Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4196—1,2,4-Triazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D233/70—One oxygen atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D233/84—Sulfur atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
  • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
  • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
  • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D249/12—Oxygen or sulfur atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

• the present disclosure relates generally to therapeutic agents that may be useful in treatment and prophylaxis of neurodegenerative disorders and/or neural inflammation.
• the blood-brain barrier formed by a tight monolayer of endothelial cells, allows passive diffusion of water, some gases and certain lipid-soluble molecules.
• OAT3 Organic anion transporter 3
• SLC22A8 “solute carrier family 22 member 8”
• DHEA dehydroepiandrosterone
• DHEAS DHEA sulfate
• uric acid and DHEA are associated with upregulation of pAkt as well as downregulation of inflammation markers such as GFAP. Nevertheless, systemic administration of uric acid would elevate the plasma concentrations leading to other deleterious effects, such as gout and hyperuricemia. There exists the need to locally increase levels of neuroprotectants such as uric acids and DHEA in the brain without significant changes in their plasma levels.
• OAT3 has been reported as a transporter for DHEAS (Miyajima et al.) and purportedly for uric acid (Bakhlya et al., 2003; Eraly et al., 2008).
• DHEAS Diyajima et al.
• uric acid purportedly for uric acid
• OAT3 By inhibiting OAT3 selectively, neuroprotective substrates such as uric acids and DHEA normally transported out of the brain by OAT3 will remain in the brain, thereby elevating their levels in the brain interstitial space.
• the present invention relates to the use of a compound that inhibits OAT3, thereby inhibiting the efflux of neuroprotectants from the brain interstitial space, hence elevating the levels of neuroprotectants in the brain to confer neuroprotection and anti- neuroinflammation.
• the compound also referred to herein as the “ion transporter inhibitor” selectively inhibits OAT3.
• the compound displays more potent inhibitory activity against OAT3 compared with its activity against other ion transporter proteins such as OAT1, OAT2, OAT3, OAT4, OAT6, OAT7, OAT9, OAT 10, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K, BCRP, PBP, and URAT1.
• kits for treating a disease or condition associated with neurodegeneration or neuroinflammation in the brain in a subject in need thereof comprising administering to the subject an effective amount of an ion transporter inhibitor, wherein the ion transporter inhibitor modulates the efflux of one or more bioactive endogenous metabolites across the blood brain barrier (BBB) of the subject.
• the condition associated with neurodegeneration is Alzheimer’s Disease, Parkinson’s Disease, fronto-temporal dementia, dementia with Lewy Bodies, PD dementia, multiple system atrophy, Huntington’s disease, Amyotrophic lateral sclerosis, progressive supranuclear palsy, or neuroinflammation.
• methods of modulating efflux of one or more bioactive endogenous metabolites across the blood brain barrier (BBB) in a subject in need thereof comprising administering to the subject in need thereof an ion transporter inhibitor.
• a method of improving neuroprotection in a subject in need thereof comprising administering to the subject an effective amount of an ion transporter inhibitor that modulates the concentration of one or more bioactive endogenous metabolites in the brain interstitial space
• kits for decreasing neuroinflammation in a subject in need thereof comprising administering to the subject an effective amount of an ion transporter inhibitor that modulates the concentration of one or more bioactive endogenous metabolites in the brain interstitial space.
• the ion transporter inhibitor is an inhibitor of organic anion transporter 3 (OAT3).
• OAT3 organic anion transporter 3
• the ion transporter inhibitor selectively inhibits OAT3 compared with other ion transporter proteins.
• the ion transporter inhibitor has an IC50 for OAT3 of about 1 mM or less.
• the ion transporter inhibitor has an IC50 for OAT3 that is at least about 10 fold lower compared with its IC50 for organic anion transporter 1 (OAT1).
• the efflux of the one or more bioactive endogenous metabolites across the BBB is reduced.
