a , -C(O)OR a , -C(O)N(R a ) 2 , - N(R a )C(O)OR f , -OC(O)-N(R a ) 2 , -N(R a )C(O)R f , -N(R a )S(O) t R f (where t is 1 or 2), -
  • Alkoxy or “alkoxyl” refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.
  • Aryl refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom.
  • the aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from 6 to 18 carbon atoms, where at least one of the rings in the ring system is fully unsaturated, z.e., it contains a cyclic, delocalized (4n+2) ⁇ -electron system in accordance with the Huckel theory.
  • the ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.
  • the aryl is a Ce-Cio aryl. In some embodiments, the aryl is a phenyl.
  • the term “aryl” or the prefix “ar-“ is meant to include aryl radicals optionally substituted as described below by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -R b -OR a , -R b -SR a , -R b -OC(O)-R a , -R b -OC(O)-OR f , -R b -OC(O)-N(R a
  • arylene refers to a divalent radical derived from an “aryl” group as described above linking the rest of the molecule to a radical group.
  • the arylene is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • the arylene is a phenylene.
  • an arylene group is optionally substituted as described above for an aryl group.
  • Cycloalkyl refers to a stable, partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems.
  • Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C3-C15 cycloalkyl), from three to ten carbon atoms (C3-C10 cycloalkyl), from three to eight carbon atoms (C 3 -Cs cycloalkyl), from three to six carbon atoms (C3-C6 cycloalkyl), from three to five carbon atoms (C3-C5 cycloalkyl), or three to four carbon atoms (C3-C4 cycloalkyl).
  • the cycloalkyl is a 3- to 6-membered cycloalkyl.
  • the cycloalkyl is a 5- to 6-membered cycloalkyl.
  • Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo[l.l.
  • cycloalkyl is meant to include cycloalkyl radicals optionally substituted as described below by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -R b -OR a , -R b -SR a , -R b -OC(O)-R a , -R b - OC(O)-OR f , -R b -OC(O)-N(R a ) 2 , -R b -N(R a ) 2 , -R b -N + (R a ) 3 , -R b -C(
  • a “cycloalkylene” refers to a divalent radical derived from a “cycloalkyl” group as described above linking the rest of the molecule to a radical group.
  • the cycloalkylene is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • a cycloalkylene group is optionally substituted as described above for a cycloalkyl group.
  • Halo or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.
  • Fluoroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like.
  • Haloalkoxy or “haloalkoxyl” refers to an alkoxyl radical, as defined above, that is substituted by one or more halo radicals, as defined above.
  • fluoroalkoxy or “fluoroalkoxyl” refers to an alkoxy radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethoxy, difluoromethoxy, fluoromethoxy, and the like.
  • Heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-), sulfur, or combinations thereof.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a Ci-Ce heteroalkyl.
  • a heteroalkyl is a polyethylene glycol (PEG).
  • PEG polyethylene glycol
  • a Ci-Cio heteroalkyl comprises from 1 to 5 PEG groups.
  • a Ci-Cio heteroalkyl comprises from 1 to 3 PEG groups.
  • “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyl radicals, as defined above, e.g., hydroxymethyl, 1 -hydroxy ethyl, 2- hydroxyethyl, 2-hydroxypropyl, 3 -hydroxypropyl, 1,2-dihydroxy ethyl, 2,3-dihydroxypropyl, 2,3,4,5,6-pentahydroxyhexyl, and the like.
  • Heterocycloalkyl refers to a stable 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized.
  • the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl.
  • the heterocycloalkyl is a 3- to 6- membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl.
  • heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidin
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. More preferably, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e., skeletal atoms of the heterocycloalkyl ring).
  • heterocycloalkyl is meant to include heterocycloalkyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -R b - OR a , -R b -SR a , -R b -OC(O)-R a , -R b -OC(O)-OR f , -R b -OC(O)-N(R a ) 2 , -R b -N(R a ) 2 , -R b -N + (R a
  • A-heterocycloalkyl refers to a heterocycloalkyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocycloalkyl radical to the rest of the molecule is through a nitrogen atom in the heterocycloalkyl radical.
  • An N- heterocycloalkyl radical is optionally substituted as described above for heterocycloalkyl radicals.
  • C-heterocycloalkyl refers to a heterocycloalkyl radical as defined above and where the point of attachment of the heterocycloalkyl radical to the rest of the molecule is through a carbon atom in the heterocycloalkyl radical.
  • a C-heterocycloalkyl radical is optionally substituted as described above for heterocycloalkyl radicals.
  • a “heterocycloalkylene” refers to a divalent radical derived from a “heterocycloalkyl” group as described above linking the rest of the molecule to a radical group.
  • the heterocycloalkylene is attached to the rest of the molecule through a single bond and to the radical group through a single bond. Unless stated otherwise specifically in the specification, a heterocycloalkylene group is optionally substituted as described above for a heterocycloalkyl group.
  • Heteroaryl refers to a radical derived from a 5- to 18-membered aromatic ring radical that comprises one to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur.
  • the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ⁇ -electron system in accordance with the Hiickel theory.
  • the heteroaryl is a 5- to 10-membered heteroaryl.
  • the heteroaryl is a monocyclic heteroaryl, or a monocyclic 5- or 6- membered heteroaryl. In some embodiments, the heteroaryl is a 6,5-fused bicyclic heteroaryl.
  • the heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized.
  • the heteroaryl is attached to the rest of the molecule through any atom of the ring(s).
  • heteroaryl is meant to include heteroaryl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -R b -0R a , -R b -SR a , -R b -0C(0)-R a , -R b -0C(0)-0R f , -R b -OC(O)- N(R a ) 2 , -R b -N(R a ) 2 , -R b -N + (R a ) 3 ,
  • a “heteroarylene” refers to a divalent radical derived from a “heteroaryl” group as described above linking the rest of the molecule to a radical group.
  • the heteroarylene is attached to the rest of the molecule through a single bond and to the radical group through a single bond. Unless stated otherwise specifically in the specification, a heteroarylene group is optionally substituted as described above for a heteroaryl group.
  • an optionally substituted group may be unsubstituted (e.g., -CH 2 CH 3 ), fully substituted (e.g., -CF 2 CF 3 ), monosubstituted (e.g., -CH 2 CH 2 F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 3 , -CFHCHF 2 , etc.).
  • substituted alkyl includes optionally substituted cycloalkyl groups, which in turn are defined as including optionally substituted alkyl groups, potentially ad infinitum
  • substitution or substitution patterns e.g., substituted alkyl includes optionally substituted cycloalkyl groups, which in turn are defined as including optionally substituted alkyl groups, potentially ad infinitum
  • modulate refers to an increase or decrease in the amount, quality, or effect of a particular activity, function or molecule.
  • activators, agonists, partial agonists, inverse agonists, antagonists, inhibitors, and allosteric modulators of an enzyme are modulators of the enzyme.
  • agonism refers to the activation of a receptor or enzyme by a modulator, or agonist, to produce a biological response.
  • agonist refers to a modulator that binds to a receptor or target enzyme and activates the receptor or enzyme to produce a biological response.
  • AMPK activator can be used to refer to a compound that exhibits an ECso with respect to AMPK activity of no more than about 100 pM, as measured in the pAMPKl kinase activation assay.
  • agonist includes super agonists, full agonists or partial agonists.
  • the term “super agonist” as used herein refers to a modulator that is capable of producing a maximal response greater than the endogenous agonist for the target receptor or enzyme, and thus has an efficacy of more than 100%.
  • full agonist refers to a modulator that binds to and activates a receptor or target enzyme with the maximum response that an endogenous agonist can elicit at the receptor or enzyme.
  • partial agonist refers to a modulator that binds to and activates a receptor or target enzyme, but has partial efficacy, that is, less than the maximal response, at the receptor or enzyme relative to a full agonist.
  • positive allosteric modulator refers to a modulator that binds to a site distinct from the orthosteric binding site and enhances or amplifies the effect of an agonist.
  • antagonist refers to the inactivation of a receptor or target enzyme by a modulator, or antagonist. Antagonism of a receptor, for example, is when a molecule binds to the receptor or target enzyme and does not allow activity to occur.
  • antagonist refers to a modulator that binds to a receptor or target enzyme and blocks a biological response.
  • An antagonist has no activity in the absence of an agonist or inverse agonist but can block the activity of either, causing no change in the biological response.
  • inverse agonist refers to a modulator that binds to the same receptor or target enzyme as an agonist but induces a pharmacological response opposite to that agonist, i.e., a decrease in biological response.
  • negative allosteric modulator refers to a modulator that binds to a site distinct from the orthosteric binding site and reduces or dampens the effect of an agonist.
  • ECso is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% activation or enhancement of a biological process. In some instances, ECso refers to the concentration of agonist that provokes a response halfway between the baseline and maximum response in an in vitro assay. In some embodiments as used herein, ECso refers to the concentration of an activator (e.g., an AMPK activator) that is required for 50% activation of AMPK.
  • an activator e.g., an AMPK activator
  • IC50 is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% inhibition of a biological process.
  • IC50 refers to the half maximal (50%) inhibitory concentration (IC) of a substance as determined in a suitable assay.
  • an IC50 is determined in an in vitro assay system.
  • IC50 refers to the concentration of a modulator (e.g., an antagonist or inhibitor) that is required for 50% inhibition of a receptor or a target enzyme.
  • mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • gut-restricted refers to a compound, e.g., an AMPK activator, that is predominantly active in the gastrointestinal system.
  • the biological activity of the gut-restricted compound e.g., a gut-restricted AMPK activator, is restricted to the gastrointestinal system.
  • gastrointestinal concentration of a gut-restricted modulator is higher than the IC50 value or the EC50 value of the gut-restricted modulator against its receptor or target enzyme, e.g., AMPK, while the plasma levels of said gut-restricted modulator, e.g., gut-restricted AMPK activator, are lower than the IC50 value or the EC50 value of the gut-restricted modulator against its receptor or target enzyme, e.g., AMPK.
  • the gut-restricted compound e.g., a gut- restricted AMPK activator, is non-systemic.
  • the gut-restricted compound e.g., a gut-restricted AMPK activator
  • the gut-restricted compound is a non-absorbed compound.
  • the gut-restricted compound e.g., a gut-restricted AMPK activator
  • the gut-restricted compound e.g., a gut-restricted AMPK activator
  • the gut-restricted AMPK activator has high efflux. In other embodiments, the gut-restricted AMPK activator is a substrate for one or more intestinal efflux transporters such as P-gp (MDR1), BCRP, or MRP2.
  • the gut-restricted modulator e.g., a gut-restricted AMPK activator
  • the modulator e.g., a gut-restricted AMPK activator
  • the systemic exposure of a gut-restricted modulator, e.g., a gut-restricted AMPK activator is, for example, less than 100, less than 50, less than 20, less than 10, or less than 5 nM, bound or unbound, in blood serum.
  • the intestinal exposure of a gut-restricted modulator is, for example, greater than 1000, 5000, 10000, 50000, 100000, or 500000 nM.
  • a modulator e.g., a gut-restricted AMPK activator
  • a modulator e.g., a gut-restricted AMPK activator
  • a modulator is covalently bonded to a kinetophore, optionally through a linker, which changes the pharmacokinetic profile of the modulator.
  • the gut-restricted modulator is a soft drug.
  • soft drug refers to a modulator that is biologically active but is rapidly metabolized to metabolites that are significantly less active than the modulator itself toward the target receptor.
  • the gut-restricted modulator is a soft drug that is rapidly metabolized in the blood to significantly less active metabolites.
  • the gut-restricted modulator is a soft drug that is rapidly metabolized in the liver to significantly less active metabolites.
  • the gut-restricted modulator is a soft drug that is rapidly metabolized in the blood and the liver to significantly less active metabolites.
  • the gut-restricted modulator is a soft drug that has low systemic exposure.
  • the biological activity of the metabolite(s) is/are 10-fold, 20-fold, 50-fold, 100-fold, 500-fold, or 1000-fold lower than the biological activity of the soft drug gut-restricted modulator.
  • kinetophore refers to a structural unit tethered to a small molecule modulator, e.g., an AMPK activator, optionally through a linker, which makes the whole molecule larger and increases the polar surface area while maintaining biological activity of the small molecule modulator.
  • the kinetophore influences the pharmacokinetic properties, for example solubility, absorption, distribution, rate of elimination, and the like, of the small molecule modulator, e.g., an AMPK activator, and has minimal changes to the binding to or association with a receptor or target enzyme.
  • a kinetophore is not its interaction with the target, for example an enzyme, but rather its effect on specific physiochemical characteristics of the modulator to which it is attached, e.g., an AMPK activator.
  • kinetophores are used to restrict a modulator, e.g., an AMPK activator, to the gut.
  • linker refers to one or more bifunctional molecules which can be used to covalently bonded to the modulator, e.g., an AMPK activator, and kinetophore.
  • the linker is attached to any part of the modulator, e.g., an AMPK activator, so long as the point of attachment does not interfere with the binding of the modulator to its receptor or target enzyme.
  • the linker is non-cleavable. In some embodiments, the linker is cleavable. In some embodiments, the linker is cleavable in the gut. In some embodiments, cleaving the linker releases the biologically active modulator, e.g., an AMPK activator, in the gut.
  • the biologically active modulator e.g., an AMPK activator
  • GI system gastrointestinal system
  • GI tract gastrointestinal tract
  • the gastrointestinal tract includes the esophagus, stomach, small intestine, which includes the duodenumjejunum, and ileum, and large intestine, which includes the cecum, colon, and rectum.
  • the GI system refers to the “gut,” meaning the stomach, small intestines, and large intestines or to the small and large intestines, including, for example, the duodenum, jejunum, and/or colon.
  • the gut-brain axis refers to the bidirectional biochemical signaling that connects the gastrointestinal tract (GI tract) with the central nervous system (CNS) through the peripheral nervous system (PNS) and endocrine, immune, and metabolic pathways.
  • the gut-brain axis comprises the GI tract; the PNS including the dorsal root ganglia (DRG) and the sympathetic and parasympathetic arms of the autonomic nervous system including the enteric nervous system and the vagus nerve; the CNS; and the neuroendocrine and neuroimmune systems including the hypothalamic-pituitary-adrenal axis (HPA axis).
  • the gut-brain axis is important for maintaining homeostasis of the body and is regulated and modulates physiology through the central and peripheral nervous systems and endocrine, immune, and metabolic pathways.
  • the gut-brain axis modulates several important aspects of physiology and behavior. Modulation by the gut-brain axis occurs via hormonal and neural circuits. Key components of these hormonal and neural circuits of the gut-brain axis include highly specialized, secretory intestinal cells that release hormones (enteroendocrine cells or EECs), the autonomic nervous system (including the vagus nerve and enteric nervous system), and the central nervous system. These systems work together in a highly coordinated fashion to modulate physiology and behavior.
  • Defects in the gut-brain axis are linked to a number of diseases, including those of high unmet need.
  • Diseases and conditions affected by the gut-brain axis include central nervous system (CNS) disorders including mood disorders, anxiety, depression, affective disorders, schizophrenia, malaise, cognition disorders, addiction, autism, epilepsy, neurodegenerative disorders, Alzheimer’s disease, and Parkinson’s disease, Lewy Body dementia, episodic cluster headache, migraine, pain; metabolic conditions including diabetes and its complications such as chronic kidney disease/diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, cardiovascular disease, metabolic syndrome, obesity, dyslipidemia, and nonalcoholic steatohepatitis (NASH); eating and nutritional disorders including hyperphagia, cachexia, anorexia nervosa, short bowel syndrome, intestinal failure, intestinal insufficiency and other eating disorders; inflammatory disorders and autoimmune diseases such as inflammatory bowel disease, ulcerative colitis, Crohn’s disease, checkpoint inhibitor-induced colitis
  • Adenosine 5'-Monophosphate-Activated Protein Kinase (AMPK) in the Gut-Brain Axis is a serine/threonine kinase and is evolutionarily conserved from yeast to mammals.
  • AMPK is a heterotrimeric protein complex that is formed by one a (al or a2), one P (p 1 or P2), and one y (yl, y2, or y3) subunit. Due to the presence of isoforms of its components, there are 12 versions of AMPK (AMPK1, AMPK2, etc., through AMPK12).
  • AMPK acts as an energy sensor and is activated by upstream enzymes when the cellular ratio of adenosine 5'- monophosphate (AMP) to adenosine triphosphate (ATP) is elevated due to nutrient deprivation.
  • activated AMPK phosphorylates downstream substrates to promote catabolism and impede anabolism, leading to ATP production and energy restoration.
  • AMPK activity can be altered due to numerous physiological factors, such as hormones, cytokines and dietary nutrients, as well as pathological conditions such as obesity, chronic inflammation and type 2 diabetes.
  • AMPK activation leads to lower hepatic glucose production and plasma glucose levels.
  • AMPK activation can act as a therapeutic agent to treat various metabolic diseases.
  • AMPK has beneficial effects for gut health, such as enhancing intestinal absorption, improving barrier function, suppressing colorectal carcinogenesis, and reducing intestinal inflammation and metabolic-related disease, and is important for the maintenance of intestinal homeostasis.
  • AMPK is essential for proper intestinal health.
  • AMPK activation enhances paracellular junctions, nutrient transporters, autophagy and apoptosis, and suppresses inflammation and carcinogenesis in the intestine.
  • this disclosure provides AMPK activators that can be broadly used for multiple conditions and disorders associated with AMPK.
  • the condition or disorder is associated with the gut-brain axis.
  • the condition or disorder is a central nervous system (CNS) disorder including mood disorders, anxiety, depression, affective disorders, schizophrenia, malaise, cognition disorders, addiction, autism, epilepsy, neurodegenerative disorders, Alzheimer’s disease, and Parkinson’s disease, Lewy Body dementia, episodic cluster headache, migraine, pain; metabolic conditions including diabetes and its complications such as chronic kidney disease/diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, cardiovascular disease, metabolic syndrome, obesity, dyslipidemia, and nonalcoholic steatohepatitis (NASH); eating and nutritional disorders including hyperphagia, cachexia, anorexia nervosa, short bowel syndrome, intestinal failure, intestinal insufficiency and other eating disorders; inflammatory disorders and autoimmune diseases such as inflammatory bowel disease, ulcer
  • the condition or disorder is a metabolic disorder.
  • the condition or disorder is type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, nonalcoholic steatohepatitis, or hypertension.
  • the condition or disorder is a nutritional disorder.
  • the condition or disorder is short bowel syndrome, intestinal failure, or intestinal insufficiency.
  • the condition or disorder is inflammatory bowel disease including ulcerative colitis, Crohn’s disease and checkpoint inhibitor-induced colitis.
  • the condition or disorder is celiac disease, enteritis including chemotherapy -induced enteritis or radiation-induced enteritis, necrotizing enterocolitis; or gastrointestinal injury resulting from toxic insults such as radiation or chemotherapy.
  • the condition or disorder is diseases/disorders of gastrointestinal barrier dysfunction including environmental enteric dysfunction, spontaneous bacterial peritonitis; allergy including food allergy, celiac sprue, and childhood allergy; graft vs.
  • the condition or disorder is associated with systemic infection and inflammation from having a leaky gut barrier.
  • the condition or disorder is 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, allergy including food allergy, celiac sprue, and childhood allergy, graft vs. host disease, irritable bowel syndrome, spontaneous bacterial peritonitis, ischemic colitis, sclerosing cholangitis, Alzheimer’s disease, Parkinson’s disease, cancer including colorectal cancer, depression, autism, or a combination thereof.
  • NASH nonalcoholic steatohepatitis
  • fibrotic disorders including scleroderma, inflammatory bowel disease including Crohn’s disease and ulcerative colitis
  • allergy including food allergy, celiac sprue, and childhood allergy
  • graft vs. host disease irritable bowel syndrome, spontaneous
  • the gut mucosa maintains immune homeostasis under physiological circumstances by serving as a barrier that restricts access of microbes, diverse microbial products, food antigens and toxins in the lumen of the gut to rest of the body.
  • the gut barrier is comprised of a single layer of epithelial cells, bound by cell-cell junctions, and a layer of mucin that covers the epithelium.
  • an impaired gut barrier e.g. a leaky gut
  • AMPK which is associated with the maintenance of tight junction in colonic epithelium, controls the progression of colitis.
  • expression and assembly of tight junctions is dependent on AMPK activity.
  • the present disclosure provides methods effective to strengthen/protect the gut barrier and reduce and/or prevent the progression of chronic diseases.
  • the gut barrier is a critical frontier that separates microbes and antigens in the lumen of the gut from the rest of the body; a compromised “leaky” gut barrier is frequently associated with systemic infection and inflammation, which is a key contributor to many chronic allergic, infectious, metabolic and autoimmune diseases such as obesity, diabetes, inflammatory bowel diseases, food allergy, and metabolic endotoxemia.
  • this disclosure provides AMPK activators that can be broadly used for multiple conditions and disorders associated with AMPK.
  • the condition or disorder is associated with systemic infection and inflammation from having a leaky gut barrier.
  • a leaky gut barrier can fuel the progression of multiple chronic diseases, including but not limited to: 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, ulcerative colitis, checkpoint inhibitor-induced colitis, allergy including food allergy, celiac sprue, and childhood allergy, graft vs.
  • metabolic syndrome including 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,
  • irritable bowel syndrome spontaneous bacterial peritonitis, ischemic colitis, sclerosing cholangitis, Alzheimer’s disease, Parkinson’s disease, cancer including colorectal cancer, depression, autism, or a combination thereof.
  • AMPK activators are useful for the treatment of gastrointestinal injury.
  • AMPK activators are useful for the treatment of gastrointestinal injury resulting from toxic insult.
  • the toxic insult is from radiation, chemotherapy, or a combination thereof.
  • the toxic insult is radiation- induced.
  • the toxic insult is chemotherapy -induced.
  • systemic AMPK activation for example, AMPK activation in the heart.
  • activating mutations in the AMPK y2-subunit lead to PRKAG2 cardiomyopathy.
  • systemic AMPK activation results in cardiac hypertrophy and increased cardiac glycogen.
  • tissue selective AMPK activation is an attractive approach for developing AMPK activators to treat disease.
  • the AMPK activator is gut-restricted. In some embodiments, the AMPK activator is designed to be substantially non-permeable or substantially non- bioavailable in the blood stream. In some embodiments, the AMPK activator is designed to activate AMPK activity in the gut and is substantially non-systemic. In some embodiments, the AMPK activator has low systemic exposure.
  • a gut-restricted AMPK activator has low oral bioavailability. In some embodiments, a gut-restricted AMPK activator has ⁇ 40% oral bioavailability, ⁇ 30% oral bioavailability, ⁇ 20% oral bioavailability, ⁇ 10% oral bioavailability, ⁇ 8% oral bioavailability, ⁇ 5% oral bioavailability, ⁇ 3% oral bioavailability, or ⁇ 2% oral bioavailability.