• the local concentrations of the one or more bioactive endogenous metabolites in the brain interstitial space are increased.
• the levels of the one or more bioactive endogenous metabolites in the brain interstitial space are increased by about 50% or more.
• the plasma levels of the one or more bioactive endogenous metabolites are decreased.
• the plasma levels of the bioactive endogenous metabolites are modulated by 50% or less. In some embodiments, the plasma levels of the bioactive endogenous metabolites are decreased by 50% or less. In some embodiments of any of the methods described herein, the one or more bioactive endogenous metabolites is an anionic neurotransmitter metabolite of epinephrine, norepinephrine, dopamine, and/or serotonin.
• the one or more bioactive endogenous metabolites are selected from the group consisting of: uric acid, glutathione, dehydroepianodrosterone (DHEA), and DHEA sulfate (DHEAS).
• the one or more bioactive endogenous metabolites have neuroprotective and/or anti-neuroinflammatory properties.
• the anti-neuroinflammatory properties include reduction of a pro- inflammatory response in the brain of the subject.
• the reduction of a pro-inflammatory response comprises reduction in gene expression of one or more of TNF, IL6, IL12/23p40 or MCP1.
• the reduction of a pro-inflammatory response is mediated by processes comprising activation of TrkA/Akt/CREB/Jmjd3 pathway in the brain of the subject.
• TrkA/Akt/CREB/Jmjd3 pathway comprises increase of pTrkA levels in the brain of the subject. In some embodiments, activation of the TrkA/Akt/CREB/Jmjd3 pathway comprises increase of pAkt levels in the brain of the subject. In some embodiments, activation of the TrkA/Akt/CREB/Jmjd3 pathway comprises increase of pCREB levels in the brain of the subject. In some embodiments, activation of the TrkA/Akt/CREB/Jmjd3 pathway comprises an increase in Jmjd3 expression in the brain of the subject. In some embodiments of any of the methods described herein, the anti-neuroinflammatory properties comprises induction of an anti-inflammatory phenotype of microglia in the subject.
• the anti-inflammatory phenotype of microglia comprises increased gene expression of one or more of M2 polarization markers comprising one or more of arginase 1, Yml (chitinase-like protein 3), Fizzl, Klf4 (Kruppel like factor 4) or IL10.
• the anti-inflammatory phenotype of microglia comprises inhibition of a pro-inflammatory phenotype of microglia in the subject.
• protease-resistant protein comprising contacting the protease- resistant protein with an effective amount of a compound that is an inhibitor of organic anion transporter 3 (OAT3), wherein the contacting is in vitro, ex vivo, or in vivo.
• OAT3 organic anion transporter 3
• the protease-resistant protein is selected from alpha synuclein, a-beta, tau, Huntingtin, and TAR DNA binding protein 43 (TDP43) proteins.