  • the unbound plasma levels of a gut-restricted AMPK activator are lower than the ECso value of the AMPK activator against AMPK. In some embodiments, the unbound plasma levels of a gut-restricted AMPK activator are significantly lower than the ECso value of the gut-restricted AMPK activator against AMPK. In some embodiments, the unbound plasma levels of the AMPK activator are 2-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, or 100-fold lower than the ECso value of the gut-restricted AMPK activator against AMPK.
  • a gut-restricted AMPK activator has low systemic exposure.
  • the systemic exposure of a gut-restricted AMPK activator is, for example, less than 500, less than 200, less than 100, less than 50, less than 20, less than 10, or less than 5 nM, bound or unbound, in blood serum.
  • the systemic exposure of a gut- restricted AMPK activator is, for example, less than 500, less than 200, less than 100, less than 50, less than 20, less than 10, or less than 5 ng/mL, bound or unbound, in blood serum.
  • a gut-restricted AMPK activator has high intestinal exposure.
  • the intestinal exposure of a gut-restricted AMPK activator is, for example, greater than 1, 5, 10, 50, 100, 250 or 500 pM.
  • a gut-restricted AMPK activator has high exposure in the colon.
  • the colon exposure of a gut-restricted AMPK activator is, for example, greater than 1, 5, 10, 50, 100, 250 or 500 pM.
  • the colon exposure of a gut-restricted AMPK activator is, for example, greater than 100 pM.
  • a gut-restricted AMPK activator has low permeability. In some embodiments, a gut-restricted AMPK activator has low intestinal permeability. In some embodiments, the permeability of a gut-restricted AMPK activator is, for example, less than 5.0x l0' 6 cm/s, less than 2.0> ⁇ 10' 6 cm/s, less than 1.5 x 10" 6 cm/s, less than l.Ox lO' 6 cm/s, less than 0.75x l0' 6 cm/s, less than 0.50x l0' 6 cm/s, less than 0.25x l0' 6 cm/s, less than O.lOx lO' 6 cm/s, or less than 0.05x l0' 6 cm/s.
  • a gut-restricted AMPK activator has low absorption. In some embodiments, the absorption of a gut-restricted AMPK activator is less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, or less than 1%.
  • a gut-restricted AMPK activator has high plasma clearance. In some embodiments, a gut-restricted AMPK activator is undetectable in plasma in less than 8 hours, less than 6 hours, less than 4 hours, less than 3 hours, less than 120 min, less than 90 min, less than 60 min, less than 45 min, less than 30 min, or less than 15 min.
  • a gut-restricted AMPK activator is rapidly metabolized upon administration.
  • a gut-restricted AMPK activator has a short half-life.
  • the half-life of a gut-restricted AMPK activator is less than less than 8 hours, less than 6 hours, less than 4 hours, less than 3 hours, less than 120 min, less than 90 min, less than 60 min, less than 45 min, less than 30 min, or less than 15 min.
  • the metabolites of a gut-restricted AMPK activator have rapid clearance.
  • the metabolites of a gut-restricted AMPK activator are undetectable in less than 8 hours, less than 6 hours, less than 4 hours, less than 3 hours, less than 120 min, less than 90 min, less than 60 min, less than 45 min, less than 30 min, or less than 15 min. In some embodiments, the metabolites of a gut-restricted AMPK activator have low bioactivity.
  • the ECso value of the metabolites of a gut-restricted AMPK activator is 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 100-fold, 500-fold, or 1000-fold higher than the EC50 value of the gut-restricted AMPK activator against AMPK.
  • the metabolites of a gut-restricted AMPK activator have rapid clearance and low bioactivity.
  • the gut-restricted AMPK activator has high efflux.
  • the gut-restricted AMPK activator is a substrate for one or more intestinal efflux transporters such as P-gp (MDR1), BCRP, or MRP2.
  • the efflux of the gut-restricted AMPK activator as measured by the B-A/A-B ratio in a cell line such as Caco-2 or MDCK with or without over-expression of one or more efflux transporters is, for example, greater than 2, greater than 5, greater than 10, greater than 25, or greater than 50.
  • the AMPK activator is gut- restricted.
  • the AMPK activator is a gut-restricted AMPK agonist. In some embodiments, the AMPK activator is a gut-restricted AMPK super agonist. In some embodiments, the AMPK activator is a gut-restricted AMPK full agonist. In some embodiments, the AMPK activator is a gut-restricted AMPK partial agonist. In some embodiments, the AMPK activator is covalently bonded to a kinetophore. In some embodiments, the AMPK activator is covalently bonded to a kinetophore through a linker.
  • R 1 , R 2 , and R 3 are each independently selected at each occurrence from halogen, hydroxyl, C 1-4 alkyl, -CN, and Ci.4 haloalkyl; n is selected from 0, 1, 2, 3, and 4; o is selected from 0, 1, 2, 3, and 4; p is selected from 0, 1, and 2;
  • R 4 is selected from hydrogen, halogen, C 1-4 alkyl, and C 1-4 haloalkyl;
  • R 5a and R 5b are each independently selected from hydrogen, C 1-4 alkyl, and C 1-4 haloalkyl;
  • R 6 is selected from hydrogen and C 1-4 alkyl
  • D is selected from -CO 2 R 11 , -P(O)(OR 11 ) 2 , -P(O)R 11 (OR 11 ), -S(O) 2 OH, and -L-K;
  • L is selected from ⁇ -(C(R 13 ) 2 ) r -, ⁇ -O(C(R 13 ) 2 ) r -, ⁇ -(C(R 13 ) 2 ) r O-, ⁇ -N(R 12 )(C(R 13 ) 2 ) S -, ⁇ -C(O)O-, ⁇ -OC(O)-, ⁇ -C(O)N(R 12 )-, ⁇ -N(R 12 )C(O)-, ⁇ -N(R 12 )S(O) 2 -, ⁇ -S(O) 2 N(R 12 )-, and 4- to 6- membered heterocycle wherein 1 denotes the connection to K; r is selected from 1, 2, and 3; s is selected from 0, 1, 2, and 3;
  • K is selected from (i) and (ii):
  • substituents are selected from among a subset of the listed alternatives.
  • Y is CR 4 .
  • R 4 is hydrogen or halogen.
  • R 4 is hydrogen or fluoro.
  • Y is N, CH, or CF.
  • Y is N.
  • Y is CH.
  • Y is CF.
  • R 6 is hydrogen. In some embodiments, R 6 is C 1-4 alkyl. In some embodiments, R 6 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, and tert-butyl. In some embodiments, R 6 is methyl or ethyl. In some embodiments, R 6 is methyl. In some embodiments, R 6 is ethyl.
  • R 6 is hydrogen, methyl, or ethyl. In some embodiments, R 6 is hydrogen or methyl.
  • the compound is represented by Formula (II): or a pharmaceutically acceptable salt thereof.
  • n is selected from 0 and 1. In some embodiments, n is selected from 1 and 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.
  • each R 1 is independently selected at each occurrence from halogen, hydroxyl, and C 1-4 alkyl. In some embodiments, each R 1 is independently selected at each occurrence from F, Cl, hydroxyl, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, secbutyl, and tert-butyl. In some embodiments, each R 1 is F, Cl, methyl, or hydroxyl. In some embodiments, each R 1 is methyl. In some embodiments, each R 1 is hydroxyl.
  • R 1 is hydroxyl
  • n is selected from 0 and 1.
  • each R 2 is independently selected at each occurrence from halogen, hydroxyl, and C 1-4 alkyl. In some embodiments, each R 2 is independently selected at each occurrence from F, Cl, hydroxyl, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec- butyl, and tert-butyl. In some embodiments, each R 2 is F, Cl, methyl, or hydroxyl.
  • p is selected from 0 and 1. In some embodiments, p is selected from 1 and 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.
  • each R 3 is independently selected at each occurrence from halogen, hydroxyl, and C 1-4 alkyl. In some embodiments, each R 3 is independently selected at each occurrence from F, Cl, hydroxyl, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec- butyl, and tert-butyl. In some embodiments, each R 3 is halogen. In some embodiments, each R 3 is F or Cl. In some embodiments, each R 3 is F. In some embodiments, each R 3 is Cl.
  • R 3 is halogen, and p is selected from 0 and 1. In some embodiments, R 3 is selected from fluoro and chloro, and p is 1. In some embodiments, R 3 is fluoro, and p is 1. In some embodiments, R 3 is chloro, and p is 1.
  • R 5a and R 5b are each independently selected from hydrogen and C 1-4 alkyl. In some embodiments, R 5a and R 5b are each independently selected from hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, and tert-butyl. In some embodiments, R 5a and R 5b are each independently selected from hydrogen, methyl, and ethyl. In some embodiments, R 5a and R 5b are each hydrogen.
  • D is selected from -CO2R 11 , -P(O)(OR n ) 2 , -P(O)R 11 (OR 11 ), and -S(O) 2 OH.
  • D is selected from -CO 2 H, -CC 2 Me, -CCFEt, -P(O)(OH) 2 , - P(O)(OMe) 2 , -P(O)Me(OMe), -P(O)Me(OH), and -S(O) 2 OH.
  • D is selected from -CO 2 H, -P(O)(OH) 2 , -P(O)Me(OH), and -S(O) 2 OH. In some embodiments, D is selected from -P(O)(OR n ) 2 , and -S(O) 2 OH. In some embodiments, D is selected from - P(O)(OH) 2 , -P(O)(OMe) 2 , and -S(O) 2 OH. In some embodiments, D is selected from -P(O)(OH) 2 and -S(O) 2 OH.
  • D is -L-K.
  • L is z -(C(R 13 ) 2 )r-. In some embodiments, L is z -O(C(R 13 ) 2)r- . In some embodiments, L is ⁇ -(C(R 13 ) 2 )rO-. In some embodiments, L is ⁇ -N(R 12 )(C(R 13 ) 2)S -. In some embodiments, L is ⁇ -C(O)O-. In some embodiments, L is ⁇ -OC(O)-. In some embodiments, L is ⁇ -C(O)N(R 12 )-. In some embodiments, L is z -N(R 12 )C(O)-.
  • L is x - N(R 12 )S(O) 2 -. In some embodiments, L is ⁇ -S(O) 2 N(R 12 )-. In some embodiments, L is 4- to 6- membered heterocycle. [00110] In some embodiments, L is selected from z -(C(R 13 ) 2 )r-, ⁇ -N(R 12 )(C(R 13 ) 2)S -, and ⁇ - N(R 12 )S(O) 2 -.
  • r is selected from 1 and 2. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3.
  • s is selected from 0, 1, and 2. In some embodiments, s is 0. In some embodiments, s is 1. In some embodiments, s is 2. In some embodiments, s is 3.
  • K is selected from (i) and (ii):
  • K is selected from C 1-10 alkyl or C 1-10 heteroalkyl, each of which is optionally substituted with one to six substituents independently selected from: halogen, -OR 14 , -N(R 14 ) 2 , -N + (R 15 ) 3 , -C(O)R 14 , -C(O)OR 14 , -OC(O)R 14 , -C(O)N(R 14 ) 2 , - N(R 14 )C(O)R 14 , -S(O) 2 R 14 , -P(O)(OR 16 ) 2 , -P(O)R 16 (OR 16 ), -S(O) 2 OH, C 3-10 carbocycle and 3- to 10-membered heterocycle.
  • K is selected from C 1-10 alkyl and C 1-10 heteroalkyl, each of which is optionally substituted with one to six substituents independently selected from -OR 14 . In some embodiments, K is selected from C 1-10 alkyl and C 1-10 heteroalkyl, each of which is optionally substituted with one to six -OH substituents.
  • K is C 1-10 alkyl, which is optionally substituted with one to six substituents independently selected from -OR 14 . In some embodiments, K is C 1-10 alkyl, each of which is optionally substituted with one to six -OH substituents.
  • K is C 1-10 heteroalkyl, which is optionally substituted with one to six substituents independently selected from -OR 14 . In some embodiments, K is C 1-10 heteroalkyl, each of which is optionally substituted with one to six -OH substituents.
  • K is selected from 3- to 10-membered heterocycle optionally substituted with one to six substituents independently selected from halogen, -OR 14 , C 1-10 alkyl, and C 1-10 heteroalkyl, wherein each C 1-10 alkyl and C 1-10 heteroalkyl is optionally substituted with one to six substituents independently selected from halogen, -OR 14 , -N(R 14 ) 2 , -P(O)(OR 16 ) 2 , -S(O) 2 OH, and S(O) 2 R 14 .
  • K is selected from azetidine and piperazine, each of which is optionally substituted with one to six substituents independently selected from C 1-10 alkyl and C 1-10 heteroalkyl, wherein each C 1-10 alkyl and C 1-10 heteroalkyl is optionally substituted with one to six substituents independently selected from -OR 14 and -N(R 14 ) 2 .
  • each R 14 is independently selected at each occurrence from hydrogen and C 1-10 alkyl optionally substituted with one to six substituents independently selected from -OR 21 .
  • each R 14 is independently selected at each occurrence from hydrogen and C 1-10 alkyl optionally substituted with one to six -OH substituents. In some embodiments, each R 14 is independently selected at each occurrence from hydrogen and C 1-6 alkyl.
  • each R 21 is independently selected at each occurrence from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 hydroxyalkyl.
  • each R 21 is independently selected at each occurrence from hydrogen and C 1-6 alkyl.
  • D is selected from:
  • the compound is a compound in one of the following tables, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.
  • the compound is a pharmaceutically acceptable salt of a compound in Table 1.
  • the compound is a pharmaceutically acceptable salt of a compound in Table 2.
  • the compounds described herein exist as “geometric isomers.” In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti,
  • Z) isomers as well as the corresponding mixtures thereof. In some situations, compounds exist as tautomers.
  • a “tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible.
  • the compounds presented herein exist as tautomers.
  • a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH.
  • the compounds described herein possess one or more chiral centers and each center exists in the (R)- configuration or (5)- configuration.
  • the compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
  • the compounds described herein are prepared as optically pure enantiomers by chiral chromatographic resolution of the racemic mixture.
  • the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers.
  • dissociable complexes are preferred (e.g., crystalline diastereomeric salts).
  • the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities.
  • the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • positional isomer refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.
  • compositions described herein include the use of crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of compounds described herein, as well as active metabolites of these compounds having the same type of activity.
  • “Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • a pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms.
  • Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
  • acetic acid trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like.
  • salts of amino acids such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 66:1- 19 (1997).
  • Acid addition salts of basic compounds are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt.
  • “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropyl amine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N- dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, 7V-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, 7V-ethylpiperidine, polyamine resins and the like.
  • prodrug is meant to indicate a compound that is, in some embodiments, converted under physiological conditions or by solvolysis to an active compound described herein.
  • prodrug refers to a precursor of an active compound that is pharmaceutically acceptable.
  • a prodrug is typically inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis.
  • the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).
  • prodrugs are also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of an active compound, as described herein are prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound.
  • Prodrugs include compounds wherein a hydroxy, amino, carboxy, or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino, free carboxy, or free mercapto group, respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amine functional groups in the active compounds and the like.
  • solvates refers to a composition of matter that is the solvent addition form.
  • solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • “Hydrates” are formed when the solvent is water, or “alcoholates” are formed when the solvent is alcohol.
  • Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein optionally exist in either unsolvated as well as solvated forms.
  • the compounds disclosed herein are used in different enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, 11 C, 13 C and/or 14 C.
  • the compound is deuterated in at least one position.
  • deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.
  • structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of the present disclosure.
  • the compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds.
  • the compounds may be labeled with isotopes, such as for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
  • isotopes such as for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
  • Isotopic substitution with 2 H, 3 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 17 O, 18 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 C1, 37 C1, 79 Br, 81 Br, 125 I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the
  • the compounds disclosed herein have some or all of the 4 H atoms replaced with 2 H atoms.
  • the methods of synthesis for deuterium-containing compounds are known in the art.
  • deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.
  • the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • the compounds described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, as described herein are substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as contaminating intermediates or by-products that are created, for example, in one or more of the steps of a synthesis method.
  • Compound B is treated with thiophosgene to afford compound C.
  • Compound C undergoes an alkylation reaction with an appropriate alkyl bromide compound to afford compound D.
  • aryl iodide D is treated under cross-coupling conditions, for example Suzuki cross-coupling, to arrive at Compounds of Formula (I).
  • additional chemical modification such as saponification, amide formation, or reductive amination, is performed on the Compounds of Formula (I) to afford additional compounds.
  • PG is a suitable protecting group; a. CH 3 I; b. [ox]; c. (substituted biphenyl)-B(OR) 2 ; d. protection; e. Na 2 S; f. X- CR 2 -CO 2 R, where X is a suitable leaving group; g. deprotection
  • Compound C undergoes a methylation reaction following by oxidation to afford compound E.
  • Aryl iodide E is treated under cross-coupling conditions, for example Suzuki cross-coupling, to arrive at compound F.
  • Compound F is suitably protected to Compound G.
  • Aryl sulfone G is converted to Compound H, which subsequently undergoes an alkylation reaction with an appropriate alkyl halide compound to afford compound J.
  • compound J is deprotected to arrive at Compounds of Formula (I).
  • additional chemical modification such as saponification, amide formation, or reductive amination, is performed on the Compounds of Formula (I) to afford additional compounds.
  • compounds described herein are prepared as described as outlined in the Examples.
  • a pharmaceutical composition comprising an AMPK activator described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, and at least one pharmaceutically acceptable excipient.
  • the AMPK activator is combined with a pharmaceutically suitable (or acceptable) carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration, e.g., oral administration, and standard pharmaceutical practice.
  • aqueous and non-aqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof; vegetable oils, such as olive oil; and injectable organic esters, such as ethyl oleate and cyclodextrins.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate and cyclodextrins.
  • Proper fluidity is maintained, for example, by the use of coating materials, such as lecithin; by the maintenance of the required particle size, in the case of dispersions; and by the use of surfactants.
  • a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof is administered in combination with one or more anti-inflammatory agents.
  • anti-inflammatory agents include, but are not limited to: aminosalicylates such as balsalazide, mesalamine, olsalazine, and sulfalazine; corticosteroids such as budesonide, prednisone, prednisolone, methylprednisolone, dexamethasone, and betamethasone; anti-TNF alpha agents such as infliximab, adalimumab, certolizumab pegol, golimumab, and PRX-106; anti-IL-12 and/or 23 agents such as ustekinumab, guse
  • a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof is administered in combination with a aminosalicylate, a corticosteroid, an anti-TNF alpha agent, an anti-IL-12 and/or 23 agent, an anti-integrin agent, a JAK inhibitor, a S1P1R modulator, a salicylate, a COX inhibitor, a COX-2 specific inhibitor, an interleukin-22 (IL-22) agent, or a combination thereof.
  • a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof is administered in combination with one or more agents that improve gastrointestinal barrier function.
  • agents that improve gastrointestinal barrier function to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof include, but are not limited to: HIF-PH inhibitors such as DS-1093, TRC-160334, and GB-004; MC1R agonists such as PL-8177; EZH2 inhibitors such as IMU-856; and DPP-4 inhibitors such as sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, teneligliptin, alogliptin, trelagliptin, omarigliptin, evogliptin, gosogliptin, and dutogliptin.
  • HIF-PH inhibitors such as DS-1093, TRC-160334, and GB-004
  • MC1R agonists such as PL-8177
  • EZH2 inhibitors such
  • a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof is administered in combination with a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, a melanocortin-1 receptor (MC1R) agonist, an enhancer of zeste homolog 2 (EZH2) inhibitor, or combinations thereof.
  • HIF-PH hypoxia-inducible factor-prolyl hydroxylase
  • M1R melanocortin-1 receptor
  • EZH2 enhancer of zeste homolog 2
  • a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof is administered in combination with a glucagon- like peptide (GLP)-l agonist, a GLP-2 agonist, a GLP-1/2 co-agonist, a peroxisome proliferator- activator receptor (PPAR) agonist, a Farsnenoid X receptor (FXR) agonist, a TGR5 agonist, a GPR40 agonist, a GPR119 agonist, an SSTR5 antagonist, an SSTR5 inverse agonist, an acetyl- CoA carboxylase (ACC) inhibitor, a stearoyl-CoA desaturase 1 (SCD-1) inhibitor, a dipeptidyl peptidase 4 (DPP-4) inhibitor, or combinations thereof.
  • GLP glucagon- like peptide
  • PPAR peroxisome proliferator- activator receptor
  • FXR Farsnenoid X
  • the pharmaceutical composition comprises one or more anti-diabetic agents. In some embodiments, the pharmaceutical composition comprises one or more anti-obesity agents. In some embodiments, the pharmaceutical composition comprises one or more agents to treat nutritional disorders.
  • a GLP-1 agonist to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof include: exenatide, liraglutide, taspoglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, OWL833 and ORMD 0901.
  • Examples of a GLP-2 agonist to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof include: tedaglutide, glepaglutide (ZP1848), elsiglutide (ZP1846), apraglutide (FE 203799), HM-15912, NB-1002, GX-G8, PE-0503, and SAN-134, and those described in WO-2011050174, WO- 2012028602, WO-2013164484, WO-2019040399, WO-2018142363, WO-2019090209, WO- 2006117565, WO-2019086559, WO-2017002786, WO-2010042145, WO-2008056155, WO- 2007067828, WO-2018229252, WO-2013040093, WO-2002066511, WO-2005067368, WO- 2009739031, WO-200963
  • Examples of a GLP-1/2 co-agonist to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include ZP-GG-72 and those described in WO-2018104561, WO-2018104558, WO- 2018103868, WO-2018104560, WO-2018104559, WO-2018009778, WO-2016066818, and WO-2014096440..
  • Examples of a PPAR agonist to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include: elafibranor (GFT505), lanifibranor, pioglitazone, rosiglitazone, saroglitazar, seladelpar, and GW501516.
  • Examples of a FXR agonist to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include: obeticholic acid, NGM-282, EYP001, GS-9674, tropifexor (LJN452), and LMB-763.