• the compound is a compound of Formula (I):
• R 1 , R 2 , and R 3 are each independently hydrogen, hydroxy, halogen, optionally substituted Ci-4 alkyl, optionally substituted Ci- 4 alkoxy, -CN, -C(0)R x , -C(0)0R x , -S(0) 2 R x , or - NR y R z ;
• R x , R y , and R z are each independently H or optionally substituted Ci- 4 alkyl, or R y and R z taken together with the nitrogen to which they are attached form an optionally substituted monocyclic heterocycloalkyl ring;
• the compound is a compound of Formula (IIA):
• G 1 is CH or N
• G 2 is CR 2a or N
• G 3 is CR 3a or N
• G 4 is CH or N
• G 1 , G 2 , G 3 , and G 4 are N;
• G 5 is CH or N
• G 6 is CR la or N
• G 7 is CH or N
• G 8 is CH or N
• R la , R 2a , and R 3a are each independently hydrogen, hydroxy, halogen, C alkyl, substituted C M alkyl, Ci- 4 alkoxy, substituted Ci- 4 alkoxy, -CN, -C(0)R x , -C(0)0R x , - S(0) 2 R x , -NR x R y , or an optionally substituted heterocyclyl;
• R x and R y are each independently H or optionally substituted Ci- 4 alkyl; or R la and R 2a are taken together with the carbons to which they are attached to form a 5- to 16- membered heterocyclyl ring;
• X is -CR 4a R 5a -, -0-, -S-, -S(O)-, -NR 6a -, -S(0) 2 -, -NR 6a S(0) 2 -, -CR 4a R 5a S(0) 2 -, -C(O)-, - NR 6a C(0)-, or -NHNHC(O)-;
• R 4a and R 5a are independently hydrogen, hydroxy, halogen, substituted C M alkyl, C M alkoxy, or substituted C M alkoxy;
• R 4a and R 5a are taken together with the carbon to which they are attached to form a 3- to 6-membered cycloalkyl ring;
• each R 6a is independently hydrogen or C M alkyl
• G 9 is CH or N
• Z 1 and Z 2 are independently S or O;
• W and R 7a are independently hydrogen or C alkyl
• the compound is a compound of Formula (II):
• G 1 is CH or N
• G 2 is CR 2a or N
• G 3 is CR 3a or N
• G 4 is CH or N
• G 1 , G 2 , G 3 , and G 4 are N;
• G 5 is CH or N;
• G 6 is CR la or N
• G 7 is CH or N
• G 8 is CH or N
• G 5 , G 6 , G 7 , and G 8 is N;
• R la , R 2a , and R 3a are each independently hydrogen, hydroxy, halogen, Ci- 4 alkyl, substituted C alkyl, Ci- 4 alkoxy, substituted Ci- 4 alkoxy, -CN, -C(0)R x , -C(0)0R x , - S(0) 2 R x , -NR x R y , or an optionally substituted heterocyclyl;
• R x and R y are each independently H or optionally substituted Ci- 4 alkyl; or R la and R 2a are taken together with the carbons to which they are attached to form a 5- to 16- membered heterocyclyl ring;
• X is -CR 4a R 5a -, -0-, -S-, -S(O)-, -NR 6a -, -S(0) 2 -, or -C(O)-;
• R 4a and R 5a are independently hydrogen, hydroxy, halogen, substituted C M alkyl, C M alkoxy, or substituted C M alkoxy;
• R 4a and R 5a are taken together with the carbon to which they are attached to form a 3- to 6-membered cycloalkyl ring;
• R 6a is hydrogen or CM alkyl
• G 9 is CH or N
• Z 1 and Z 2 are independently S or O;
• W and R 7a are independently hydrogen or CM alkyl
• G 1 is CH or N
• G 2 is CR 2a or N
• G 3 is CR 3a or N
• G 4 is CH or N
• G 1 , G 2 , G 3 , and G 4 are N;
• G 5 is CH or N
• G 6 is CR la or N
• G 7 is CH or N
• G 8 is CH or N
• G 5 , G 6 , G 7 , and G 8 is N;
• R la , R 2a , and R 3a are each independently hydrogen, hydroxy, halogen, Ci- 4 alkyl, substituted Ci- 4 alkyl, Ci- 4 alkoxy, substituted Ci- 4 alkoxy, -CN, -C(0)R x , -C(0)0R x , - S(0) 2 R x , -NR x R y , or an optionally substituted heterocyclyl;