  • Examples of a TGR5 agonist to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof include: INT-777, XL-475, SRX-1374, RDX-8940, RDX-98940, SB-756050, and those disclosed in WO-2008091540, WO-2010059853, WO-2011071565, WO-2018005801, WO-2010014739, WO-2018005794, WO-2016054208, WO-2015160772, WO-2013096771, WO-2008067222, WO-2008067219, WO-2009026241, WO-2010016846, WO-2012082947, WO-2012149236, WO-2008097976, WO-2016205475, WO-2015183794, WO-2013054338, WO-2010059859, WO-2010014836, WO-20160
  • Examples of a GPR40 agonist to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof include: fasiglifam, MR-1704, SCO-267, SHR-0534, HXP-0057-SS, LY-2922470, P-11187, JTT-851, ASP-4178, AMG-837, ID-11014A, HD-C715, CNX-011-67, JNJ-076, TU-5113, HD-6277, MK-8666, LY-2881835, CPL-207-280, ZYDG-2, and those described in US-07750048, WO- 2005051890, WO-2005095338, WO-2006011615, WO-2006083612, WO-2006083781, WO- 2007088857, WO-2007123225, WO-2007136572, WO-2008054674, WO-20080546
  • Examples of a GPR119 agonist to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof include: DS-8500a, HD-2355, LC34AD3, PSN-491, HM-47000, PSN-821, MBX-2982, GSK-1292263, APD597, DA-1241, and those described in WO-2009141238, WO-2010008739, WO- 2011008663, WO-2010013849, WO-2012046792, WO-2012117996, WO-2010128414, WO- 2011025006, WO-2012046249, WO-2009106565, WO-2011147951, WO-2011127106, WO- 2012025811, WO-2011138427, WO-2011140161, WO-2011061679, WO-2017175066, WO- 2017175068, WO-2015080446, WO-20131
  • Examples of a SSTR5 antagonist or inverse agonist to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof include those described in: WO-03104816, WO-2009050309, WO- 2015052910, WO-2011146324, WO-2006128803, WO-2010056717, WO-2012024183, and WO-2016205032.
  • Examples of an ACC inhibitor to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include: firsocostat, GS-834356, and PF-05221304.
  • Examples of a SCD-1 inhibitor to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include aramchol.
  • Examples of a DPP -4 inhibitor to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof include: sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, teneligliptin, alogliptin, trelagliptin, omarigliptin, evogliptin, gosogliptin, and dutogliptin.
  • anti-diabetic agents examples include: GLP-1 receptor agonists such as exenatide, liraglutide, taspoglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, OWL833 and ORMD 0901; SGLT2 inhibitors such as dapagliflozin, canagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin, sergliflozin, sotagliflozin, and tofogliflozin; biguinides such as metformin; insulin and insulin analogs.
  • GLP-1 receptor agonists such as exenatide, liraglutide, taspoglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, OWL833 and ORMD 0901
  • SGLT2 inhibitors such as
  • anti-obesity agents examples include: GLP-1 receptor agonists such as liraglutide, semaglutide; SGLT1/2 inhibitors such as LIK066, pramlintide and other amylin analogs such as AM-833, AC2307, and BI 473494; PYY analogs such as NN-9747, NN-9748, AC-162352, AC-163954, GT-001, GT-002, GT-003, and RHS-08; GIP receptor agonists such as APD-668 and APD-597; GLP-l/GIP co-agonists such as tirzepatide (LY329176), BHM-089, LBT-6030, CT-868, SCO-094, NNC-0090-2746, RG-7685, NN-9709, and SAR-438335; GLP-l
  • agents for nutritional disorders include: GLP-2 receptor agonists such as tedaglutide, glepaglutide (ZP1848), elsiglutide (ZP1846), apraglutide (FE 203799), HM-15912, NB-1002, GX-G8, PE-0503, SAN- 134, and those described in WO-2011050174, WO-2012028602, WO-2013164484, WO- 2019040399, WO-2018142363, WO-2019090209, WO-2006117565, WO-2019086559, WO- 2017002786, WO-2010042145, WO-2008056155, WO-2007067828, WO-2018229252, WO- 2013040093, WO-2002066511, WO-2005067368, WO-200973
  • the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).
  • an adjuvant i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced.
  • the benefit experienced by a patient is increased by administering one of the compounds described herein with another agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
  • a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof is co-administered with one or more additional therapeutic agents, wherein the compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, and the additional therapeutic agent(s) modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.
  • the additional therapeutic agent(s) is a glucagon-like peptide (GLP)-l agonist, a GLP-2 agonist, a GLP-1/2 co-agonist, a peroxisome proliferator-activator receptor (PPAR) agonist, a Farsnenoid X receptor (FXR) agonist, a stearoyl-CoA desaturase 1 (SCD-1) inhibitor, a dipeptidyl peptidase 4 (DPP -4) inhibitor, or a combination thereof.
  • the second therapeutic agent is an anti-inflammatory agent.
  • the additional therapeutic agent(s) is an aminosalicylate, a corticosteroid, an anti-TNF alpha agent, an anti-IL- 12 and/or 23 agent, an anti-integrin agent, a JAK inhibitor, a S1P1R modulator, a salicylate, a COX inhibitor, a COX-2 specific inhibitor, an IL-22 agent, or a combination thereof.
  • the second therapeutic agent is an agent that improves gastrointestinal barrier function.
  • the additional therapeutic agent(s) is a HIF-PH inhibitor, an MC1R agonist, an EZH2 inhibitor, or a combination thereof.
  • the overall benefit experienced by the patient is additive of the two (or more) therapeutic agents. In other embodiments, the patient experiences a synergistic benefit of the two (or more) therapeutic agents.
  • the multiple therapeutic agents are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills).
  • the compounds described herein, or pharmaceutically acceptable salts, solvates, stereoisomers, or prodrugs thereof, as well as combination therapies, are administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies.
  • the compounds described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition.
  • the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms.
  • a compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease.
  • a compound described herein, or a pharmaceutically acceptable salt thereof is administered in combination with anti-inflammatory agent, anti-cancer agent, immunosuppressive agent, steroid, non-steroidal anti-inflammatory agent, antihistamine, analgesic, hormone blocking therapy, radiation therapy, monoclonal antibodies, or combinations thereof.
  • Step 1 2-(2-(((4'-bromo-[l,l'-biphenyl]-4-yl)methyl)amino)ethoxy)ethanol (21-1):
  • Step 2 tert-butyl ((4'-bromo-[l,l'-biphenyl]-4-yl)methyl)(2-(2- hydroxyethoxy)ethyl)carbamate (21-2): To a solution of 21-1 (17 g, 48 mmol, 1 eq) in THF (200 mL) was added DIEA (28 g, 0.22 mol, 38 mL, 4.5 eq) and BOC2O (42 g, 0.2 mol, 45 mL, 4 eq). The mixture was stirred at 25 °C for 2 hours. The solution was diluted with water (100 mL), then extracted with EA (100 mL x 6).
  • Step 3 tert-butyl (2-(2-hydroxyethoxy)ethyl)((4'-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-[l,l'-biphenyl]-4-yl)methyl)carbamate (21-3): To a solution of 21-2 (18 g, 40 mmol, 1 eq) in dioxane (400 mL) was added KO Ac (12 g, 0.12 mol, 3 eq) and BPD (15 g, 60 mmol, 1.5 eq).
  • Step 6 5-chloro-6-iodopyridine-2,3-diamine (21-6): To a solution 21-5 of (60 g, 0.20 mol, 1 eq) in EtOH (300 mL) was added SnC1 2 2H 2 O (0.18 kg, 0.80 mol, 4 eq). The mixture was stirred at 70 °C for 0.5 hr. To the mixture was added water (450 mL) and KF (0.18 kg), and the mixture was stirred for 0.5 h, then extracted with ethyl acetate (2 x 100 mL). The organic phase was washed with saturated brine (2 x 50 mL), then concentrated in vacuo.
  • Step 7 6-chloro-5-iodo-l//-imid:izo
  • LCMS (ES + ): m/z (M+H) + 311.8.
  • Step 8 6-chloro-5-iodo-2-(methylthio)-3//-imid:izo [4,5-6] pyridine (21-8): A solution of 21-7 (22 g, 70 mmol, 1 eq) and KOH (4.7 g, 84 mmol, 1.2 eq) in EtOH (440 mL) was stirred at room temperature for 0.5 hr. Mel (10.0 g, 70 mmol, 4.4 mL, 1 eq) was added, and the reaction was stirred at room temperature for another 1 hr.
  • Step 9 6-chloro-5-iodo-2-(niethylsullonyl)-3//-iniid:izo [4,5-6] pyridine (21-9): To a solution of 21-8 (16 g, 49 mmol, 1 eq) in ACN (320 mL) and H2O (320 mL) was added Oxone (66 g, 0.11 mmol, 2.2 eq). The mixture was stirred at room temperature for 12 hrs. The mixture was extracted with ethyl acetate (3 x 400 mL).
  • Step 10 tert-butyl ((4'-(6-chloro-2-(methylsulfonyl)-lH-imidazo[4,5-b]pyridin-5- yl)-[l,l'-biphenyl]-4-yl)methyl)(2-(2-hydroxyethoxy)ethyl)carbamate (21-10): To a solution of 21-9 (20 g, 28 mmol, 50% purity, 1 eq) and 21-3 (28 g, 28 mmol, 50% purity, 1 eq) in dioxane (500 mL) and water (100 mL) was added Na 2 CO 3 (8.9 g, 84 mmol, 3 eq) and Pd(dppf)C12*CH2C12 (2.3 g, 2.8 mmol, 0.1 eq).
  • Step 11 tert-butyl ((4'-(6-chloro-2-(methylsulfonyl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-5-yl)-[l,l'-biphenyl]-4- yl)methyl)(2-(2-hydroxyethoxy)ethyl)carbamate (21-11): To a solution of 21-10 (16 g, 27 mmol, 1 eq) in THF (200 mL) was added SEM-C1 (5.3 g, 32 mmol, 5.7 mL, 1.2 eq) and TEA (4.0 g, 40 mmol, 5.6 mL, 1.5 eq) at 0 °C.
  • Step 12 tert-butyl ((4'-(6-chloro-2-thioxo-l-((2-(trimethylsilyl)ethoxy)methyl)- 2,3-dihydro-lH-imidazo[4,5-b]pyridin-5-yl)-[l,l'-biphenyl]-4-yl)methyl)(2-(2- hydroxyethoxy)ethyl)carbamate (21-12): To a solution of 21-11 (17 g, 23.24 mmol, 1 eq) in DMF (170 mL) was added Na2S (5.4 g, 70 mmol, 2.9 mL, 3 eq).
  • Step 13 2-[5-[4-[4-[[tert-butoxycarbonyl-[2-(2- hydroxyethoxy)ethyl]amino]methyl]phenyl]phenyl]-6-chloro-l-(2- trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-2-yl]sulfanylpropanoic acid (21-13): To a solution of 21-12 (0.40 g, 0.58 mmol, 1 eq) and 2-chloropropanoic acid (0.09 g, 0.88 mmol, 1.5 eq) in DMF (8 mL) was added K 2 CO 3 (0.17 g, 1.2 mmol, 2 eq) and Nal (20 mg, 0.12 mmol, 0.2 eq).
  • Step 14 2-((6-chloro-5-(4'-(((2-(2-hydroxyethoxy)ethyl)amino)methyl)-[l,l'- biphenyl]-4-yl)-lH-imidazo[4,5-b]pyridin-2-yl)thio)propanoic acid (Compound 21): A solution of 21-13 (300 mg, crude) in 4N HCl/dioxane (3 mL) was stirred at 25 °C for 12 hours. The reaction solution was concentrated under reduced pressure to give a residue. The residue was dissolved in DMSO (5 mL), then filtered to give a filtrate.
  • Example A-l In Vitro pAMPKl Kinase Activation Assay
  • Compound effect on AMPK enzyme activation was determined in a cell-free format with a 12-point concentration curve.
  • the ADP-Glo detection system was used to determine phosphorylation of a SAMS peptide substrate.
  • Recombinant AMPK al/pi/yl complex was preactivated by phosphorylation with CAMKK2 followed by incubated with compound for 15 minutes prior to the SAMS phosphorylation reaction.
  • Activity curves and ECso values were fitted by interpolation to an ATP:ADP standard curve as indicated by the ADP-Glo manufacturer using Prism software.
  • Results for exemplary compounds are shown in Table A, where A ⁇ 10 nM ⁇ B ⁇ 100 nM ⁇ C ⁇ 1000 nM ⁇ D.

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Abstract

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, super agonists, full agonists, or partial agonists.

Description

AMPK ACTIVATORS
CROSS-REFERENCE
[0001] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63/282,486, filed November 23, 2021; which is incorporated herein by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] Adenosine 5 '-monophosphate-activated protein kinase (AMPK) is a serine/threonine kinase and is evolutionarily conserved from yeast to mammals. AMPK acts as an energy sensor and is activated by upstream enzymes when the cellular ratio of adenosine 5 '-monophosphate (AMP) to adenosine triphosphate (ATP) is elevated due to nutrient deprivation. Activated AMPK phosphorylates downstream substrates to promote catabolism and impede anabolism, leading to ATP production and energy restoration. AMPK activity can be altered due to numerous physiological factors, such as hormones, cytokines and dietary nutrients, as well as pathological conditions such as obesity, chronic inflammation and type 2 diabetes. AMPK activation can lead to lower hepatic glucose production and plasma glucose levels. Thus, AMPK is an attractive target to treat various metabolic diseases.
[0003] Additionally, AMPK has beneficial effects for gut health, such as enhancing intestinal absorption, improving barrier function, suppressing colorectal carcinogenesis, and reducing intestinal inflammation and metabolic-related disease, and is important for the maintenance of intestinal homeostasis. For example, AMPK activation enhances paracellular junctions, nutrient transporters, autophagy and apoptosis, and suppresses inflammation and carcinogenesis in the intestine. Accordingly, AMPK is associated with the maintenance of tight junctions in colonic epithelium and controls the progression of colitis.
[0004] In various mouse models of colitis, treatment with a direct AMPK activator has been shown to be efficacious at restoring gut barrier function (see, for example, WO 2018/189683; Sun, X., et al. (2017), Cell Death and Differentiation, 24(5), 819-831; Xue, Y., et al. (2016), PLoS ONE, 11(12), 1-18; and Sun, X., et al. (2017), Open Biology, 7(8)). This effect has also been recapitulated with metformin, which is an indirect AMPK activator having additional biological activities (see, for example, WO 2018/161077; and Di Fusco, D., et al. (2018), Clinical Science, 132(11)). However, there are safety concerns with sustained direct AMPK activation, particularly in the heart. Chronic treatment with systemic, direct activators can lead to cardiac hypertrophy (concomitant with increased cardiac glycogen) in rodents and non-human primates (See, Myers, R. W., et al. (2017), Science, 357(6350), 507-511). Additionally, human genetic polymorphisms in AMPK are associated with cardiac glycogen deposition, cardiac hypertrophy and Wolff-Parkinson-White syndrome, a condition characterized by electrocardiogram (ECG) abnormalities (see, Burwinkel, B., et al. (2005), Am Journal of Human Genetics, 76(6), 1034-1049). Due to this risk of cardiac hypertrophy, treatment with known AMPK activators, which are systemic in nature, is unsuitable to address the problem of treating IBD, colitis, and other diseases with a leaky gut barrier with a direct AMPK activator.
[0005] All reported direct AMPK activators which have been optimized and entered clinical studies (for example, PF- 06409577 from Pfizer) or extensive preclinical evaluation (for example, MK-3903 and MK-8722 from Merck) are systemic AMPK activators and have been developed for systemic engagement, as is reflected in the routes of administration and biological assays present in patent applications and published manuscripts relating to direct AMPK activators. A delayed-release formulation has been investigated to deliver higher concentrations of the indirect AMPK activator metformin to the colon for treatment of IBD. However, metformin does not optimally activate AMPK, metformin has other activities, and this approach requires specific formulation development. Thus it is not an optimal solution to the problem. [0006] Disclosed herein is the discovery and development of the first gut-restricted, direct AMPK activators that do not require sophisticated formulations to reach the target tissue and avoid systemic circulation.
BRIEF SUMMARY OF THE INVENTION
[0007] Disclosed herein, in some embodiments, are adenosine 5 '-monophosphate-activated protein kinase (5' AMP-activated protein kinase, 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, the 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 or selectively modulate AMPK located in the gut. In some embodiments, the condition is selected from the group consisting of: central nervous system (CNS) disorders including mood disorders, anxiety, depression, affective disorders, schizophrenia, malaise, cognition disorders, addiction, autism, epilepsy, neurodegenerative disorders, Alzheimer’s disease, and Parkinson’s disease, Lewy Body dementia, episodic cluster headache, migraine, pain; metabolic conditions including diabetes and its complications such as chronic kidney disease/diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, cardiovascular disease, metabolic syndrome, obesity, dyslipidemia, and nonalcoholic steatohepatitis (NASH); eating and nutritional disorders including hyperphagia, cachexia, anorexia nervosa, short bowel syndrome, intestinal failure, intestinal insufficiency and other eating disorders; inflammatory disorders and autoimmune diseases such as inflammatory bowel disease, ulcerative colitis, Crohn’s disease, checkpoint inhibitor-induced colitis, psoriasis and celiac disease; necrotizing enterocolitis; gastrointestinal injury resulting from toxic insults such as radiation or chemotherapy; diseases/disorders of gastrointestinal barrier dysfunction including environmental enteric dysfunction; spontaneous bacterial peritonitis; allergy including food allergy, celiac sprue, and childhood allergy; graft vs. host disease; functional gastrointestinal disorders such as irritable bowel syndrome, functional dyspepsia, functional abdominal bloating/distension, functional diarrhea, functional constipation, and opioid-induced constipation; gastroparesis; nausea and vomiting; disorders related to microbiome dysbiosis, and other conditions involving the gut-brain axis.
[0008] Disclosed herein, in some embodiments, is a compound of Formula (I): wherein
Figure imgf000004_0001
R1, R2, and R3 are each independently selected at each occurrence from halogen, hydroxyl, C1-4 alkyl, -CN, and Ci.4 haloalkyl; n is selected from 0, 1, 2, 3, and 4; o is selected from 0, 1, 2, 3, and 4; p is selected from 0, 1, and 2;
R4 is selected from hydrogen, halogen, C1-4 alkyl, and C1-4 haloalkyl;
R5a and R5b are each independently selected from hydrogen, C1-4 alkyl, and C1-4 haloalkyl;
R6 is selected from hydrogen and C1-4 alkyl;
D is selected from -CO2R11, -P(O)(ORU)2, -P(O)Rn(ORn), -S(O)2OH, and -L-K;
L is selected from z-(C(R13)2)r-, z-O(C(R13)2)r-, z-(C(R13)2)rO-, λ-N(R12)(C(R13)2)S-, λ-C(O)O-, λ-OC(O)-, λ-C(O)N(R12)-, λ-N(R12)C(O)-, λ-N(R12)S(O)2-, λ-S(O)2N(R12)-, and 4- to 6- membered heterocycle wherein 1 denotes the connection to K; r is selected from 1, 2, and 3; s is selected from 0, 1, 2, and 3;
K is selected from (i) and (ii):
(i) C1-10 alkyl or C1-10 heteroalkyl, each of which is substituted with one to six substituents independently selected from: halogen, -OR14, -SR14, -N(R14)2, -N+(R15)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -OC(O)N(R14)2, -C(O)N(R14)2, -N(R14)C(O)R14, - N(R14)C(O)OR14, -N(R14)C(O)N(R14)2, -N(R14)S(O)2(R14), -S(O)R14, -S(O)2R14, - S(O)2N(R14)2, =0, -CN, -P(O)(OR16)2, -P(O)R16(OR16), -S(O)2OH, C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle and 3- to 10-membered heterocycle is optionally substituted with one to six substituents independently selected from halogen, C1-6 alkyl, -OR14, =0, and -S(O)2OH; and
(ii) C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one to six substituents independently selected from halogen, -OR14, - SR14, -N(R14)2, -N+(R15)3, -C(O)R14, -C(O)OR14, -OC(O)R14, -OC(O)N(R14)2J - C(O)N(R14)2, -N(R14)C(O)R14, -N(R14)C(O)OR14, -N(R14)C(O)N(R14)2, - N(R14)S(O)2(R14), -S(O)R14, -S(O)2R14, -S(O)2N(R14)2, -P(O)(OR16)2, - P(O)R16(OR16), -S(O)2OH, =0, -CN, Ci-10 alkyl, and C1-10 heteroalkyl, wherein each C1-10 alkyl and C1-10 heteroalkyl is optionally substituted with one to six substituents independently selected from halogen, -OR14, -SR14, - N(R14)2, -N+(R15)3, -C(O)OR14, -P(O)(OR16)2, -P(O)R16(OR16), -S(O)2OH, S(O)2R14, and =0; each R11 is independently selected at each occurrence from hydrogen, C1-4 alkyl, and C1-4 haloalkyl; each R12 is independently selected at each occurrence from hydrogen and C1-4 alkyl optionally substituted with halogen, -OH, -NH2, and -C(0)NH2; each R13 is independently selected at each occurrence from hydrogen, C1-4 alkyl, CM haloalkyl, and C1-4 hydroxyalkyl; each R14 is independently selected at each occurrence from: hydrogen; and C1-10 alkyl and C1-10 heteroalkyl optionally substituted with one to six substituents independently selected from halogen, -OR21, -SR21, -N(R21)2, -N+(R15)3, -C(0)R21, - C(0)0R21, -0C(0)R21, -OC(O)N(R21)2, -C(O)N(R21)2, -N(R21)C(O)R21-P(O)(OR16)2, -P(O)R16(OR16), -S(O)2OH, =0, and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle and 3- to 10-membered heterocycle is optionally substituted with one to six substituents independently selected from halogen, Ci-6 alkyl, -OR21, -N+(R15)3, -S(O)R21, -P(O)(OR16)2, - P(O)R16(OR16), -S(O)2OH, -S(O)2R21, -S(O)2N(R21)2, =0, and -CN; each R15 is independently selected at each occurrence from C1-4 alkyl; each R16 is independently selected at each occurrence from hydrogen and C1-6 alkyl; each R21 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, and C3-6 carbocycle, wherein the C3-6 carbocycle is optionally substituted with one to six substituents independently selected from -OH, C1-6 alkyl, C1-6 haloalkyl, Ci-e hydroxyalkyl, and =0.
[0009] Any combination of the groups described above or below for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.
[0010] Disclosed herein, in some embodiments, are pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, and at least one pharmaceutically acceptable excipient.
[0011] Disclosed herein, in some embodiments, are methods 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 disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof. In some embodiments, the condition or disorder involves the gut-brain axis. In some embodiments, the condition or disorder is a nutritional disorder. In some embodiments, the condition or disorder is short bowel syndrome, intestinal failure, or intestinal insufficiency. In some embodiments, the condition or disorder is associated with systemic infection and inflammation from having a leaky gut barrier. In some embodiments, the condition or disorder is 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, ulcerative colitis, and checkpoint inhibitor-induced 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, graft vs. host disease, irritable bowel syndrome, spontaneous bacterial peritonitis, ischemic colitis, sclerosing cholangitis, Alzheimer’s disease, Parkinson’s disease, cancer including colorectal cancer, depression, autism, or a combination thereof.
[0012] Also disclosed herein, in some embodiments, are methods of treating gastrointestinal injury resulting from toxic insult, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof. In some embodiments, the toxic insult is from radiation, chemotherapy, or a combination thereof. In some embodiments, the toxic insult is radiation-induced. In some embodiments, the toxic insult is chemotherapy-induced. [0013] Also disclosed herein, in some embodiments, is the use of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, as a medicine.
[0014] Also disclosed herein, in some embodiments, is the use of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, for the treatment of an adenosine 5 '-monophosphate-activated protein kinase (AMPK) associated condition or disorder in a subject in need thereof. In some embodiments, the condition or disorder involves the gut-brain axis. In some embodiments, the condition or disorder is a nutritional disorder. In some embodiments, the condition or disorder is short bowel syndrome, intestinal failure, or intestinal insufficiency. In some embodiments, the condition or disorder is associated with systemic infection and inflammation from having a leaky gut barrier. In some embodiments, the condition or disorder is 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, ulcerative colitis, and checkpoint inhibitor-induced 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, graft vs. host disease, irritable bowel syndrome, spontaneous bacterial peritonitis, ischemic colitis, sclerosing cholangitis, Alzheimer’s disease, Parkinson’s disease, cancer including colorectal cancer, depression, autism, or a combination thereof.
[0015] Also disclosed herein, in some embodiments, is the use of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, for the treatment of gastrointestinal injury resulting from toxic insult in a subject in need thereof. In some embodiments, the toxic insult is from radiation, chemotherapy, or a combination thereof. In some embodiments, the toxic insult is radiation-induced. In some embodiments, the toxic insult is chemotherapy induced.
[0016] Also disclosed herein, in some embodiments, is the use of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, for the preparation of a medicament for the treatment of the diseases disclosed herein.
DETAILED DESCRIPTION OF THE INVENTION
[0017] This disclosure is directed, at least in part, to AMPK activators useful for the treatment of conditions or disorders involving the gut-brain axis. In some embodiments, the AMPK activators are gut-restricted compounds. In some embodiments, the AMPK activators are agonists, super agonists, full agonists, or partial agonists. [0018] Compounds disclosed herein directly activate AMPK in the intestine without systemic engagement. The preferred compounds are more potent, efficacious at lower doses, and have decreased systemic exposure compared to other previously-known AMPK activators.
Definitions
[0019] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included.
[0020] The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range.
[0021] The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of’ or “consist essentially of’ the described features.
[0022] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below:
[0023] As used herein, Ci-Cx includes C1-C2, C1-C3 . . . Ci-Cx. By way of example only, a group designated as “C1-C4” indicates that there are one to four carbon atoms in the moiety, i.e., groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, “C1-C4 alkyl” indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, Ao-propyl, //-butyl, isobutyl, sec-butyl, and /-butyl.
[0024] “Alkyl” refers to an optionally substituted straight-chain, or optionally substituted branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, or more preferably, from one to six carbon atoms, wherein an sp3-hybridized carbon of the alkyl residue is attached to the rest of the molecule by a single bond. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2-methyl- 1 -butyl, 3 -methyl- 1 -butyl, 2-methyl-3 -butyl, 2,2-dimethyl-l -propyl, 2-methyl-l -pentyl, 3- m ethyl- 1 -pentyl, 4-methyl-l -pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l -butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl, and the like. Whenever it appears herein, a numerical range such as “Ci-Ce alkyl” means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a Ci-Cio alkyl, a C1-C9 alkyl, a Ci-C8 alkyl, a C1-C7 alkyl, a Ci-C6 alkyl, a Ci-C5 alkyl, a C1-C4 alkyl, a C1-C3 alkyl, a C1-C2 alkyl, or a Ci alkyl. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, - SRa, -OC(O)Ra, -OC(O)-ORf, -N(Ra)2, -N+(Ra)3, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORf, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRf (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRf (where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each Rf is independently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.
[0025] “Alkenyl” refers to an optionally substituted straight-chain, or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms, wherein an sp2-hybridized carbon or an sp3-hybridized carbon of the alkenyl residue is attached to the rest of the molecule by a single bond. The group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to ethenyl (-CH=CH2), n-propenyl
(-CH=CHCH3, -CH2CH=CH2), isopropenyl (-C(CH3)=CH2), butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C2-Ce alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. In some embodiments, the alkenyl is a C2-Cio alkenyl, a C2-C9 alkenyl, a C2-Cs alkenyl, a C2-C? alkenyl, a C2-Ce alkenyl, a C2-Cs alkenyl, a C2-C4 alkenyl, a C2-C3 alkenyl, or a C2 alkenyl. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Rf, -OC(O)-ORf, -N(Ra)2, -N+(Ra)3, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORf, -OC(O)-N(Ra)2, -N(Ra)C(O)Rf, -N(Ra)S(O)tRf (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRf (where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each Rf is independently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.
[0026] “Alkynyl” refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms, wherein an sp-hybridized carbon or an sp3-hybridized carbon of the alkynyl residue is attached to the rest of the molecule by a single bond. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkynyl” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. In some embodiments, the alkynyl is a C2-C10 alkynyl, a C2-C9 alkynyl, a C2-Cs alkynyl, a C2-C7 alkynyl, a C2-C6 alkynyl, a C2-C5 alkynyl, a C2-C4 alkynyl, a C2-C3 alkynyl, or a C2 alkynyl. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)Ra, -OC(O)-ORf, - N(Ra)2, -N+(Ra)3, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORf, -OC(O)-N(Ra)2, - N(Ra)C(O)Rf, -N(Ra)S(O)tRf (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRf (where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each Rf is independently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroaryl alkyl.
[0027] “Alkylene” or “alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, ^-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)Ra, -OC(O)-ORf, -N(Ra)2, -N+(Ra)3, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORf, -OC(O)-N(Ra)2, -N(Ra)C(O)Rf, -N(Ra)S(O)tRf (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRf (where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each Rf is independently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.
[0028] “Alkenylene” or “alkenylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. Unless stated otherwise specifically in the specification, an alkenylene group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Rf, -OC(O)-ORf, -N(Ra)2, -N+(Ra)3, -C(O)Ra, -C(O)ORa, - C(O)N(Ra)2, -N(Ra)C(O)ORf, -OC(O)-N(Ra)2, -N(Ra)C(O)Rf, -N(Ra)S(O)tRf (where t is 1 or 2), - S(O)tORa (where t is 1 or 2), -S(O)tRf (where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each Rf is independently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.
[0029] “Alkynylene” or “alkynylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. Unless stated otherwise specifically in the specification, an alkynylene group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, - ORa, -SRa, -OC(O)Ra, -OC(O)-ORf, -N(Ra)2, -N+(Ra)3, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORf, -OC(O)-N(Ra)2, -N(Ra)C(O)Rf, -N(Ra)S(O)tRf (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRf (where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each Rf is independently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.
[0030] “Alkoxy” or “alkoxyl” refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.
[0031] “Aryl” refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from 6 to 18 carbon atoms, where at least one of the rings in the ring system is fully unsaturated, z.e., it contains a cyclic, delocalized (4n+2) ^-electron system in accordance with the Huckel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. In some embodiments, the aryl is a Ce-Cio aryl. In some embodiments, the aryl is a phenyl. Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar-“ (such as in “aralkyl”) is meant to include aryl radicals optionally substituted as described below by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -Rb-ORa, -Rb-SRa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORf, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-N+(Ra)3, -Rb-C(O)Ra, -Rb- C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORf, -Rb-N(Ra)C(O)Ra, -Rb- N(Ra)S(O)tRf (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2), -Rb-S(O)tRf (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, Rf is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain.
[0032] An “arylene” refers to a divalent radical derived from an “aryl” group as described above linking the rest of the molecule to a radical group. The arylene is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In some embodiments, the arylene is a phenylene. Unless stated otherwise specifically in the specification, an arylene group is optionally substituted as described above for an aryl group. [0033] “Cycloalkyl” refers to a stable, partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C3-C15 cycloalkyl), from three to ten carbon atoms (C3-C10 cycloalkyl), from three to eight carbon atoms (C3-Cs cycloalkyl), from three to six carbon atoms (C3-C6 cycloalkyl), from three to five carbon atoms (C3-C5 cycloalkyl), or three to four carbon atoms (C3-C4 cycloalkyl). In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo[l.l. l]pentyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, cis-decalyl, trans-decalyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, and the like. Unless otherwise stated specifically in the specification, the term “cycloalkyl” is meant to include cycloalkyl radicals optionally substituted as described below by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -Rb-ORa, -Rb-SRa, -Rb-OC(O)-Ra, -Rb- OC(O)-ORf, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-N+(Ra)3, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb- C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORf, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRf (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2), -Rb-S(O)tRf (where t is 1 or 2) and -Rb- S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, Rf is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain.
[0034] A “cycloalkylene” refers to a divalent radical derived from a “cycloalkyl” group as described above linking the rest of the molecule to a radical group. The cycloalkylene is attached to the rest of the molecule through a single bond and to the radical group through a single bond. Unless stated otherwise specifically in the specification, a cycloalkylene group is optionally substituted as described above for a cycloalkyl group.
[0035] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
[0036] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. [0037] “Fluoroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like.
[0038] “Haloalkoxy” or “haloalkoxyl” refers to an alkoxyl radical, as defined above, that is substituted by one or more halo radicals, as defined above. [0039] “Fluoroalkoxy” or “fluoroalkoxyl” refers to an alkoxy radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethoxy, difluoromethoxy, fluoromethoxy, and the like.
[0040] “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-), sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci-Ce heteroalkyl. In one aspect, a heteroalkyl is a polyethylene glycol (PEG). In some embodiments, a Ci-Cio heteroalkyl comprises from 1 to 5 PEG groups. In some embodiments, a Ci-Cio heteroalkyl comprises from 1 to 3 PEG groups.
[0041] “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyl radicals, as defined above, e.g., hydroxymethyl, 1 -hydroxy ethyl, 2- hydroxyethyl, 2-hydroxypropyl, 3 -hydroxypropyl, 1,2-dihydroxy ethyl, 2,3-dihydroxypropyl, 2,3,4,5,6-pentahydroxyhexyl, and the like.
[0042] “Heterocycloalkyl” refers to a stable 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6- membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-l-yl, 3-oxo-l,3- dihydroisobenzofuran-l-yl, methyl-2-oxo-l,3-dioxol-4-yl, and 2-oxo-l,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. More preferably, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e., skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, the term “heterocycloalkyl” is meant to include heterocycloalkyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -Rb- ORa, -Rb-SRa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORf, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-N+(Ra)3, -Rb- C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORf, -Rb- N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRf (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2), -Rb- S(O)tRf (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroaryl alkyl, Rf is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroaryl alkyl, each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain.
[0043] “A-heterocycloalkyl” refers to a heterocycloalkyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocycloalkyl radical to the rest of the molecule is through a nitrogen atom in the heterocycloalkyl radical. An N- heterocycloalkyl radical is optionally substituted as described above for heterocycloalkyl radicals.
[0044] “ C-heterocycloalkyl” refers to a heterocycloalkyl radical as defined above and where the point of attachment of the heterocycloalkyl radical to the rest of the molecule is through a carbon atom in the heterocycloalkyl radical. A C-heterocycloalkyl radical is optionally substituted as described above for heterocycloalkyl radicals.
[0045] A “heterocycloalkylene” refers to a divalent radical derived from a “heterocycloalkyl” group as described above linking the rest of the molecule to a radical group. The heterocycloalkylene is attached to the rest of the molecule through a single bond and to the radical group through a single bond. Unless stated otherwise specifically in the specification, a heterocycloalkylene group is optionally substituted as described above for a heterocycloalkyl group.
[0046] “Heteroaryl” refers to a radical derived from a 5- to 18-membered aromatic ring radical that comprises one to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ^-electron system in accordance with the Hiickel theory. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a monocyclic heteroaryl, or a monocyclic 5- or 6- membered heteroaryl. In some embodiments, the heteroaryl is a 6,5-fused bicyclic heteroaryl. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Unless stated otherwise specifically in the specification, the term “heteroaryl” is meant to include heteroaryl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -Rb-0Ra, -Rb-SRa, -Rb-0C(0)-Ra, -Rb-0C(0)-0Rf, -Rb-OC(O)- N(Ra)2, -Rb-N(Ra)2, -Rb-N+(Ra)3, -Rb-C(0)Ra, -Rb-C(0)0Ra, -Rb-C(0)N(Ra)2, -Rb-0-Rc- C(0)N(Ra)2, -Rb-N(Ra)C(0)0Rf, -Rb-N(Ra)C(0)Ra, -Rb-N(Ra)S(0)tRf (where t is 1 or 2), -Rb- S(O)tORa (where t is 1 or 2), -Rb-S(O)tRf (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroaryl alkyl, Rf is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroaryl alkyl, each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain.
[0047] A “heteroarylene” refers to a divalent radical derived from a “heteroaryl” group as described above linking the rest of the molecule to a radical group. The heteroarylene is attached to the rest of the molecule through a single bond and to the radical group through a single bond. Unless stated otherwise specifically in the specification, a heteroarylene group is optionally substituted as described above for a heteroaryl group.
[0048] The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns (e.g., substituted alkyl includes optionally substituted cycloalkyl groups, which in turn are defined as including optionally substituted alkyl groups, potentially ad infinitum) that are sterically impractical and/or synthetically non-feasible.
[0049] The term “modulate” or “modulating” or “modulation” refers to an increase or decrease in the amount, quality, or effect of a particular activity, function or molecule. By way of illustration and not limitation, activators, agonists, partial agonists, inverse agonists, antagonists, inhibitors, and allosteric modulators of an enzyme are modulators of the enzyme. [0050] The term “agonism” as used herein refers to the activation of a receptor or enzyme by a modulator, or agonist, to produce a biological response.
[0051] The term “agonist” or “activator” as used herein refers to a modulator that binds to a receptor or target enzyme and activates the receptor or enzyme to produce a biological response. By way of example, “AMPK activator” can be used to refer to a compound that exhibits an ECso with respect to AMPK activity of no more than about 100 pM, as measured in the pAMPKl kinase activation assay. In some embodiments, the term “agonist” includes super agonists, full agonists or partial agonists.
[0052] The term “super agonist” as used herein refers to a modulator that is capable of producing a maximal response greater than the endogenous agonist for the target receptor or enzyme, and thus has an efficacy of more than 100%.
[0053] The term “full agonist” refers to a modulator that binds to and activates a receptor or target enzyme with the maximum response that an endogenous agonist can elicit at the receptor or enzyme.
[0054] The term “partial agonist” refers to a modulator that binds to and activates a receptor or target enzyme, but has partial efficacy, that is, less than the maximal response, at the receptor or enzyme relative to a full agonist.
[0055] The term “positive allosteric modulator” refers to a modulator that binds to a site distinct from the orthosteric binding site and enhances or amplifies the effect of an agonist. [0056] The term “antagonism” or “inhibition” as used herein refers to the inactivation of a receptor or target enzyme by a modulator, or antagonist. Antagonism of a receptor, for example, is when a molecule binds to the receptor or target enzyme and does not allow activity to occur.
[0057] The term “antagonist” or “neutral antagonist” or “inhibitor” as used herein refers to a modulator that binds to a receptor or target enzyme and blocks a biological response. An antagonist has no activity in the absence of an agonist or inverse agonist but can block the activity of either, causing no change in the biological response. [0058] The term “inverse agonist” refers to a modulator that binds to the same receptor or target enzyme as an agonist but induces a pharmacological response opposite to that agonist, i.e., a decrease in biological response.
[0059] The term “negative allosteric modulator” refers to a modulator that binds to a site distinct from the orthosteric binding site and reduces or dampens the effect of an agonist.
[0060] As used herein, “ECso” is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% activation or enhancement of a biological process. In some instances, ECso refers to the concentration of agonist that provokes a response halfway between the baseline and maximum response in an in vitro assay. In some embodiments as used herein, ECso refers to the concentration of an activator (e.g., an AMPK activator) that is required for 50% activation of AMPK.
[0061] As used herein, “IC50” is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% inhibition of a biological process. For example, IC50 refers to the half maximal (50%) inhibitory concentration (IC) of a substance as determined in a suitable assay. In some instances, an IC50 is determined in an in vitro assay system. In some embodiments as used herein, IC50 refers to the concentration of a modulator (e.g., an antagonist or inhibitor) that is required for 50% inhibition of a receptor or a target enzyme.
[0062] The terms “subject,” “individual,” and “patient” are used interchangeably. These terms encompass mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
[0063] The term “gut-restricted” as used herein refers to a compound, e.g., an AMPK activator, that is predominantly active in the gastrointestinal system. In some embodiments, the biological activity of the gut-restricted compound, e.g., a gut-restricted AMPK activator, is restricted to the gastrointestinal system. In some embodiments, gastrointestinal concentration of a gut-restricted modulator, e.g., a gut-restricted AMPK activator, is higher than the IC50 value or the EC50 value of the gut-restricted modulator against its receptor or target enzyme, e.g., AMPK, while the plasma levels of said gut-restricted modulator, e.g., gut-restricted AMPK activator, are lower than the IC50 value or the EC50 value of the gut-restricted modulator against its receptor or target enzyme, e.g., AMPK. In some embodiments, the gut-restricted compound, e.g., a gut- restricted AMPK activator, is non-systemic. In some embodiments, the gut-restricted compound, e.g., a gut-restricted AMPK activator, is a non-absorbed compound. In other embodiments, the gut-restricted compound, e.g., a gut-restricted AMPK activator, is absorbed, but is rapidly metabolized to metabolites that are significantly less active than the modulator itself toward the target receptor or enzyme, i.e., a “soft drug.” In other embodiments, the gut-restricted compound, e.g., a gut-restricted AMPK activator, is minimally absorbed and rapidly metabolized to metabolites that are significantly less active than the modulator itself toward the target receptor or enzyme. In some embodiments, the gut-restricted AMPK activator has high efflux. In other embodiments, the gut-restricted AMPK activator is a substrate for one or more intestinal efflux transporters such as P-gp (MDR1), BCRP, or MRP2.
[0064] In some embodiments, the gut-restricted modulator, e.g., a gut-restricted AMPK activator, is non-systemic but is instead localized to the gastrointestinal system. For example, the modulator, e.g., a gut-restricted AMPK activator, may be present in high levels in the gut, but low levels in serum. In some embodiments, the systemic exposure of a gut-restricted modulator, e.g., a gut-restricted AMPK activator, is, for example, less than 100, less than 50, less than 20, less than 10, or less than 5 nM, bound or unbound, in blood serum. In some embodiments, the intestinal exposure of a gut-restricted modulator, e.g., a gut-restricted AMPK activator, is, for example, greater than 1000, 5000, 10000, 50000, 100000, or 500000 nM. In some embodiments, a modulator, e.g., a gut-restricted AMPK activator, is gut-restricted due to poor absorption of the modulator itself, or because of absorption of the modulator which is rapidly metabolized in serum resulting in low systemic circulation, or due to both poor absorption and rapid metabolism in the serum. In some embodiments, a modulator, e.g., a gut-restricted AMPK activator, is covalently bonded to a kinetophore, optionally through a linker, which changes the pharmacokinetic profile of the modulator.
[0065] In other embodiments, the gut-restricted modulator is a soft drug. The term “soft drug” as used herein refers to a modulator that is biologically active but is rapidly metabolized to metabolites that are significantly less active than the modulator itself toward the target receptor. In some embodiments, the gut-restricted modulator is a soft drug that is rapidly metabolized in the blood to significantly less active metabolites. In some embodiments, the gut-restricted modulator is a soft drug that is rapidly metabolized in the liver to significantly less active metabolites. In some embodiments, the gut-restricted modulator is a soft drug that is rapidly metabolized in the blood and the liver to significantly less active metabolites. In some embodiments, the gut-restricted modulator is a soft drug that has low systemic exposure. In some embodiments, the biological activity of the metabolite(s) is/are 10-fold, 20-fold, 50-fold, 100-fold, 500-fold, or 1000-fold lower than the biological activity of the soft drug gut-restricted modulator.
[0066] The term “kinetophore” as used herein refers to a structural unit tethered to a small molecule modulator, e.g., an AMPK activator, optionally through a linker, which makes the whole molecule larger and increases the polar surface area while maintaining biological activity of the small molecule modulator. The kinetophore influences the pharmacokinetic properties, for example solubility, absorption, distribution, rate of elimination, and the like, of the small molecule modulator, e.g., an AMPK activator, and has minimal changes to the binding to or association with a receptor or target enzyme. The defining feature of a kinetophore is not its interaction with the target, for example an enzyme, but rather its effect on specific physiochemical characteristics of the modulator to which it is attached, e.g., an AMPK activator. In some instances, kinetophores are used to restrict a modulator, e.g., an AMPK activator, to the gut.
[0067] The term “linked” as used herein refers to a covalent linkage between a modulator, e.g., an AMPK activator, and a kinetophore. The linkage can be through a covalent bond, or through a “linker.” As used herein, “linker” refers to one or more bifunctional molecules which can be used to covalently bonded to the modulator, e.g., an AMPK activator, and kinetophore. In some embodiments, the linker is attached to any part of the modulator, e.g., an AMPK activator, so long as the point of attachment does not interfere with the binding of the modulator to its receptor or target enzyme. In some embodiments, the linker is non-cleavable. In some embodiments, the linker is cleavable. In some embodiments, the linker is cleavable in the gut. In some embodiments, cleaving the linker releases the biologically active modulator, e.g., an AMPK activator, in the gut.
[0068] The term “gastrointestinal system” (GI system) or “gastrointestinal tract” (GI tract) as used herein, refers to the organs and systems involved in the process of digestion. The gastrointestinal tract includes the esophagus, stomach, small intestine, which includes the duodenumjejunum, and ileum, and large intestine, which includes the cecum, colon, and rectum. In some embodiments herein, the GI system refers to the “gut,” meaning the stomach, small intestines, and large intestines or to the small and large intestines, including, for example, the duodenum, jejunum, and/or colon.
Gut-Brain Axis
[0069] The gut-brain axis refers to the bidirectional biochemical signaling that connects the gastrointestinal tract (GI tract) with the central nervous system (CNS) through the peripheral nervous system (PNS) and endocrine, immune, and metabolic pathways.
[0070] In some instances, the gut-brain axis comprises the GI tract; the PNS including the dorsal root ganglia (DRG) and the sympathetic and parasympathetic arms of the autonomic nervous system including the enteric nervous system and the vagus nerve; the CNS; and the neuroendocrine and neuroimmune systems including the hypothalamic-pituitary-adrenal axis (HPA axis). The gut-brain axis is important for maintaining homeostasis of the body and is regulated and modulates physiology through the central and peripheral nervous systems and endocrine, immune, and metabolic pathways.