• R x and R y are each independently H or optionally substituted Ci- 4 alkyl; or R la and R 2a are taken together with the carbons to which they are attached to form a 5- to 16- membered heterocyclyl ring;
• X is -CR 4a R 5a -, -0-, -S-, -S(O)-, -NR 6a -, -S(0) 2 -, -NR 6a S(0) 2 -, -CR 4a R 5a S(0) 2 -, -C(O)-, - NR 6a C(0)-, or -NHNHC(O)-;
• R 4a and R 5a are independently hydrogen, hydroxy, halogen, substituted Ci- 4 alkyl, Ci- 4 alkoxy, or substituted Ci- 4 alkoxy;
• R 4a and R 5a are taken together with the carbon to which they are attached to form a 3- to 6-membered cycloalkyl ring;
• each R 6a is independently hydrogen or Ci- 4 alkyl
• G 9 is CH or N
• Z 1 and Z 2 are independently S or O;
• W and R 7a are independently hydrogen or Ci- 4 alkyl
• X is -CR 4a R 5a -, -0-, -S-, -S(O)-, -NR 6a -, -NR 6a S(0) 2 -, -CR 4a R 5a S(0) 2 -, -C(O)-, - NR 6a C(0)-, or -NHNHC(O)-;
• R la is an optionally substituted heterocyclyl, wherein when the heterocyclyl is monocyclic, the point of connection is via a carbon atom;
• R 2a is an optionally substituted heterocyclyl, wherein when the heterocyclyl is monocyclic, the point of connection is via a carbon atom;
• R 3a is an optionally substituted heterocyclyl, wherein when the heterocyclyl is monocyclic, the point of connection is via a carbon atom;
• R 2a and R 3a are taken together with the carbons to which they are attached to form a 5- to 16- membered heterocyclyl ring;
• G 1 is CH or N
• G 2 is CR 2a or N
• G 3 is CR 3a or N
• G 4 is CH or N; wherein no more than two of G 1 , G 2 , G 3 , and G 4 are N;
• G 5 is CH or N
• G 6 is CR la or N
• G 7 is CH or N
• G 8 is CH or N
• G 5 , G 6 , G 7 , and G 8 is N;
• R la , R 2a , and R 3a are each independently hydrogen, hydroxy, halogen, Ci- 4 alkyl, substituted Ci- 4 alkyl, Ci- 4 alkoxy, substituted Ci- 4 alkoxy, -CN, -C(0)R x , -C(0)0R x , - S(0) 2 R x , -NR x R y , or an optionally substituted heterocyclyl;
• R x and R y are each independently H or optionally substituted Ci- 4 alkyl; or R la and R 2a are taken together with the carbons to which they are attached to form a 5- to 16- membered heterocyclyl ring;
• X is -CR 4a R 5a -, -0-, -S-, -S(O)-, -NR 6a -, -S(0) 2 -, or -C(O)-;
• R 4a and R 5a are independently hydrogen, hydroxy, halogen, substituted Ci- 4 alkyl, Ci- 4 alkoxy, or substituted Ci- 4 alkoxy;
• R 4a and R 5a are taken together with the carbon to which they are attached to form a 3- to 6-membered cycloalkyl ring;
• R 6a is hydrogen or Ci- 4 alkyl
• G 9 is CH or N
• Z 1 and Z 2 are independently S or O;
• W and R 7a are independently hydrogen or Ci- 4 alkyl
• X is -CR 4a R 5a -, -0-, -S-, -S(0)-, -NR a -, or -C(O)-;
• R la is an optionally substituted heterocyclyl, wherein when the heterocyclyl is monocyclic, the point of connection is via a carbon atom;
• R 2a is an optionally substituted heterocyclyl, wherein when the heterocyclyl is monocyclic, the point of connection is via a carbon atom;
• R 3a is an optionally substituted heterocyclyl, wherein when the heterocyclyl is monocyclic, the point of connection is via a carbon atom;
• R 2a and R 3a are taken together with the carbons to which they are attached to form a 5- to 16- membered heterocyclyl ring;
• FIG. 1 shows a dose response curve for the activity of Compound 1 in the inhibition of organic anion transporter 3 (OAT3) in the uptake of 3H-PAH, using MDCK-II transfected with an OAT3 expression vector.