[0071] The gut-brain axis modulates several important aspects of physiology and behavior. Modulation by the gut-brain axis occurs via hormonal and neural circuits. Key components of these hormonal and neural circuits of the gut-brain axis include highly specialized, secretory intestinal cells that release hormones (enteroendocrine cells or EECs), the autonomic nervous system (including the vagus nerve and enteric nervous system), and the central nervous system. These systems work together in a highly coordinated fashion to modulate physiology and behavior.
[0072] Defects in the gut-brain axis are linked to a number of diseases, including those of high unmet need. Diseases and conditions affected by the gut-brain axis, include central nervous system (CNS) disorders including mood disorders, anxiety, depression, affective disorders, schizophrenia, malaise, cognition disorders, addiction, autism, epilepsy, neurodegenerative disorders, Alzheimer’s disease, and Parkinson’s disease, Lewy Body dementia, episodic cluster headache, migraine, pain; metabolic conditions including diabetes and its complications such as chronic kidney disease/diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, cardiovascular disease, metabolic syndrome, obesity, dyslipidemia, and nonalcoholic steatohepatitis (NASH); eating and nutritional disorders including hyperphagia, cachexia, anorexia nervosa, short bowel syndrome, intestinal failure, intestinal insufficiency and other eating disorders; inflammatory disorders and autoimmune diseases such as inflammatory bowel disease, ulcerative colitis, Crohn’s disease, checkpoint inhibitor-induced colitis, psoriasis, celiac disease, and enteritis, including chemotherapy-induced enteritis or radiation-induced enteritis; necrotizing enterocolitis; gastrointestinal injury resulting from toxic insults such as radiation or chemotherapy; diseases/disorders of gastrointestinal barrier dysfunction including environmental enteric dysfunction, spontaneous bacterial peritonitis; allergy including food allergy, celiac sprue, and childhood allergy; graft vs. host disease; functional gastrointestinal disorders such as irritable bowel syndrome, functional dyspepsia, functional abdominal bloating/distension, functional diarrhea, functional constipation, and opioid-induced constipation; gastroparesis; nausea and vomiting; disorders related to microbiome dysbiosis, and other conditions involving the gut-brain axis.
Adenosine 5'-Monophosphate-Activated Protein Kinase (AMPK) in the Gut-Brain Axis [0073] Adenosine 5 '-monophosphate-activated protein kinase (AMPK) is a serine/threonine kinase and is evolutionarily conserved from yeast to mammals. In some instances, AMPK is a heterotrimeric protein complex that is formed by one a (al or a2), one P (p 1 or P2), and one y (yl, y2, or y3) subunit. Due to the presence of isoforms of its components, there are 12 versions of AMPK (AMPK1, AMPK2, etc., through AMPK12). In some instances, AMPK acts as an energy sensor and is activated by upstream enzymes when the cellular ratio of adenosine 5'- monophosphate (AMP) to adenosine triphosphate (ATP) is elevated due to nutrient deprivation. In some instances, activated AMPK phosphorylates downstream substrates to promote catabolism and impede anabolism, leading to ATP production and energy restoration. In some instances, AMPK activity can be altered due to numerous physiological factors, such as hormones, cytokines and dietary nutrients, as well as pathological conditions such as obesity, chronic inflammation and type 2 diabetes. In some instances, AMPK activation leads to lower hepatic glucose production and plasma glucose levels. Thus, in some instances, AMPK activation can act as a therapeutic agent to treat various metabolic diseases.
[0074] In some instances, AMPK has beneficial effects for gut health, such as enhancing intestinal absorption, improving barrier function, suppressing colorectal carcinogenesis, and reducing intestinal inflammation and metabolic-related disease, and is important for the maintenance of intestinal homeostasis. In some instances, AMPK is essential for proper intestinal health. In some instances, AMPK activation enhances paracellular junctions, nutrient transporters, autophagy and apoptosis, and suppresses inflammation and carcinogenesis in the intestine.
[0075] In some embodiments, this disclosure provides AMPK activators that can be broadly used for multiple conditions and disorders associated with AMPK. In some embodiments, the condition or disorder is associated with the gut-brain axis. In some embodiments, the condition or disorder is a central nervous system (CNS) disorder including mood disorders, anxiety, depression, affective disorders, schizophrenia, malaise, cognition disorders, addiction, autism, epilepsy, neurodegenerative disorders, Alzheimer’s disease, and Parkinson’s disease, Lewy Body dementia, episodic cluster headache, migraine, pain; metabolic conditions including diabetes and its complications such as chronic kidney disease/diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, cardiovascular disease, metabolic syndrome, obesity, dyslipidemia, and nonalcoholic steatohepatitis (NASH); eating and nutritional disorders including hyperphagia, cachexia, anorexia nervosa, short bowel syndrome, intestinal failure, intestinal insufficiency and other eating disorders; inflammatory disorders and autoimmune diseases such as inflammatory bowel disease, ulcerative colitis, Crohn’s disease, checkpoint inhibitor-induced colitis, psoriasis, celiac disease, and enteritis, including chemotherapy-induced enteritis or radiation-induced enteritis; necrotizing enterocolitis; gastrointestinal injury resulting from toxic insults such as radiation or chemotherapy; diseases/disorders of gastrointestinal barrier dysfunction including environmental enteric dysfunction, spontaneous bacterial peritonitis; allergy including food allergy, celiac sprue, and childhood allergy; graft vs. host disease; functional gastrointestinal disorders such as irritable bowel syndrome, functional dyspepsia, functional abdominal bloating/distension, functional diarrhea, functional constipation, and opioid-induced constipation; gastroparesis; nausea and vomiting; disorders related to microbiome dysbiosis, and other conditions involving the gut-brain axis. In some embodiments, the condition or disorder is a metabolic disorder. In some embodiments, the condition or disorder is type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, nonalcoholic steatohepatitis, or hypertension. In some embodiments, the condition or disorder is a nutritional disorder. In some embodiments, the condition or disorder is short bowel syndrome, intestinal failure, or intestinal insufficiency. In some embodiments, the condition or disorder is inflammatory bowel disease including ulcerative colitis, Crohn’s disease and checkpoint inhibitor-induced colitis. In some embodiments, the condition or disorder is celiac disease, enteritis including chemotherapy -induced enteritis or radiation-induced enteritis, necrotizing enterocolitis; or gastrointestinal injury resulting from toxic insults such as radiation or chemotherapy. In some embodiments, the condition or disorder is diseases/disorders of gastrointestinal barrier dysfunction including environmental enteric dysfunction, spontaneous bacterial peritonitis; allergy including food allergy, celiac sprue, and childhood allergy; graft vs. host disease; functional gastrointestinal disorders such as irritable bowel syndrome, functional dyspepsia, functional abdominal bloating/distension, functional diarrhea, functional constipation, opioid-induced constipation; gastroparesis; or nausea and vomiting. In some embodiments, the condition or disorder is associated with systemic infection and inflammation from having a leaky gut barrier. In some embodiments, the condition or disorder is 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, allergy including food allergy, celiac sprue, and childhood allergy, graft vs. host disease, irritable bowel syndrome, spontaneous bacterial peritonitis, ischemic colitis, sclerosing cholangitis, Alzheimer’s disease, Parkinson’s disease, cancer including colorectal cancer, depression, autism, or a combination thereof.
Adenosine 5'-Monophosphate-Activated Protein Kinase (AMPK) and the Gut Barrier [0076] In some instances, the gut mucosa maintains immune homeostasis under physiological circumstances by serving as a barrier that restricts access of microbes, diverse microbial products, food antigens and toxins in the lumen of the gut to rest of the body. In some instances, the gut barrier is comprised of a single layer of epithelial cells, bound by cell-cell junctions, and a layer of mucin that covers the epithelium. In some instances, loosening of the junctions induced either by exogenous or endogenous stressors, compromises the gut barrier and allows microbes and antigens to leak through and encounter the host immune system, thereby generating inflammation and systemic endotoxemia. In some instances, an impaired gut barrier (e.g. a leaky gut) is a major contributor to the initiation and/or progression of various chronic diseases including, but not limited to, metabolic endotoxemia, type 2 diabetes, fatty liver disease, obesity, atherosclerosis, inflammatory bowel diseases, and cancers. In some instances, activation of AMPK, which is associated with the maintenance of tight junction in colonic epithelium, controls the progression of colitis. In some instances, expression and assembly of tight junctions is dependent on AMPK activity.
[0077] In some embodiments, the present disclosure provides methods effective to strengthen/protect the gut barrier and reduce and/or prevent the progression of chronic diseases. The gut barrier is a critical frontier that separates microbes and antigens in the lumen of the gut from the rest of the body; a compromised “leaky” gut barrier is frequently associated with systemic infection and inflammation, which is a key contributor to many chronic allergic, infectious, metabolic and autoimmune diseases such as obesity, diabetes, inflammatory bowel diseases, food allergy, and metabolic endotoxemia.
[0078] In some embodiments, this disclosure provides AMPK activators that can be broadly used for multiple conditions and disorders associated with AMPK. In some embodiments, the condition or disorder is associated with systemic infection and inflammation from having a leaky gut barrier. In some embodiments, a leaky gut barrier can fuel the progression of multiple chronic diseases, including but not limited to: 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, ulcerative colitis, checkpoint inhibitor-induced colitis, allergy including food allergy, celiac sprue, and childhood allergy, graft vs. host disease, irritable bowel syndrome, spontaneous bacterial peritonitis, ischemic colitis, sclerosing cholangitis, Alzheimer’s disease, Parkinson’s disease, cancer including colorectal cancer, depression, autism, or a combination thereof.
[0079] In some instances, injury to the intestinal mucosa is frequently a dose-limiting complication of radiotherapy and chemotherapy. Approaches to limit the damage to the intestine during radiation and chemotherapy have been largely ineffective. In some embodiments described herein, AMPK activators are useful for the treatment of gastrointestinal injury. In some embodiments, AMPK activators are useful for the treatment of gastrointestinal injury resulting from toxic insult. In some embodiments, the toxic insult is from radiation, chemotherapy, or a combination thereof. In some embodiments, the toxic insult is radiation- induced. In some embodiments, the toxic insult is chemotherapy -induced. Gut-Restricted Modulators
[0080] In some instances, there are concerns associated with systemic AMPK activation, for example, AMPK activation in the heart. For example, in some instances, activating mutations in the AMPK y2-subunit lead to PRKAG2 cardiomyopathy. In other instances, systemic AMPK activation results in cardiac hypertrophy and increased cardiac glycogen. In some instances, given the potential association of adverse effects with systemic AMPK activation, tissue selective AMPK activation is an attractive approach for developing AMPK activators to treat disease.
[0081] In some embodiments, the AMPK activator is gut-restricted. In some embodiments, the AMPK activator is designed to be substantially non-permeable or substantially non- bioavailable in the blood stream. In some embodiments, the AMPK activator is designed to activate AMPK activity in the gut and is substantially non-systemic. In some embodiments, the AMPK activator has low systemic exposure.
[0082] In some embodiments, a gut-restricted AMPK activator has low oral bioavailability. In some embodiments, a gut-restricted AMPK activator has <40% oral bioavailability, <30% oral bioavailability, <20% oral bioavailability, < 10% oral bioavailability, < 8% oral bioavailability, < 5% oral bioavailability, < 3% oral bioavailability, or < 2% oral bioavailability.
[0083] In some embodiments, the unbound plasma levels of a gut-restricted AMPK activator are lower than the ECso value of the AMPK activator against AMPK. In some embodiments, the unbound plasma levels of a gut-restricted AMPK activator are significantly lower than the ECso value of the gut-restricted AMPK activator against AMPK. In some embodiments, the unbound plasma levels of the AMPK activator are 2-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, or 100-fold lower than the ECso value of the gut-restricted AMPK activator against AMPK.
[0084] In some embodiments, a gut-restricted AMPK activator has low systemic exposure. In some embodiments, the systemic exposure of a gut-restricted AMPK activator is, for example, less than 500, less than 200, less than 100, less than 50, less than 20, less than 10, or less than 5 nM, bound or unbound, in blood serum. In some embodiments, the systemic exposure of a gut- restricted AMPK activator is, for example, less than 500, less than 200, less than 100, less than 50, less than 20, less than 10, or less than 5 ng/mL, bound or unbound, in blood serum.
[0085] In some embodiments, a gut-restricted AMPK activator has high intestinal exposure. In some embodiments, the intestinal exposure of a gut-restricted AMPK activator is, for example, greater than 1, 5, 10, 50, 100, 250 or 500 pM.
[0086] In some embodiments, a gut-restricted AMPK activator has high exposure in the colon. In some embodiments, the colon exposure of a gut-restricted AMPK activator is, for example, greater than 1, 5, 10, 50, 100, 250 or 500 pM. In some embodiments, the colon exposure of a gut-restricted AMPK activator is, for example, greater than 100 pM.
[0087] In some embodiments, a gut-restricted AMPK activator has low permeability. In some embodiments, a gut-restricted AMPK activator has low intestinal permeability. In some embodiments, the permeability of a gut-restricted AMPK activator is, for example, less than 5.0x l0'6 cm/s, less than 2.0>< 10'6 cm/s, less than 1.5 x 10"6 cm/s, less than l.Ox lO'6 cm/s, less than 0.75x l0'6 cm/s, less than 0.50x l0'6 cm/s, less than 0.25x l0'6 cm/s, less than O.lOx lO'6 cm/s, or less than 0.05x l0'6 cm/s.
[0088] In some embodiments, a gut-restricted AMPK activator has low absorption. In some embodiments, the absorption of a gut-restricted AMPK activator is less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, or less than 1%.
[0089] In some embodiments, a gut-restricted AMPK activator has high plasma clearance. In some embodiments, a gut-restricted AMPK activator is undetectable in plasma in less than 8 hours, less than 6 hours, less than 4 hours, less than 3 hours, less than 120 min, less than 90 min, less than 60 min, less than 45 min, less than 30 min, or less than 15 min.
[0090] In some embodiments, a gut-restricted AMPK activator is rapidly metabolized upon administration. In some embodiments, a gut-restricted AMPK activator has a short half-life. In some embodiments, the half-life of a gut-restricted AMPK activator is less than less than 8 hours, less than 6 hours, less than 4 hours, less than 3 hours, less than 120 min, less than 90 min, less than 60 min, less than 45 min, less than 30 min, or less than 15 min. In some embodiments, the metabolites of a gut-restricted AMPK activator have rapid clearance. In some embodiments, the metabolites of a gut-restricted AMPK activator are undetectable in less than 8 hours, less than 6 hours, less than 4 hours, less than 3 hours, less than 120 min, less than 90 min, less than 60 min, less than 45 min, less than 30 min, or less than 15 min. In some embodiments, the metabolites of a gut-restricted AMPK activator have low bioactivity. In some embodiments, the ECso value of the metabolites of a gut-restricted AMPK activator is 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 100-fold, 500-fold, or 1000-fold higher than the EC50 value of the gut-restricted AMPK activator against AMPK. In some embodiments, the metabolites of a gut-restricted AMPK activator have rapid clearance and low bioactivity.
[0091] In some embodiments, the gut-restricted AMPK activator has high efflux. In some embodiments, the gut-restricted AMPK activator is a substrate for one or more intestinal efflux transporters such as P-gp (MDR1), BCRP, or MRP2. In some embodiments, the efflux of the gut-restricted AMPK activator as measured by the B-A/A-B ratio in a cell line such as Caco-2 or MDCK with or without over-expression of one or more efflux transporters is, for example, greater than 2, greater than 5, greater than 10, greater than 25, or greater than 50. [0092] In some embodiments of the methods described herein, the AMPK activator is gut- restricted. In some embodiments, the AMPK activator is a gut-restricted AMPK agonist. In some embodiments, the AMPK activator is a gut-restricted AMPK super agonist. In some embodiments, the AMPK activator is a gut-restricted AMPK full agonist. In some embodiments, the AMPK activator is a gut-restricted AMPK partial agonist. In some embodiments, the AMPK activator is covalently bonded to a kinetophore. In some embodiments, the AMPK activator is covalently bonded to a kinetophore through a linker.
Compounds
[0093] Disclosed herein, in some embodiments, is a compound of Formula (I): wherein
Figure imgf000027_0001
R1, R2, and R3 are each independently selected at each occurrence from halogen, hydroxyl, C1-4 alkyl, -CN, and Ci.4 haloalkyl; n is selected from 0, 1, 2, 3, and 4; o is selected from 0, 1, 2, 3, and 4; p is selected from 0, 1, and 2;
R4 is selected from hydrogen, halogen, C1-4 alkyl, and C1-4 haloalkyl;
R5a and R5b are each independently selected from hydrogen, C1-4 alkyl, and C1-4 haloalkyl;
R6 is selected from hydrogen and C1-4 alkyl;
D is selected from -CO2R11, -P(O)(OR11)2, -P(O)R11(OR11), -S(O)2OH, and -L-K;
L is selected from λ-(C(R13)2)r-, λ-O(C(R13)2)r-, λ-(C(R13)2)rO-, λ-N(R12)(C(R13)2)S-, λ-C(O)O-, λ-OC(O)-, λ-C(O)N(R12)-, λ-N(R12)C(O)-, λ-N(R12)S(O)2-, λ-S(O)2N(R12)-, and 4- to 6- membered heterocycle wherein 1 denotes the connection to K; r is selected from 1, 2, and 3; s is selected from 0, 1, 2, and 3;
K is selected from (i) and (ii):
(i) C1-10 alkyl or C1-10 heteroalkyl, each of which is substituted with one to six substituents independently selected from: halogen, -OR14, -SR14, -N(R14)2, -N+(R15)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -OC(O)N(R14)2, -C(O)N(R14)2, -N(R14)C(O)R14, - N(R14)C(O)OR14, -N(R14)C(O)N(R14)2, -N(R14)S(O)2(R14), -S(O)R14, -S(O)2R14, - S(O)2N(R14)2, =0, -CN, -P(O)(OR16)2, -P(O)R16(OR16), -S(O)2OH, C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle and 3- to 10-membered heterocycle is optionally substituted with one to six substituents independently selected from halogen, C1-6 alkyl, -OR14, =0, and -S(O)2OH; and
(ii) C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one to six substituents independently selected from halogen, -OR14, - SR14, -N(R14)2, -N+(R15)3, -C(O)R14, -C(O)OR14, -OC(O)R14, -OC(O)N(R14)2, - C(O)N(R14)2, -N(R14)C(O)R14, -N(R14)C(O)OR14, -N(R14)C(O)N(R14)2, - N(R14)S(O)2(R14), -S(O)R14, -S(O)2R14, -S(O)2N(R14)2, -P(O)(OR16)2, - P(O)R16(OR16), -S(O)2OH, =0, -CN, C1-10 alkyl, and C1-10 heteroalkyl, wherein each C1-10 alkyl and C1-10 heteroalkyl is optionally substituted with one to six substituents independently selected from halogen, -OR14, -SR14, - N(R14)2, -N+(R15)3, -C(O)OR14, -P(O)(OR16)2, -P(O)R16(OR16), -S(O)2OH, S(O)2R14, and =0; each R11 is independently selected at each occurrence from hydrogen, C1-4 alkyl, and C1-4 haloalkyl; each R12 is independently selected at each occurrence from hydrogen and C1-4 alkyl optionally substituted with halogen, -OH, -NH2, and -C(0)NH2; each R13 is independently selected at each occurrence from hydrogen, C1-4 alkyl, C1-4 haloalkyl, and C1-4 hydroxyalkyl; each R14 is independently selected at each occurrence from: hydrogen; and C1-10 alkyl and C1-10 heteroalkyl optionally substituted with one to six substituents independently selected from halogen, -OR21, -SR21, -N(R21)2, -N+(R15)3, -C(0)R21, - C(0)OR21, -0C(0)R21, -OC(O)N(R21)2, -C(O)N(R21)2, -N(R21)C(O)R21-P(O)(OR16)2, -P(O)R16(OR16), -S(O)2OH, =0, and -CN; and
C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle and 3- to 10-membered heterocycle is optionally substituted with one to six substituents independently selected from halogen, C1-6 alkyl, -OR21, -N+(R15)3, -S(O)R21, -P(O)(OR16)2, - P(O)R16(OR16), -S(O)2OH, -S(O)2R21, -S(O)2N(R21)2, =0, and -CN; each R15 is independently selected at each occurrence from C1-4 alkyl; each R16 is independently selected at each occurrence from hydrogen and C1-6 alkyl; each R21 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, and C3-6 carbocycle, wherein the C3-6 carbocycle is optionally substituted with one to six substituents independently selected from -OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, and =0.
[0094] For any and all of the embodiments, substituents are selected from among a subset of the listed alternatives. For example, in some embodiments, Y is CR4. In some embodiments, R4 is hydrogen or halogen. In some embodiments, R4 is hydrogen or fluoro. In some embodiments, Y is N, CH, or CF. In some embodiments, Y is N. In some embodiments, Y is CH. In some embodiments, Y is CF.
[0095] In some embodiments, R6 is hydrogen. In some embodiments, R6 is C1-4 alkyl. In some embodiments, R6 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, and tert-butyl. In some embodiments, R6 is methyl or ethyl. In some embodiments, R6 is methyl. In some embodiments, R6 is ethyl.
[0096] In some embodiments, R6 is hydrogen, methyl, or ethyl. In some embodiments, R6 is hydrogen or methyl.
[0097] In some embodiments, the compound is represented by Formula (II):
Figure imgf000029_0001
or a pharmaceutically acceptable salt thereof.
[0098] In some embodiments, n is selected from 0 and 1. In some embodiments, n is selected from 1 and 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.
[0099] In some embodiments, each R1 is independently selected at each occurrence from halogen, hydroxyl, and C1-4 alkyl. In some embodiments, each R1 is independently selected at each occurrence from F, Cl, hydroxyl, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, secbutyl, and tert-butyl. In some embodiments, each R1 is F, Cl, methyl, or hydroxyl. In some embodiments, each R1 is methyl. In some embodiments, each R1 is hydroxyl.
[00100] In some embodiments, R1 is hydroxyl, and n is selected from 0 and 1.
[00101] In some embodiments, o is selected from 0 and 1. In some embodiments, o is selected from 1 and 2. In some embodiments, o is 0. In some embodiments, o is 1. In some embodiments, o is 2. [00102] In some embodiments, each R2 is independently selected at each occurrence from halogen, hydroxyl, and C1-4 alkyl. In some embodiments, each R2 is independently selected at each occurrence from F, Cl, hydroxyl, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec- butyl, and tert-butyl. In some embodiments, each R2 is F, Cl, methyl, or hydroxyl.
[00103] In some embodiments, p is selected from 0 and 1. In some embodiments, p is selected from 1 and 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.
[00104] In some embodiments, each R3 is independently selected at each occurrence from halogen, hydroxyl, and C1-4 alkyl. In some embodiments, each R3 is independently selected at each occurrence from F, Cl, hydroxyl, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec- butyl, and tert-butyl. In some embodiments, each R3 is halogen. In some embodiments, each R3 is F or Cl. In some embodiments, each R3 is F. In some embodiments, each R3 is Cl.
[00105] In some embodiments, R3 is halogen, and p is selected from 0 and 1. In some embodiments, R3 is selected from fluoro and chloro, and p is 1. In some embodiments, R3 is fluoro, and p is 1. In some embodiments, R3 is chloro, and p is 1.
[00106] In some embodiments, R5a and R5b are each independently selected from hydrogen and C1-4 alkyl. In some embodiments, R5a and R5b are each independently selected from hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, and tert-butyl. In some embodiments, R5a and R5b are each independently selected from hydrogen, methyl, and ethyl. In some embodiments, R5a and R5b are each hydrogen.
[00107] In some embodiments, D is selected from -CO2R11, -P(O)(ORn)2, -P(O)R11(OR11), and -S(O)2OH. In some embodiments, D is selected from -CO2H, -CC2Me, -CCFEt, -P(O)(OH)2, - P(O)(OMe)2, -P(O)Me(OMe), -P(O)Me(OH), and -S(O)2OH. In some embodiments, D is selected from -CO2H, -P(O)(OH)2, -P(O)Me(OH), and -S(O)2OH. In some embodiments, D is selected from -P(O)(ORn)2, and -S(O)2OH. In some embodiments, D is selected from - P(O)(OH)2, -P(O)(OMe)2, and -S(O)2OH. In some embodiments, D is selected from -P(O)(OH)2 and -S(O)2OH.
[00108] In some embodiments, D is -L-K.
[00109] In some embodiments, L is z-(C(R13)2)r-. In some embodiments, L is z-O(C(R13)2)r-. In some embodiments, L is λ-(C(R13)2)rO-. In some embodiments, L is λ-N(R12)(C(R13)2)S-. In some embodiments, L is λ-C(O)O-. In some embodiments, L is λ-OC(O)-. In some embodiments, L is λ-C(O)N(R12)-. In some embodiments, L is z-N(R12)C(O)-. In some embodiments, L is x- N(R12)S(O)2-. In some embodiments, L is λ-S(O)2N(R12)-. In some embodiments, L is 4- to 6- membered heterocycle. [00110] In some embodiments, L is selected from z-(C(R13)2)r-, λ-N(R12)(C(R13)2)S-, and λ- N(R12)S(O)2-.
[00111] In some embodiments, r is selected from 1 and 2. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3.
[00112] In some embodiments, s is selected from 0, 1, and 2. In some embodiments, s is 0. In some embodiments, s is 1. In some embodiments, s is 2. In some embodiments, s is 3.
[00113] In some embodiments, K is selected from (i) and (ii):
(i) C1-10 alkyl or C1-10 heteroalkyl, each of which is optionally substituted with one to six substituents independently selected from: halogen, -OR14, -N(R14)2, -N+(R15)3, -C(O)R14, -C(O)OR14, -OC(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -S(O)2R14, -P(O)(OR16)2, - P(O)R16(OR16), -S(O)2OH, C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle and 3- to 10-membered heterocycle is optionally substituted with one to six substituents independently selected from halogen, C1-6 alkyl, -OR14, =0, and -S(O)2OH; and
(ii) C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one to six substituents independently selected from halogen, -OR14, - N(R14)2, -N+(R15)3, -C(O)R14, =0, C1-10 alkyl, and C1-10 heteroalkyl, wherein each C1-10 alkyl and C1-10 heteroalkyl is optionally substituted with one to six substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, - N+(R15)3, -C(O)OR14, -P(O)(OR16)2, -P(O)R16(OR16), -S(O)2OH, S(O)2R14, and =0.
[00114] In some embodiments, K is selected from C1-10 alkyl or C1-10 heteroalkyl, each of which is optionally substituted with one to six substituents independently selected from: halogen, -OR14, -N(R14)2, -N+(R15)3, -C(O)R14, -C(O)OR14, -OC(O)R14, -C(O)N(R14)2, - N(R14)C(O)R14, -S(O)2R14, -P(O)(OR16)2, -P(O)R16(OR16), -S(O)2OH, C3-10 carbocycle and 3- to 10-membered heterocycle. In some embodiments, K is selected from C1-10 alkyl or C1-10 heteroalkyl, each of which is optionally substituted with one to six substituents independently selected from: halogen, -OR14, -N(R14)2, -N+(R15)3, -C(O)R14, -C(O)OR14, -OC(O)R14, - C(O)N(R14)2, -N(R14)C(O)R14, -S(O)2R14, -P(O)(OR16)2, -P(O)R16(OR16), -S(O)2OH, C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle and 3- to 10- membered heterocycle is optionally substituted with one to six substituents independently selected from halogen, C1-6 alkyl, -OR14, =0, and -S(O)2OH. In some embodiments, K is selected from C1-10 alkyl and C1-10 heteroalkyl, each of which is optionally substituted with one to six substituents independently selected from: halogen, -OR14, -N(R14)2, -N+(R15)3, -C(O)OR14, -C(O)N(R14)2, -P(O)(OR16)2, -S(O)2OH, C3-10 carbocycle and 3- to 10-membered heterocycle, and wherein each C3-10 carbocycle and 3- to 10-membered heterocycle is optionally substituted with one to six substituents independently selected from halogen, -OR14, =0, and -S(O)2OH. [00115] In some embodiments, K is selected from C1-10 alkyl and C1-10 heteroalkyl, each of which is optionally substituted with one to six substituents independently selected from -OR14. In some embodiments, K is selected from C1-10 alkyl and C1-10 heteroalkyl, each of which is optionally substituted with one to six -OH substituents.
[00116] In some embodiments, K is C1-10 alkyl, which is optionally substituted with one to six substituents independently selected from: halogen, -OR14, -N(R14)2, -N+(R15)3, -C(O)OR14, - C(O)N(R14)2, -P(O)(OR16)2, -S(O)2OH, C3-10 carbocycle and 3- to 10-membered heterocycle, and wherein each C3-10 carbocycle and 3- to 10-membered heterocycle is optionally substituted with one to six substituents independently selected from halogen, -OR14, =0, and -S(O)2OH. In some embodiments, K is C1-10 alkyl, which is optionally substituted with one to six substituents independently selected from -OR14. In some embodiments, K is C1-10 alkyl, each of which is optionally substituted with one to six -OH substituents.
[00117] In some embodiments, K is C1-10 heteroalkyl, which is optionally substituted with one to six substituents independently selected from: halogen, -OR14, -N(R14)2, -N+(R15)3, -C(O)OR14, -C(O)N(R14)2, -P(O)(OR16)2, -S(O)2OH, C3-10 carbocycle and 3- to 10-membered heterocycle, and wherein each C3-10 carbocycle and 3- to 10-membered heterocycle is optionally substituted with one to six substituents independently selected from halogen, -OR14, =0, and -S(O)2OH. In some embodiments, K is C1-10 heteroalkyl, which is optionally substituted with one to six substituents independently selected from -OR14. In some embodiments, K is C1-10 heteroalkyl, each of which is optionally substituted with one to six -OH substituents.
[00118] In some embodiments, K is selected from C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one to six substituents independently selected from halogen, -OR14, -N(R14)2, -N+(R15)3, -C(O)R14, =0, C1-10 alkyl, and C1-10 heteroalkyl. In some embodiments, K is selected from C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one to six substituents independently selected from halogen, -OR14, -N(R14)2, -N+(R15)3, -C(O)R14, =0, C1-10 alkyl, and C1-10 heteroalkyl, wherein each C1-10 alkyl and C1-10 heteroalkyl is optionally substituted with one to six substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -N+(R15)3, - C(O)OR14, -P(O)(OR16)2, -P(O)R16(OR16), -S(O)2OH, S(O)2R14, and =0.
[00119] In some embodiments, K is selected from 3- to 10-membered heterocycle, optionally substituted with one to six substituents independently selected from halogen, -OR14, -N(R14)2, - N+(R15)3, -C(O)R14, =0, C1-10 alkyl, and C1-10 heteroalkyl, wherein each C1-10 alkyl and C1-10 heteroalkyl is optionally substituted with one to six substituents independently selected from halogen, -OR14, -N(R14)2, N+(R15)3, -C(O)OR14, -P(O)(OR16)2, -P(O)R16(OR16), -S(O)2OH, S(O)2R14, and =0.
[00120] In some embodiments, K is selected from 3- to 10-membered heterocycle optionally substituted with one to six substituents independently selected from halogen, -OR14, C1-10 alkyl, and C1-10 heteroalkyl, wherein each C1-10 alkyl and C1-10 heteroalkyl is optionally substituted with one to six substituents independently selected from halogen, -OR14, -N(R14)2, -P(O)(OR16)2, -S(O)2OH, and S(O)2R14. In some embodiments, K is selected from azetidine and piperazine, each of which is optionally substituted with one to six substituents independently selected from C1-10 alkyl and C1-10 heteroalkyl, wherein each C1-10 alkyl and C1-10 heteroalkyl is optionally substituted with one to six substituents independently selected from -OR14 and -N(R14)2. [00121] In some embodiments, each R14 is independently selected at each occurrence from hydrogen; C1-10 alkyl optionally substituted with one to six substituents independently selected from, -OR21, -N(R21)2, -P(O)(OR16)2, -S(O)2OH; and C3-10 carbocycle optionally substituted with one to six substituents independently selected from -OH and =0. In some embodiments, each R14 is independently selected at each occurrence from hydrogen and C1-10 alkyl optionally substituted with one to six substituents independently selected from -OR21. In some embodiments, each R14 is independently selected at each occurrence from hydrogen and C1-10 alkyl optionally substituted with one to six -OH substituents. In some embodiments, each R14 is independently selected at each occurrence from hydrogen and C1-6 alkyl.
[00122] In some embodiments, each R21 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 hydroxyalkyl, and C3-6 carbocycle, wherein the C3-6 carbocycle is optionally substituted with one to six substituents independently selected from -OH and =0. In some embodiments, each R 21 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and C1-6 hydroxyalkyl. In some embodiments, each R 21 is independently selected at each occurrence from hydrogen and C1-6 alkyl.
[00123] In some embodiments, D is selected from:
Figure imgf000033_0001
Figure imgf000033_0002
Figure imgf000034_0001
[00124] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.
[00125] In some embodiments, the compound is a compound in one of the following tables, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.
Table 1.
Figure imgf000034_0002
Figure imgf000035_0001
Figure imgf000036_0001
[00126] Compounds in Table 1 are named:
1: 2-((6-chloro-5-(4'-((3-(((2-(2-hydroxyethoxy)ethyl)amino)methyl)azetidin-l-yl)methyl)-[l,T- biphenyl]-4-yl)-lH-imidazo[4,5-b]pyridin-2-yl)thio)acetic acid;
2: 2-((6-chloro-5-(4'-(((l,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)methyl)-[l,T- biphenyl]-4-yl)-lH-imidazo[4,5-b]pyridin-2-yl)thio)acetic acid;
3: 2-((5-(4'-((4,4-bis(hydroxymethyl)piperidin-l-yl)methyl)-[l,T-biphenyl]-4-yl)-6-chloro-lH- imidazo[4,5-b]pyridin-2-yl)thio)acetic acid; 4: 2-((6-chloro-5-(4'-((((2S,3R,4R,5R)-2, 3,4,5, 6-pentahydroxyhexyl)amino)methyl)-[ 1,1'- biphenyl]-4-yl)-lH-imidazo[4,5-b]pyridin-2-yl)thio)acetic acid;
5: 2-((5-(4'-((3,3-bis(hydroxymethyl)azetidin-l-yl)methyl)-[l,l'-biphenyl]-4-yl)-6-chloro-lH- imidazo[4,5-b]pyridin-2-yl)thio)acetic acid;
6: 2-((6-chloro-5-(4'-(((2-(2-hydroxyethoxy)ethyl)amino)methyl)-[l,l'-biphenyl]-4-yl)-lH- imidazo[4,5-b]pyridin-2-yl)thio)acetic acid;
7 : 2-((6-chloro-5-(4'-((4-(2-(2-hydroxyethoxy)ethyl)piperazin- 1 -yl)methyl)-[ 1 , 1 '-biphenyl] -4- yl)-lH-imidazo[4,5-b]pyridin-2-yl)thio)acetic acid;
8: 2-((6-chloro-5-(4'-((3-((((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)methyl)azetidin- l-yl)methyl)-[l,l'-biphenyl]-4-yl)-lH-imidazo[4,5-b]pyridin-2-yl)thio)acetic acid;
9: 2-((6-chloro-5-(2'-hydroxy-4'-(((2-(2-hydroxyethoxy)ethyl)amino)methyl)-[l,l'-biphenyl]-4- yl)-lH-imidazo[4,5-b]pyridin-2-yl)thio)acetic acid;
10: 2-((6-chloro-5-(2'-hydroxy-4'-((((2S,3R,4R,5R)-2,3,4,5,6- pentahydroxyhexyl)amino)methyl)-[l,r-biphenyl]-4-yl)-lH-imidazo[4,5-b]pyri din-2- yl)thio)acetic acid;
11: 2-((6-chloro-5-(4'-(N-(2-(2-hydroxyethoxy)ethyl)sulfamoyl)-[l,l'-biphenyl]-4-yl)-lH- imidazo[4,5-b]pyridin-2-yl)thio)acetic acid;
12: 2-((6-chloro-5-(2'-hydroxy-4'-((3-((((2S,3R,4R,5R)-2,3,4,5,6- pentahydroxyhexyl)amino)methyl)azetidin-l-yl)methyl)-[l,l'-biphenyl]-4-yl)-lH-imidazo[4,5- b]pyridin-2-yl)thio)acetic acid;
13: 2-((6-chloro-5-(2'-hydroxy-4'-((3-(((2-(2-hydroxyethoxy)ethyl)amino)methyl)azetidin-l- yl)methyl)-[l,l'-biphenyl]-4-yl)-lH-imidazo[4,5-b]pyridin-2-yl)thio)acetic acid;
14: methyl 2-((6-chloro-5-(2'-hydroxy-4'-(((2-(2-hydroxyethoxy)ethyl)amino)methyl)-[l, 1'- biphenyl]-4-yl)-lH-imidazo[4,5-b]pyridin-2-yl)thio)acetate;
15: methyl 2-((6-chloro-5-(4'-(((2-(2-hydroxyethoxy)ethyl)amino)methyl)-[l,l'-biphenyl]-4-yl)- lH-imidazo[4,5-b]pyridin-2-yl)thio)acetate;
16: 2-((6-chloro-5-(4'-((3-((2-hydroxy ethoxy )methyl)azeti din- l-yl)methyl)-[ l,l'-biphenyl]-4- yl)-lH-imidazo[4,5-b]pyridin-2-yl)thio)acetic acid;
17: methyl 2-((6-chloro-5-(4'-((3 -((2-hydroxyethoxy)methyl)azetidin- 1 -yl)methyl)-[ 1 ,1'- biphenyl]-4-yl)-lH-benzo[d]imidazol-2-yl)thio)acetate;
18: 2-((6-chloro-5-(4'-(((2-(2-hydroxyethoxy)ethyl)amino)methyl)-[l,l'-biphenyl]-4-yl)-lH- imidazo[4,5-b]pyridin-2-yl)thio)butanoic acid;
19: 2-((6-chloro-5-(4'-(((2-(2-hydroxyethoxy)ethyl)amino)methyl)-[l,l'-biphenyl]-4-yl)-lH- imidazo[4,5-b]pyridin-2-yl)thio)-2-methylpropanoic acid; 20: 2-((6-chloro-5-(4'-(((2-(2-((2-hydroxy-3,4-dioxocyclobut-l-en-l- yl)amino)ethoxy)ethyl)amino)methyl)-[l,r-biphenyl]-4-yl)-lH-imidazo[4,5-b]pyridin-2- yl)thio)acetic acid;
21: 2-((6-chloro-5-(4'-(((2-(2-hydroxyethoxy)ethyl)amino)methyl)-[l,l'-biphenyl]-4-yl)-lH- imidazo[4,5-b]pyridin-2-yl)thio)propanoic acid.
[00127] In some embodiments, the compound is a pharmaceutically acceptable salt of a compound in Table 1.
Table 2.
Figure imgf000038_0001
[00128] Compounds in Table 2 are named:
22: 2-((6-chloro-5-(2'-hydroxy-4'-(((2-(2-hydroxyethoxy)ethyl)amino)methyl)-[l,T-biphenyl]-4- yl)-lH-imidazo[4,5-b]pyridin-2-yl)thio)butanoic acid;
23: 2-((6-chloro-5-(4'-(2-(2-methoxy-3,4-dioxocyclobut-l-en-l-yl)-13-((2-methoxy-3,4- dioxocyclobut- 1 -en- 1 -yl)amino)-5,8, 11 -tri oxa-2 -azatri decyl )-[ 1 , 1 '-biphenyl]-4-yl)- 1 H- imidazo[4,5-b]pyridin-2-yl)thio)acetic acid.
[00129] In some embodiments, the compound is a pharmaceutically acceptable salt of a compound in Table 2.
Further Forms of Compounds
[00130] Furthermore, in some embodiments, the compounds described herein exist as “geometric isomers.” In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (£), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, compounds exist as tautomers.
[00131] A “tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. In some embodiments, the compounds presented herein exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:
Figure imgf000039_0001
[00132] In some situations, the compounds described herein possess one or more chiral centers and each center exists in the (R)- configuration or (5)- configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as optically pure enantiomers by chiral chromatographic resolution of the racemic mixture. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. [00133] The term “positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.
[00134] The methods and formulations described herein include the use of crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of compounds described herein, as well as active metabolites of these compounds having the same type of activity. [00135] “Pharmaceutically acceptable salt” includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
[00136] “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 66:1- 19 (1997). Acid addition salts of basic compounds are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt.
[00137] “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropyl amine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N- dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, 7V-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, 7V-ethylpiperidine, polyamine resins and the like. See Berge et al., supra. [00138] “Prodrug” is meant to indicate a compound that is, in some embodiments, converted under physiological conditions or by solvolysis to an active compound described herein. Thus, the term prodrug refers to a precursor of an active compound that is pharmaceutically acceptable. A prodrug is typically inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).
[00139] A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987. [00140] The term “prodrug” is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound, as described herein, are prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino, carboxy, or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino, free carboxy, or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amine functional groups in the active compounds and the like.
[00141] “Pharmaceutically acceptable solvate” refers to a composition of matter that is the solvent addition form. In some embodiments, solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like. “Hydrates” are formed when the solvent is water, or “alcoholates” are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein optionally exist in either unsolvated as well as solvated forms.
[00142] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of 2H, 3H, 11C, 13C and/or 14C. In some embodiments, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.
[00143] Unless otherwise stated, structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13C- or 14C-enriched carbon are within the scope of the present disclosure.
[00144] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with 2H, 3H, 11C, 13C, 14C, 15C, 12N, 13N, 15N, 16N, 17O, 18O, 14F, 15F, 16F, 17F, 18F, 33S, 34S, 35S, 36S, 35C1, 37C1, 79Br, 81Br, 125I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.
[00145] In some embodiments, the compounds disclosed herein have some or all of the 4H atoms replaced with 2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art. In some embodiments deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.
[00146] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
[00147] In some embodiments, the compounds described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, as described herein are substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as contaminating intermediates or by-products that are created, for example, in one or more of the steps of a synthesis method.
Preparation of the Compounds
[00148] Compounds described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with methods described herein.
[00149] Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed.
[00150] Compounds are prepared using standard organic chemistry techniques such as those described in, for example, March’s Advanced Organic Chemistry, 6th Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be employed such as variation of solvent, reaction temperature, reaction time, as well as different chemical reagents and other reaction conditions.
[00151] In some embodiments, compounds described herein are prepared as outlined in the Schemes below.
Scheme 1.
Figure imgf000043_0001
a. Sn CI2-2H2O; b. C(S)C12; c. Br-CR2-CO2R; d. (substituted biphenyl)-B(OR)2
[00152] Briefly, nitropyridine (Y=N) or nitrophenyl (Y=CH or CR4) compound A is reduced to diaminoaryl compound B. Compound B is treated with thiophosgene to afford compound C. Compound C undergoes an alkylation reaction with an appropriate alkyl bromide compound to afford compound D. Finally, aryl iodide D is treated under cross-coupling conditions, for example Suzuki cross-coupling, to arrive at Compounds of Formula (I). In some instances, additional chemical modification, such as saponification, amide formation, or reductive amination, is performed on the Compounds of Formula (I) to afford additional compounds.
Scheme 2.
Figure imgf000044_0001
PG is a suitable protecting group; a. CH3I; b. [ox]; c. (substituted biphenyl)-B(OR)2; d. protection; e. Na2S; f. X- CR2-CO2R, where X is a suitable leaving group; g. deprotection
[00153] Compound C undergoes a methylation reaction following by oxidation to afford compound E. Aryl iodide E is treated under cross-coupling conditions, for example Suzuki cross-coupling, to arrive at compound F. Compound F is suitably protected to Compound G. Aryl sulfone G is converted to Compound H, which subsequently undergoes an alkylation reaction with an appropriate alkyl halide compound to afford compound J. Finally, compound J is deprotected to arrive at Compounds of Formula (I). In some instances, additional chemical modification, such as saponification, amide formation, or reductive amination, is performed on the Compounds of Formula (I) to afford additional compounds. [00154] In some embodiments, compounds described herein are prepared as described as outlined in the Examples.
Pharmaceutical Compositions
[00155] In some embodiments, disclosed herein is a pharmaceutical composition comprising an AMPK activator described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, the AMPK activator is combined with a pharmaceutically suitable (or acceptable) carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration, e.g., oral administration, and standard pharmaceutical practice.
[00156] Examples of suitable aqueous and non-aqueous carriers which are employed in the pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof; vegetable oils, such as olive oil; and injectable organic esters, such as ethyl oleate and cyclodextrins. Proper fluidity is maintained, for example, by the use of coating materials, such as lecithin; by the maintenance of the required particle size, in the case of dispersions; and by the use of surfactants.
Combination Therapies
[00157] In some embodiments, it is appropriate to administer at least one compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, in combination with one or more other therapeutic agents.
[00158] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered in combination with one or more anti-inflammatory agents. Examples of anti-inflammatory agents to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include, but are not limited to: aminosalicylates such as balsalazide, mesalamine, olsalazine, and sulfalazine; corticosteroids such as budesonide, prednisone, prednisolone, methylprednisolone, dexamethasone, and betamethasone; anti-TNF alpha agents such as infliximab, adalimumab, certolizumab pegol, golimumab, and PRX-106; anti-IL-12 and/or 23 agents such as ustekinumab, guselkumab, brazikumab, mirikizumab, risankizumab, and PTG-200; anti-integrin agents such as natalizumab, vedolizumab, etrolizumab, SHP 647 (PF-00547659), alicaforsen, abrilumab, AJM300, and PTG-100; JAK inhibitors such as tofacitinib, filgotinib, peficitinib, itacitinib, ABT-494, and TD-1473; S IP 1R modulators such as ozanimod, amiselimod, etrasimod, and CBP-307; salicylates such as aspirin, salicylic acid, gentisic acid, choline magnesium salicylate, choline salicylate, choline magnesium salicylate, choline salicylate, magnesium salicylate, sodium salicylate, and diflunisal; COX inhibitors such as carprofen, fenoprofen, fenoprofen calcium, fluorobiprofen, ibuprofen, ketoprofen, nabutone, ketolorac, ketorolac tromethamine, naproxen, oxaprozin, diclofenac, etodolac, indomethacin, sulindac, tolmetin, meclofenamate, meclofenamate sodium, mefenamic acid, piroxicam, and meloxicam; COX-2 specific inhibitors such as, but not limited to, celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib, lumiracoxib, CS-502, JTE-522, L-745 337, and NS398; and IL-22 agents such as RG-7880. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered in combination with a aminosalicylate, a corticosteroid, an anti-TNF alpha agent, an anti-IL-12 and/or 23 agent, an anti-integrin agent, a JAK inhibitor, a S1P1R modulator, a salicylate, a COX inhibitor, a COX-2 specific inhibitor, an interleukin-22 (IL-22) agent, or a combination thereof. [00159] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered in combination with one or more agents that improve gastrointestinal barrier function. Examples of agents that improve gastrointestinal barrier function to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include, but are not limited to: HIF-PH inhibitors such as DS-1093, TRC-160334, and GB-004; MC1R agonists such as PL-8177; EZH2 inhibitors such as IMU-856; and DPP-4 inhibitors such as sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, teneligliptin, alogliptin, trelagliptin, omarigliptin, evogliptin, gosogliptin, and dutogliptin. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered in combination with a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, a melanocortin-1 receptor (MC1R) agonist, an enhancer of zeste homolog 2 (EZH2) inhibitor, or combinations thereof.
[00160] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered in combination with a glucagon- like peptide (GLP)-l agonist, a GLP-2 agonist, a GLP-1/2 co-agonist, a peroxisome proliferator- activator receptor (PPAR) agonist, a Farsnenoid X receptor (FXR) agonist, a TGR5 agonist, a GPR40 agonist, a GPR119 agonist, an SSTR5 antagonist, an SSTR5 inverse agonist, an acetyl- CoA carboxylase (ACC) inhibitor, a stearoyl-CoA desaturase 1 (SCD-1) inhibitor, a dipeptidyl peptidase 4 (DPP-4) inhibitor, or combinations thereof. In some embodiments, the pharmaceutical composition comprises one or more anti-diabetic agents. In some embodiments, the pharmaceutical composition comprises one or more anti-obesity agents. In some embodiments, the pharmaceutical composition comprises one or more agents to treat nutritional disorders. [00161] Examples of a GLP-1 agonist to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include: exenatide, liraglutide, taspoglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, OWL833 and ORMD 0901.
[00162] Examples of a GLP-2 agonist to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include: tedaglutide, glepaglutide (ZP1848), elsiglutide (ZP1846), apraglutide (FE 203799), HM-15912, NB-1002, GX-G8, PE-0503, and SAN-134, and those described in WO-2011050174, WO- 2012028602, WO-2013164484, WO-2019040399, WO-2018142363, WO-2019090209, WO- 2006117565, WO-2019086559, WO-2017002786, WO-2010042145, WO-2008056155, WO- 2007067828, WO-2018229252, WO-2013040093, WO-2002066511, WO-2005067368, WO- 2009739031, WO-2009632414, and W02008028117
[00163] Examples of a GLP-1/2 co-agonist to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include ZP-GG-72 and those described in WO-2018104561, WO-2018104558, WO- 2018103868, WO-2018104560, WO-2018104559, WO-2018009778, WO-2016066818, and WO-2014096440..
[00164] Examples of a PPAR agonist to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include: elafibranor (GFT505), lanifibranor, pioglitazone, rosiglitazone, saroglitazar, seladelpar, and GW501516.
[00165] Examples of a FXR agonist to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include: obeticholic acid, NGM-282, EYP001, GS-9674, tropifexor (LJN452), and LMB-763.
[00166] Examples of a TGR5 agonist to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include: INT-777, XL-475, SRX-1374, RDX-8940, RDX-98940, SB-756050, and those disclosed in WO-2008091540, WO-2010059853, WO-2011071565, WO-2018005801, WO-2010014739, WO-2018005794, WO-2016054208, WO-2015160772, WO-2013096771, WO-2008067222, WO-2008067219, WO-2009026241, WO-2010016846, WO-2012082947, WO-2012149236, WO-2008097976, WO-2016205475, WO-2015183794, WO-2013054338, WO-2010059859, WO-2010014836, WO-2016086115, WO-2017147159, WO-2017147174, WO-2017106818, WO-2016161003, WO-2014100025, WO-2014100021, WO-2016073767, WO-2016130809, WO-2018226724, WO-2018237350, WO-2010093845, WO-2017147137, WO-2015181275, WO-2017027396, WO-2018222701, WO-2018064441, WO-2017053826, WO-2014066819, WO-2017079062, WO-2014200349, WO-2017180577, WO-2014085474.
[00167] Examples of a GPR40 agonist to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include: fasiglifam, MR-1704, SCO-267, SHR-0534, HXP-0057-SS, LY-2922470, P-11187, JTT-851, ASP-4178, AMG-837, ID-11014A, HD-C715, CNX-011-67, JNJ-076, TU-5113, HD-6277, MK-8666, LY-2881835, CPL-207-280, ZYDG-2, and those described in US-07750048, WO- 2005051890, WO-2005095338, WO-2006011615, WO-2006083612, WO-2006083781, WO- 2007088857, WO-2007123225, WO-2007136572, WO-2008054674, WO-2008054675, WO- 2008063768, WO-2009039942, WO-2009039943, WO-2009054390, WO-2009054423, WO- 2009054468, WO-2009054479, WO-2009058237, WO-2010085522, WO-2010085525, WO- 2010085528, WO-2010091176, WO-2010123016, WO-2010123017, WO-2010143733, WO- 2011046851, WO-2011052756, WO-2011066183, WO-2011078371, WO-2011161030, WO- 2012004269, WO-2012004270, WO-2012010413, WO-2012011125, WO-2012046869, WO- 2012072691, WO-2012111849, WO-2012147518, WO-2013025424, WO-2013057743, WO- 2013104257, WO-2013122028, WO-2013122029, WO-2013128378, WO-2013144097, WO- 2013154163, WO-2013164292, WO-2013178575, WO-2014019186, WO-2014073904, WO- 2014082918, WO-2014086712, WO-2014122067, WO-2014130608, WO-2014146604,WO- 2014169817, WO-2014170842,WO-2014187343, WO-2015000412, WO-2015010655, WO- 2015020184, WO-2015024448, WO-2015024526, WO-2015028960, WO-2015032328, WO- 2015044073, WO-2015051496, WO-2015062486, WO-2015073342, WO-2015078802, WO- 2015084692, WO-2015088868, WO-2015089809, WO-2015097713, WO-2015105779, WO- 2015105786, WO-2015119899, WO-2015176267, WG-201600771, WO-2016019587, WO- 2016022446, WO-2016022448, WO-2016022742, WO-2016032120, WO-2016057731, WO- 2017025368, WO-2017027309, WO-2017027310, WO-2017027312, WO-2017042121, WO- 2017172505, WO-2017180571, WO-2018077699, WO-2018081047, WO-2018095877, WO- 2018106518, WO-2018111012, WO-2018118670, WO-2018138026, WO-2018138027, WO- 2018138028, WO-2018138029, WO-2018138030, WO-2018146008, WO-2018172727, WO- 2018181847, WO-2018182050, WO-2018219204, WO-2019099315, and WO-2019134984.
[00168] Examples of a GPR119 agonist to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include: DS-8500a, HD-2355, LC34AD3, PSN-491, HM-47000, PSN-821, MBX-2982, GSK-1292263, APD597, DA-1241, and those described in WO-2009141238, WO-2010008739, WO- 2011008663, WO-2010013849, WO-2012046792, WO-2012117996, WO-2010128414, WO- 2011025006, WO-2012046249, WO-2009106565, WO-2011147951, WO-2011127106, WO- 2012025811, WO-2011138427, WO-2011140161, WO-2011061679, WO-2017175066, WO- 2017175068, WO-2015080446, WO-2013173198, US-20120053180, WO-2011044001, WO- 2010009183, WO-2012037393, WO-2009105715, WO-2013074388, WO-2013066869, WO- 2009117421, WO-201008851, WO-2012077655, WO-2009106561, WO-2008109702, WO- 2011140160, WO-2009126535, WO-2009105717, WO-2013122821, WO-2010006191, WO- 2009012275, WO-2010048149, WO-2009105722, WO-2012103806, WO-2008025798, WO- 2008097428, WO-2011146335, WO-2012080476, WO-2017106112, WO-2012145361, WO- 2012098217, WO-2008137435, WO-2008137436, WO-2009143049, WO-2014074668, WO- 2014052619, WO-2013055910, WO-2012170702, WO-2012145604, WO-2012145603, WO- 2011030139, WO-2018153849, WO-2017222713, WO-2015150565, WO-2015150563, WO- 2015150564, WO-2014056938, WO-2007120689, WO-2016068453, WO-2007120702, WO- 2013167514, WO-2011113947, WO-2007003962, WO-2011153435, WO-2018026890, WO- 2011163090, WO-2011041154, WO-2008083238, WO-2008070692, WO-2011150067, and WO-2009123992.
[00169] Examples of a SSTR5 antagonist or inverse agonist to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include those described in: WO-03104816, WO-2009050309, WO- 2015052910, WO-2011146324, WO-2006128803, WO-2010056717, WO-2012024183, and WO-2016205032.
[00170] Examples of an ACC inhibitor to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include: firsocostat, GS-834356, and PF-05221304.
[00171] Examples of a SCD-1 inhibitor to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include aramchol.
[00172] Examples of a DPP -4 inhibitor to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include: sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, teneligliptin, alogliptin, trelagliptin, omarigliptin, evogliptin, gosogliptin, and dutogliptin.
[00173] Examples of anti-diabetic agents to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include: GLP-1 receptor agonists such as exenatide, liraglutide, taspoglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, OWL833 and ORMD 0901; SGLT2 inhibitors such as dapagliflozin, canagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin, sergliflozin, sotagliflozin, and tofogliflozin; biguinides such as metformin; insulin and insulin analogs.
[00174] Examples of anti-obesity agents to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include: GLP-1 receptor agonists such as liraglutide, semaglutide; SGLT1/2 inhibitors such as LIK066, pramlintide and other amylin analogs such as AM-833, AC2307, and BI 473494; PYY analogs such as NN-9747, NN-9748, AC-162352, AC-163954, GT-001, GT-002, GT-003, and RHS-08; GIP receptor agonists such as APD-668 and APD-597; GLP-l/GIP co-agonists such as tirzepatide (LY329176), BHM-089, LBT-6030, CT-868, SCO-094, NNC-0090-2746, RG-7685, NN-9709, and SAR-438335; GLP-l/glucagon co-agonist such as cotadutide (MEDI0382), BI 456906, TT-401, G-49, H&D-001A, ZP-2929, and HM-12525A; GLP-1 /GIP/glucagon triple agonist such as SAR-441255, HM-15211, and NN-9423; GLP-1 /secretin co-agonists such as GUB06-046; leptin analogs such as metrel eptin; GDF15 modulators such as those described in WO2012138919, W02015017710, WO2015198199, WO-2017147742 and WO-2018071493; FGF21 receptor modulators such as NN9499, NGM386, NGM313, BFKB8488A (RG7992), AKR-001, LLF-580, CVX-343, LY-2405319, BI089-100, and BMS-986036; MC4 agonists such as setmelanotide; MetAP2 inhibitors such as ZGN-1061; ghrelin receptor modulators such as HM04 and AZP-531; and oxytocin analogs such as carbetocin.
[00175] Examples of agents for nutritional disorders to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include: GLP-2 receptor agonists such as tedaglutide, glepaglutide (ZP1848), elsiglutide (ZP1846), apraglutide (FE 203799), HM-15912, NB-1002, GX-G8, PE-0503, SAN- 134, and those described in WO-2011050174, WO-2012028602, WO-2013164484, WO- 2019040399, WO-2018142363, WO-2019090209, WO-2006117565, WO-2019086559, WO- 2017002786, WO-2010042145, WO-2008056155, WO-2007067828, WO-2018229252, WO- 2013040093, WO-2002066511, WO-2005067368, WO-2009739031, WO-2009632414, and W02008028117; and GLP-l/GLP-2 receptor co-agonists such as ZP-GG-72 and those described in WO-2018104561, WO-2018104558, WO-2018103868, WO-2018104560, WO-2018104559, WO-2018009778, WO-2016066818, and WO-2014096440.
[00176] In one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, in some embodiments, the benefit experienced by a patient is increased by administering one of the compounds described herein with another agent (which also includes a therapeutic regimen) that also has therapeutic benefit. [00177] In one specific embodiment, a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is co-administered with one or more additional therapeutic agents, wherein the compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, and the additional therapeutic agent(s) modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone. In some embodiments, the additional therapeutic agent(s) is a glucagon-like peptide (GLP)-l agonist, a GLP-2 agonist, a GLP-1/2 co-agonist, a peroxisome proliferator-activator receptor (PPAR) agonist, a Farsnenoid X receptor (FXR) agonist, a stearoyl-CoA desaturase 1 (SCD-1) inhibitor, a dipeptidyl peptidase 4 (DPP -4) inhibitor, or a combination thereof. In some embodiments, the second therapeutic agent is an anti-inflammatory agent. In some embodiments, the additional therapeutic agent(s) is an aminosalicylate, a corticosteroid, an anti-TNF alpha agent, an anti-IL- 12 and/or 23 agent, an anti-integrin agent, a JAK inhibitor, a S1P1R modulator, a salicylate, a COX inhibitor, a COX-2 specific inhibitor, an IL-22 agent, or a combination thereof. In some embodiments, the second therapeutic agent is an agent that improves gastrointestinal barrier function. In some embodiments, the additional therapeutic agent(s) is a HIF-PH inhibitor, an MC1R agonist, an EZH2 inhibitor, or a combination thereof.
[00178] In some embodiments, the overall benefit experienced by the patient is additive of the two (or more) therapeutic agents. In other embodiments, the patient experiences a synergistic benefit of the two (or more) therapeutic agents.
[00179] In combination therapies, the multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills).
[00180] The compounds described herein, or pharmaceutically acceptable salts, solvates, stereoisomers, or prodrugs thereof, as well as combination therapies, are administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies. Thus, in one embodiment, the compounds described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition. In another embodiment, the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms. In specific embodiments, a compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease. [00181] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is administered in combination with anti-inflammatory agent, anti-cancer agent, immunosuppressive agent, steroid, non-steroidal anti-inflammatory agent, antihistamine, analgesic, hormone blocking therapy, radiation therapy, monoclonal antibodies, or combinations thereof.
EXAMPLES
List of Abbreviations
[00182] As used above, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:
ACN or MeCN acetonitrile
AcOH or HO Ac acetic acid
ADP adenosine diphosphate
AMP adenosine monophosphate
AMPK 5' AMP-activated protein kinase or adenosine 5 '-monophosphate- activated protein kinase
ATP adenosine triphosphate aq aqueous
BPD bis(pinacolato)diboron
Boc tert-butyl oxy carb ony 1
CDI 1 , 1 '-carbonyldiimidazole
DCM dichloromethane
DIEA or DIPEA A,A-diisopropylethylamine
DMA dimethylacetamide
DMAP dimethylaminopyridine
DME dimethoxy ethane
DMF dimethylformamide
DMSO dimethyl sulfoxide eq equivalent(s)
Et ethyl
EtOH ethanol
EtO Ac or EA ethyl acetate
FA formic acid
Fmoc fluorenylmethoxy carbonyl h, hr(s) hour(s)
HATU 1-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- b]pyridinium 3 -oxide hexafluorophosphate
HPLC high performance liquid chromatography iPrOH iso-propanol
KOAc potassium acetate
LCMS liquid chromatography-mass spectrometry mCPBA meta-chloroperoxybenzoic acid
Me methyl
MeOH methanol
Mel methyl iodide min(s) minute(s)
NaBH(OAc)3 sodium triacetoxyborohydride
NCS N-chlorosuccinimide
NIS N-iodosuccinimide
NMR nuclear magnetic resonance
Oxone potassium peroxysulfate
Cy3P Pd G3 [(tricyclohexylphosphine)-2-(2'-aminobiphenyl)]palladium(II) methanesulfonate
Pd(dppf)C12 [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
Pd(dppf)Cl2 CH2Cl2 [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex
Pd(PPh3)4 palladium-tetrakis(triphenylphosphine)
PE petroleum ether
SEM 2-(trimethylsilyl)ethoxymethyl
SEM-C1 2-(trimethylsilyl)ethoxymethyl chloride
SFC supercritical fluid chromatography rt or RT room temperature
Tf trifluorom ethyl sulfonyl tBu tert-butyl
TEA triethylamine
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin layer chromatography I. Chemical Synthesis
[00183] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Anhydrous solvents and oven-dried glassware were used for synthetic transformations sensitive to moisture and/or oxygen. Yields were not optimized. Reaction times are approximate and were not optimized. Column chromatography and thin layer chromatography (TLC) were performed on silica gel unless otherwise noted.
Example 1: 2-((6-chloro-5-(4'-(((2-(2-hydroxyethoxy)ethyl)amino)methyl)-[l,l'-biphenyl]-4-yl)- lH-imidazo[4,5-b]pyridin-2-yl)thio)propanoic acid (Compound 21)
Figure imgf000054_0001
[00184] Step 1: 2-(2-(((4'-bromo-[l,l'-biphenyl]-4-yl)methyl)amino)ethoxy)ethanol (21-1):
To a solution of 4'-bromo-[l,T-biphenyl]-4-carbaldehyde (13 g, 49 mmol, 1 eq) and 2-(2- aminoethoxy)ethanol (7.8 g, 74 mmol, 7.5 mL, 1.5 eq) in THF (130 mL) was added AcOH (8.9 g, 0.15 mol, 8.5 mL, 3 eq). The mixture was stirred at 40 °C for 1 hour, then NaBH(OAc)3 (21 g, 99 mmol, 2 eq) was added to the solution at 0 °C. The mixture was stirred at 25 °C for 11 hours. The solution was concentrated under reduced pressure to give 21-1 (41 g, 73% yield, 96% purity) as a yellow oil. LCMS: (ES+) m/z (M+H)+ =349.9. 'H NMR (400 MHz, CDCh-d) 8 = 7.62 - 7.52 (m, 4H), 7.52 - 7.47 (m, 2H), 7.42 (d, J= 8.8 Hz, 2H), 4.20 - 4.04 (m, 2H), 3.72 - 3.70 (m, 2H), 3.62 - 3.51 (m, 4H), 3.11 - 3.07 (m, 2H).
[00185] Step 2: tert-butyl ((4'-bromo-[l,l'-biphenyl]-4-yl)methyl)(2-(2- hydroxyethoxy)ethyl)carbamate (21-2): To a solution of 21-1 (17 g, 48 mmol, 1 eq) in THF (200 mL) was added DIEA (28 g, 0.22 mol, 38 mL, 4.5 eq) and BOC2O (42 g, 0.2 mol, 45 mL, 4 eq). The mixture was stirred at 25 °C for 2 hours. The solution was diluted with water (100 mL), then extracted with EA (100 mL x 6). The combined organic layers were washed with brine (100 mL x 2), dried over Na2COU, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether/Ethyl acetate=100/l to 1/1) to give 21-2 (22 g, 45 mmol, 93% yield, 92% purity) as a yellow oil. LCMS: (ES+) m/z (M+H)+ =450.1. 'H NMR (400 MHz, CDCh-d) 8 = 7.60 - 7.49 (m, 4H), 7.45 (d, J= 8.4 Hz, 2H), 7.31 (br s, 2H), 4.55 (br s, 2H), 3.67 - 3.24 (m, 6H), 1.60 - 1.38 (m, 9H).
[00186] Step 3: tert-butyl (2-(2-hydroxyethoxy)ethyl)((4'-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-[l,l'-biphenyl]-4-yl)methyl)carbamate (21-3): To a solution of 21-2 (18 g, 40 mmol, 1 eq) in dioxane (400 mL) was added KO Ac (12 g, 0.12 mol, 3 eq) and BPD (15 g, 60 mmol, 1.5 eq). The mixture was purged with N2 three times, then Pd(dppf)C12*CH2C12 (3.3 g, 4 mmol, 0.1 eq) was added. The mixture was purged with N2 three times, then stirred at 80 °C for 12 hours. The solution was diluted with water (100 mL) and extracted with EA (100 mL x
6). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether/Ethyl acetate=100/l to 1/1) to give 21-3 (17 g, 28 mmol, 71% yield, 82.6% purity) as a yellow oil. LCMS: (ES+) m/z (M+H)+ =498.1. TH NMR (400 MHz, CDCh-d) 8 = 7.88 (d, J= 8.0 Hz, 2H), 7.60 (br t, J= 7.6 Hz, 4H), 7.31 (br s, 2H), 4.56 (d, J= 8.2 Hz, 2H), 3.75 - 3.67 (m, 2H), 3.66 - 3.35 (m, 6H), 1.57 - 1.42 (m, 9H), 1.37 (s, 12H).
Figure imgf000055_0001
21-8 21-9
[00187] Step 4: 5,6-dichloro-3-nitropyridin-2-amine (21-4): To a solution of 6-chloro-3- nitro-pyridin-2-amine (50 g, 0.29 mol, 1 eq) in AcOH (250 mL) was added NCS (46 g, 0.35 mmol, 1.2 eq). The mixture was stirred at 100 °C for 3 hrs. The mixture was cooled to room temperature, then filtered. The filter cake was washed with ethanol (100 mL), then dried in vacuo to give 21-4 (48 g, crude) as a yellow solid. LCMS (ES+): m/z (M+H)+ = 207.9.
[00188] Step 5: 5-chloro-6-iodo-3-nitropyridin-2-amine (21-5): To a solution of 21-4 (48 g, 0.23 mol, 1 eq) in AcOH (250 mL) was added Nal (73 g, 0.48 mol, 2.1 eq). The mixture was stirred at 90 °C for 12 hrs. The mixture was poured into water (500 mL), then filtered. The filter cake was washed with water (200 mL), then dried in vacuo to give 21-5 (60 g, crude) as a yellow solid. LCMS (ES+): m/z (M+H)+ = 299.8. [00189] Step 6: 5-chloro-6-iodopyridine-2,3-diamine (21-6): To a solution 21-5 of (60 g, 0.20 mol, 1 eq) in EtOH (300 mL) was added SnC122H2O (0.18 kg, 0.80 mol, 4 eq). The mixture was stirred at 70 °C for 0.5 hr. To the mixture was added water (450 mL) and KF (0.18 kg), and the mixture was stirred for 0.5 h, then extracted with ethyl acetate (2 x 100 mL). The organic phase was washed with saturated brine (2 x 50 mL), then concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 2: 1 to 0: 1) to give 21-6 (41 g, 73% yield, 96% purity) as an off-white solid. LCMS (ES+): m/z (M+H)+ = 269.9.
[00190] Step 7: 6-chloro-5-iodo-l//-imid:izo|4.5-6|pyridine-2(3//)-thione (21-7): To a solution of 21-6 (20 g, 74 mmol, 1 eq) and DMAP (26 g, 0.22 mol, 2.9 eq) in THF (400 mL) was added dropwise thiocarbonyl dichloride (12 g, 0.10 mol, 8.0 mL, 1.4 eq) at 0 °C under N2. The mixture was stirred at room temperature for 24 hr. To the reaction mixture was added ethyl acetate (2000 mL) and 2 N aqueous HC1 (200 mL). The organic layer was washed with saturated brine (2 x 300 mL), then concentrated in vacuo to give 21-7 (17 g) as a yellow solid. LCMS (ES+): m/z (M+H)+ = 311.8.
[00191] Step 8: 6-chloro-5-iodo-2-(methylthio)-3//-imid:izo [4,5-6] pyridine (21-8): A solution of 21-7 (22 g, 70 mmol, 1 eq) and KOH (4.7 g, 84 mmol, 1.2 eq) in EtOH (440 mL) was stirred at room temperature for 0.5 hr. Mel (10.0 g, 70 mmol, 4.4 mL, 1 eq) was added, and the reaction was stirred at room temperature for another 1 hr. The reaction mixture was concentrated in vacuo to give a residue, then ethyl acetate (300 mL) was added followed by 2 N aqueous HC1 (50 mL). The organic layer was washed with saturated brine (2 x 50 mL), then concentrated in vacuo. The residue was purified by column chromatography (SiCO2, petroleum ether : ethyl acetate = 5: 1 to 1 : 1) to give 21-8 (16 g, 48% yield, 68% purity) as a yellow solid, added m/z (M+H)+ = 325.8.
[00192] Step 9: 6-chloro-5-iodo-2-(niethylsullonyl)-3//-iniid:izo [4,5-6] pyridine (21-9): To a solution of 21-8 (16 g, 49 mmol, 1 eq) in ACN (320 mL) and H2O (320 mL) was added Oxone (66 g, 0.11 mmol, 2.2 eq). The mixture was stirred at room temperature for 12 hrs. The mixture was extracted with ethyl acetate (3 x 400 mL). The combined organic layers were washed with saturated Na2SO3 solution (2 x 200 mL) and brine (2 x 200 mL), then concentrated in vacuo to give 21-9 (16 g) as a yellow solid which was used for next step directly. LCMS (ES+): m/z (M+H)+ = 357.8.
Figure imgf000057_0001
[00193] Step 10: tert-butyl ((4'-(6-chloro-2-(methylsulfonyl)-lH-imidazo[4,5-b]pyridin-5- yl)-[l,l'-biphenyl]-4-yl)methyl)(2-(2-hydroxyethoxy)ethyl)carbamate (21-10): To a solution of 21-9 (20 g, 28 mmol, 50% purity, 1 eq) and 21-3 (28 g, 28 mmol, 50% purity, 1 eq) in dioxane (500 mL) and water (100 mL) was added Na2CO3 (8.9 g, 84 mmol, 3 eq) and Pd(dppf)C12*CH2C12 (2.3 g, 2.8 mmol, 0.1 eq). The mixture was purged with N2 3 times and stirred at 100 °C for 3 hours. The solution was diluted with water (500 mL) and extracted with EA (500 mL x 4). The combined organic layers were washed with saturated brine (100 mLx 2), dried over by Na2SO4, filtered and concentrated under reduced pressure to give 21-10 (16 g, 47% yield, 50% purity) as a yellow solid. LCMS: (ES+) m/z (M+H)+ =601.0.
[00194] Step 11: tert-butyl ((4'-(6-chloro-2-(methylsulfonyl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-5-yl)-[l,l'-biphenyl]-4- yl)methyl)(2-(2-hydroxyethoxy)ethyl)carbamate (21-11): To a solution of 21-10 (16 g, 27 mmol, 1 eq) in THF (200 mL) was added SEM-C1 (5.3 g, 32 mmol, 5.7 mL, 1.2 eq) and TEA (4.0 g, 40 mmol, 5.6 mL, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 12 hours. The reaction mixture was diluted with water (200 mL) and extracted with EA (400 mL x 4). The combined organic layers were washed with saturated brine (300 mL x 3), dried over Na2CO4, filtered and concentrated under reduced pressure to give 21-11 (17 g, 19 mmol, 71% yield, 81% purity) as a yellow solid. LCMS: (ES+) m/z (M+H)+=731.7.
[00195] Step 12: tert-butyl ((4'-(6-chloro-2-thioxo-l-((2-(trimethylsilyl)ethoxy)methyl)- 2,3-dihydro-lH-imidazo[4,5-b]pyridin-5-yl)-[l,l'-biphenyl]-4-yl)methyl)(2-(2- hydroxyethoxy)ethyl)carbamate (21-12): To a solution of 21-11 (17 g, 23.24 mmol, 1 eq) in DMF (170 mL) was added Na2S (5.4 g, 70 mmol, 2.9 mL, 3 eq). The mixture was stirred at 25 °C for 12 hours. The reaction mixture was diluted with water (100 mL) and extracted with EA (100 mL x 6). The organic layers were washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=100/0 to 10/1) to give 21-12 (28 g, 72% yield, 90% purity) as a white solid. LCMS: (ES+) m/z (M+H)+ =685.4.
[00196] Step 13: 2-[5-[4-[4-[[tert-butoxycarbonyl-[2-(2- hydroxyethoxy)ethyl]amino]methyl]phenyl]phenyl]-6-chloro-l-(2- trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-2-yl]sulfanylpropanoic acid (21-13): To a solution of 21-12 (0.40 g, 0.58 mmol, 1 eq) and 2-chloropropanoic acid (0.09 g, 0.88 mmol, 1.5 eq) in DMF (8 mL) was added K2CO3 (0.17 g, 1.2 mmol, 2 eq) and Nal (20 mg, 0.12 mmol, 0.2 eq). The mixture was stirred at 25 °C for 12 hours. The reaction solution was diluted with water (50 mL) and extracted with EA (50 mL x 3). The combined organic layers were washed with saturated brine (50 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give 21-13 (300 mg, crude) as a yellow oil. LCMS: (ES+) m/z (M+H)+ =757.4.
[00197] Step 14: 2-((6-chloro-5-(4'-(((2-(2-hydroxyethoxy)ethyl)amino)methyl)-[l,l'- biphenyl]-4-yl)-lH-imidazo[4,5-b]pyridin-2-yl)thio)propanoic acid (Compound 21): A solution of 21-13 (300 mg, crude) in 4N HCl/dioxane (3 mL) was stirred at 25 °C for 12 hours. The reaction solution was concentrated under reduced pressure to give a residue. The residue was dissolved in DMSO (5 mL), then filtered to give a filtrate. The filtrate was purified by prep- HPLC (column: 3_Phenomenex Luna C18 75 x 30 mm x 3 urn; mobile phase: [A: water (0.225% FA), B: ACN]; B%: 3%-33%) to give Compound 21 (20 mg, 9% yield, 95% purity, FA salt) as a white solid. LCMS: (ES+) m/z (M+H)+ =527.1. 'H NMR (400 MHz, methanol-t/4) δ ppm 7.94 (1 H, s) 7.82- 7.60 (6 H, m) 7.58 (2 H, d, J=7.2 Hz) 4.45 - 4.34 (1 H, m) 4.30 (2 H, s) 3.88 - 3.76 (2 H, m) 3.72 (2 H, d, .J=4,0 Hz) 3.62 (2 H, d, J=3.6 Hz) 3.28 - 3.25 (2 H, m) 1.68 (3 H, d, ./=6,8 Hz).
[00198] The following compounds were prepared according to the procedures described in Example 1 using the appropriate intermediates.
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0004
II. Biological Evaluation
Example A-l: In Vitro pAMPKl Kinase Activation Assay
[00199] Compound effect on AMPK enzyme activation was determined in a cell-free format with a 12-point concentration curve. The ADP-Glo detection system was used to determine phosphorylation of a SAMS peptide substrate. Recombinant AMPK al/pi/yl complex was preactivated by phosphorylation with CAMKK2 followed by incubated with compound for 15 minutes prior to the SAMS phosphorylation reaction. Activity curves and ECso values were fitted by interpolation to an ATP:ADP standard curve as indicated by the ADP-Glo manufacturer using Prism software.
[00200] Results for exemplary compounds are shown in Table A, where A < 10 nM < B < 100 nM < C < 1000 nM < D.
Table A.
Figure imgf000061_0002
Figure imgf000061_0001
Figure imgf000061_0003

Claims

CLAIMS We Claim:
1. A compound or pharmaceutically acceptable salt of Formula (I): wherein
Figure imgf000062_0001
R1, R2, and R3 are each independently selected at each occurrence from halogen, hydroxyl, C1-4 alkyl, -CN, and Ci.4 haloalkyl; n is selected from 0, 1, 2, 3, and 4; o is selected from 0, 1, 2, 3, and 4; p is selected from 0, 1, and 2;
R4 is selected from hydrogen, halogen, C1-4 alkyl, and C1-4 haloalkyl;
R5a and R5b are each independently selected from hydrogen, C1-4 alkyl, and C 1.4 haloalkyl;
R6 is selected from hydrogen and C1-4 alkyl;
D is selected from -CO2R11, -P(O)(OR11)2, -P(O)R11(OR11), -S(O)2OH, and -L-K;
L is selected from λ-(C(R13)2)r-, λ-O(C(R13)2)r-, z-(C(R13)2)rO-, λ-N(R12)(C(R13)2)S-, λ-C(O)O-, λ-OC(O)-, λ-C(O)N(R12)-, λ-N(R12)C(O)-, λ-N(R12)S(O)2-, λ-S(O)2N(R12)-, and 4- to 6- membered heterocycle wherein 1 denotes the connection to K; r is selected from 1, 2, and 3; s is selected from 0, 1, 2, and 3;
K is selected from (i) and (ii):
(i) C1-10 alkyl or C1-10 heteroalkyl, each of which is substituted with one to six substituents independently selected from: halogen, -OR14, -SR14, -N(R14)2, -N+(R15)3, -C(O)R14, -C(O)OR14, -OC(O)R14, -OC(O)N(R14)2, -C(O)N(R14)2, -N(R14)C(O)R14, - N(R14)C(O)OR14, -N(R14)C(O)N(R14)2, -N(R14)S(O)2(R14), -S(O)R14, -S(O)2R14, - S(O)2N(R14)2, =0, -CN, -P(O)(OR16)2, -P(O)R16(OR16), -S(O)2OH, C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle and 3- to 10-membered heterocycle is optionally substituted with one to six substituents independently selected from halogen, C1-6 alkyl, -OR14, =0, and -S(O)2OH; and (ii) C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one to six substituents independently selected from halogen, -OR14, - SR14, -N(R14)2, -N+(R15)3, -C(O)R14, -C(O)OR14, -OC(O)R14, -OC(O)N(R14)2, - C(O)N(R14)2, -N(R14)C(O)R14, -N(R14)C(O)OR14, -N(R14)C(O)N(R14)2, - N(R14)S(O)2(R14), -S(O)R14, -S(O)2R14, -S(O)2N(R14)2, -P(O)(OR16)2, - P(O)R16(OR16), -S(O)2OH, =0, -CN, Ci-10 alkyl, and C1-10 heteroalkyl, wherein each C1-10 alkyl and C1-10 heteroalkyl is optionally substituted with one to six substituents independently selected from halogen, -OR14, -SR14, - N(R14)2, -N+(R15)3, -C(O)OR14, -P(O)(OR16)2, -P(O)R16(OR16), -S(O)2OH, S(O)2R14, and =0; each R11 is independently selected at each occurrence from hydrogen, C1-4 alkyl, and C1-4 haloalkyl; each R12 is independently selected at each occurrence from hydrogen and C1-4 alkyl optionally substituted with halogen, -OH, -NH2, and -C(0)NH2; each R13 is independently selected at each occurrence from hydrogen, C1-4 alkyl, CM haloalkyl, and C1-4 hydroxyalkyl; each R14 is independently selected at each occurrence from: hydrogen; and C1-10 alkyl and C1-10 heteroalkyl optionally substituted with one to six substituents independently selected from halogen, -OR21, -SR21, -N(R21)2, -N+(R15)3, -C(O)R21, - C(O)OR21, -OC(O)R21, -OC(O)N(R21)2, -C(O)N(R21)2, -N(R21)C(O)R21-P(O)(OR16)2, -P(O)R16(OR16), -S(O)2OH, =0, and -CN; and
C3-io carbocycle and 3- to 10-membered heterocycle, wherein each C3-io carbocycle and 3- to 10-membered heterocycle is optionally substituted with one to six substituents independently selected from halogen, Ci-6 alkyl, -OR21, -N+(R15)3, -S(O)R21, -P(O)(OR16)2, - P(O)R16(OR16), -S(O)2OH, -S(O)2R21, -S(O)2N(R21)2, =0, and -CN; each R15 is independently selected at each occurrence from C1-4 alkyl; each R16 is independently selected at each occurrence from hydrogen and C1-6 alkyl; each R21 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, and C3-6 carbocycle, wherein the C3-6 carbocycle is optionally substituted with one to six substituents independently selected from -OH, C1-6 alkyl, C1-6 haloalkyl, Ci-e hydroxyalkyl, and =0. The compound or salt of claim 1, wherein R1 is hydroxyl, and n is selected from 0 and 1. The compound or salt of any one of claims 1 to 2, wherein o is 0. The compound or salt of any one of claims 1 to 3, wherein R3 is halogen, and p is selected from 0 and 1. The compound or salt of claim 4, wherein R3 is chloro, and p is 1. The compound or salt of any one of claims 1 to 5, wherein Y is -N-. The compound or salt of any one of claims 1 to 6, wherein R5a and R5b are each independently selected from hydrogen and C1-4 alkyl. The compound or salt of claim 7, wherein R5a and R5b are each hydrogen. The compound or salt of any one of claims 1 to 8, wherein R6 is hydrogen. The compound or salt of any one of claims 1 to 8, wherein R6 is C1-4 alkyl. The compound or salt of any one of claims 1 to 10, wherein D is selected from -CO2R11, -
P(O)(ORU)2, -P(O)Rn(ORn), and -S(O)2OH. The compound or salt of any one of claims 1 to 11, wherein D is selected from -P(O)(ORn)2 and -S(O)2OH. The compound or salt of any one of claims 1 to 10, wherein D is selected from -L-K. The compound or salt of claim 13, wherein L is selected from z-(C(R13)2)r-, x- N(R12)(C(R13)2)S-, and λ-N(R12)S(O)2-. The compound or salt of any one of claims 13 to 14, wherein r is 1. The compound or salt of any one of claims 13 to 14, wherein s is 1. The compound or salt of any one of claims 13 to 16, wherein K is selected from (i) and (ii):
(i) C1-10 alkyl or C1-10 heteroalkyl, each of which is optionally substituted with one to six substituents independently selected from: halogen, -OR14, -N(R14)2, -N+(R15)3, -C(O)R14, -C(O)OR14, -OC(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -S(O)2R14, -P(O)(OR16)2, - P(O)R16(OR16), -S(O)2OH, C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle and 3- to 10-membered heterocycle is optionally substituted with one to six substituents independently selected from halogen, C1-6 alkyl, -OR14, =0, and -S(O)2OH; and (ii) C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one to six substituents independently selected from halogen, -OR14, - N(R14)2, -N+(R15)3, -C(O)R14, =0, C1-10 alkyl, and C1-10 heteroalkyl, wherein each C1-10 alkyl and C1-10 heteroalkyl is optionally substituted with one to six substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, - N+(R15)3, -C(O)OR14, -P(O)(OR16)2, -P(O)R16(OR16), -S(O)2OH, S(O)2R14, and =0. The compound or salt of claim 17, wherein K is selected from C1-10 alkyl and C1-10 heteroalkyl, each of which is optionally substituted with one to six substituents independently selected from: halogen, -OR14, -N(R14)2, -N+(R15)3, -C(O)OR14, -C(O)N(R14)2, -P(O)(OR16)2, -S(O)2OH, C3-IO carbocycle and 3- to 10-membered heterocycle, and wherein each C3-io carbocycle and 3- to 10-membered heterocycle is optionally substituted with one to six substituents independently selected from halogen, -OR14, =0, and -S(O)2OH. The compound or salt of claim 18, wherein K is selected from C1-10 alkyl and C1-10 heteroalkyl, each of which is optionally substituted with one to six substituents independently selected from -OR14. The compound or salt of claim 17, wherein K is selected from 3- to 10-membered heterocycle, optionally substituted with one to six substituents independently selected from halogen, -OR14, -N(R14)2, -N+(R15)3, -C(O)R14, =0, C1-10 alkyl, and C1-10 heteroalkyl, wherein each C1-10 alkyl and C1-10 heteroalkyl is optionally substituted with one to six substituents independently selected from halogen, -OR14, -N(R14)2, N+(R15)3, -C(O)OR14, - P(O)(OR16)2, -P(O)R16(OR16), -S(O)2OH, S(O)2R14, and =0. The compound or salt of claim 20, wherein K is selected from 3- to 10-membered heterocycle optionally substituted with one to six substituents independently selected from halogen, -OR14, C 1-10 alkyl, and C1-10 heteroalkyl, wherein each C1-10 alkyl and C1-10 heteroalkyl is optionally substituted with one to six substituents independently selected from halogen, -OR14, -N(R14)2, -P(O)(OR16)2, -S(O)2OH, and S(O)2R14. The compound or salt of claim 21, K is selected from azetidine and piperazine, each of which is optionally substituted with one to six substituents independently selected from C1-10 alkyl and C1-10 heteroalkyl, wherein each C1-10 alkyl and C1-10 heteroalkyl is optionally substituted with one to six substituents independently selected from -OR14 and -N(R14)2. The compound or salt of any one of claims 1 to 22, wherein each R14 is independently selected at each occurrence from: hydrogen; C1-10 alkyl optionally substituted with one to six substituents independently selected from, -OR21, -N(R21)2, -P(O)(OR16)2, -S(O)2OH; and C3-10 carbocycle optionally substituted with one to six substituents independently selected from -OH and =0. The compound or salt of any one of claims 1 to 23, wherein each R21 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 hydroxyalkyl, and C3-6 carbocycle, wherein the C3-6 carbocycle is optionally substituted with one to six substituents independently selected from -OH and =0. The compound or salt of any one of claims 1 to 10, wherein D is selected from:
Figure imgf000066_0001
The compound or salt of claim 1, wherein the compound is represented by a structure selected from:
Figure imgf000067_0001
Figure imgf000068_0001
The compound or salt of claim 1, wherein the compound is represented by a structure selected from:
Figure imgf000068_0002
thereof. A pharmaceutical composition comprising a compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. 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 any one of claims 1-27, or a pharmaceutically acceptable salt thereof. The method of claim 29, wherein the condition or disorder involves the gut-brain axis. The method of claim 29 or claim 30, wherein the condition or disorder is a nutritional disorder. The method of claim 31, wherein the condition or disorder is short bowel syndrome, intestinal failure, or intestinal insufficiency. The method of claim 29 or claim 30, wherein the condition or disorder is associated with systemic infection and inflammation from having a leaky gut barrier. The method of claim 29 or claim 30, wherein the condition or disorder is metabolic syndrome, obesity, type 2 diabetes, coronary artery disease, fatty liver, nonalcoholic steatohepatitis (NASH), cirrhosis, hepatic encephalopathy, scleroderma, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, checkpoint inhibitor-induced colitis, psoriasis, celiac disease, necrotizing enterocolitis, gastrointestinal injury resulting from toxic insults, environmental enteric dysfunction, allergy, food allergy, celiac sprue, childhood allergy, graft vs. host disease, irritable bowel syndrome, spontaneous bacterial peritonitis, ischemic colitis, sclerosing cholangitis, Alzheimer’s disease, Parkinson’s disease, cancer, colorectal cancer, depression, autism, or a combination thereof. 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 any one of claims 1-27, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof. The method of claim 35, wherein the toxic insult is from radiation, chemotherapy, or a combination thereof. The method of claim 35 or claim 36, wherein the toxic insult is chemotherapy induced. Use of a compound of any one of claims 1-27, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, as a medicine. Use of a compound of any one of claims 1-27, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, for the treatment of an adenosine 5 '-monophosphate- activated protein kinase (AMPK) associated condition or disorder in a subject in need thereof. The use of claim 39, wherein the condition or disorder involves the gut-brain axis. The use of claim 39 or claim 40, wherein the condition or disorder is a nutritional disorder. The use of claim 41, wherein the condition or disorder is short bowel syndrome, intestinal failure, or intestinal insufficiency. The use of claim 39 or claim 40, wherein the condition or disorder is associated with systemic infection and inflammation from having a leaky gut barrier. The use of claim 39 or claim 40, wherein the condition or disorder is metabolic syndrome, obesity, type 2 diabetes, coronary artery disease, fatty liver, nonalcoholic steatohepatitis (NASH), cirrhosis, hepatic encephalopathy, scleroderma, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, checkpoint inhibitor-induced colitis, psoriasis, celiac disease, necrotizing enterocolitis, gastrointestinal injury resulting from toxic insults, environmental enteric dysfunction, allergy, food allergy, celiac sprue, childhood allergy, graft vs. host disease, irritable bowel syndrome, spontaneous bacterial peritonitis, ischemic colitis, sclerosing cholangitis, Alzheimer’s disease, Parkinson’s disease, cancer, colorectal cancer, depression, autism, or a combination thereof. Use of a compound of any one of claims 1-27, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, for the preparation of a medicament for the treatment of gastrointestinal injury resulting from toxic insult in a subject in need thereof. The use of claim 45, wherein the toxic insult is from radiation, chemotherapy, or a combination thereof. The use of claim 45 or claim 46, wherein the toxic insult is chemotherapy induced.
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