• OAT3 organic anion transporter 3
• FIG. 2 shows a dose response curve for the activity of Compound 1 in the inhibition of organic anion transporter 1 (OAT1) in the uptake of 3H-PAH, using MDCK-II transfected with an OAT1 expression vector.
• OAT1 organic anion transporter 1
• FIG. 3A shows the concentration of uric acid in the brain of mice administered (p.o.) with 50 mg/kg of compound 1.
• FIG. 3B shows the concentration of uric acid in blood plasma of mice administered (p.o.) with 50 mg/kg of compound 1.
• FIG. 4A shows the concentration of DHEAS in the brain of mice administered (p.o.) with 50 mg/kg of compound 1.
• FIG. 4B shows the concentration of DHEAS in blood plasma of mice administered (p.o.) with 50 mg/kg of compound 1.
• FIG. 5A shows the concentration of DHEA in the brain of mice administered (p.o.) with 50 mg/kg of compound 1.
• FIG. 5B shows the concentration of DHEA in blood plasma of mice administered (p.o.) with 50 mg/kg of compound 1.
• FIG. 6A shows a 1H NMR spectrum of Compound 1 in DMSO-d6 (400 MHz).
• FIG. 6B shows a 2D NOESY spectrum of Compound 1 in DMSO-d6 (400 MHz) as synthesized from Route B.
• FIG. 6C shows an expansion of the 2D NOESY spectrum of compound 1 in DMSO-d6 (500 mHz) as synthesized from Route B.
• FIG. 6D shows a 2D NOESY spectrum of Compound 1 in DMSO-d6 (400 MHz) as synthesized from Route C.
• FIG. 6E shows the HMBC of Compound 1 in DMSO-d6 (400 MHz) as synthesized from Route C.
• FIG. 7 A shows the PXRD diffractogram of Compound 1.
• FIG. 7B shows the overlayed PXRD diffractogram of four different spray dried formulations of Compound 1.
• FIG. 8A shows the overlay of the DSC and TGA thermograms for Compound 1.
• FIG. 8B and FIG. 8C show the TGA and DSC thermograms, respectively, for spray dry dispersion (SDD) #1.
• FIG. 8D and FIG. 8E show the TGA and DSC thermograms, respectively, for spray dry dispersion (SDD) #2.
• FIG. 8F and FIG. 8G show the TGA and DSC thermograms, respectively, for spray dry dispersion (SDD) #3.
• FIG. 8H and FIG. 81 show the TGA and DSC thermograms, respectively, for spray dry dispersion (SDD) #4.
• FIG. 9A shows the pharmacokinetic curves of Compound 1 in free base form (FB) and two spray dry dispersions of Compound 1 (SDD #1 and SDD #3).
• FIG. 9B shows the AUC vs. dose for Compound 1 in free base form (FB) and two spray dry dispersions of Compound 1 (SDD #1 and SDD #3).
• FIG. 10A shows the single crystal structural analysis of Compound 1 (4-(4-((4- chloro-3-(trifluoromethyl)phenyl)sulfonyl)phenyl)-2,4-dihydro-3H-l,2,4-triazole-3-thione).
• FIG. 10B shows the single crystal structural analysis of an asymmetric unit of Compound 1.
• FIG. 11 shows the X-ray powder diffractogram (XRPD) of Compound 1.
• FIGs. 12A-C show the optical density of total alpha-synuclein deposits in the (12A) cortex, (12B) hippocampus, and (12C) striatum of L61 ASYN transgenic mice after i.p. administration of Compound 1 (1, 5, or 10 mg/kg per day) or a vehicle (5% DMSO + 20% Cremphor EL + 0.9% normal saline) for 1 month.
• Non-transgenic mice were used as a control group and were administered (i.p.) with Compound 1 (10 mg/kg per day) or a vehicle (5% DMSO + 20% Cremphor EL + 0.9% normal saline) for 1 month.
• FIG. 13 shows the total alpha-synuclein deposits in representative images of cross-sections of the cortex, hippocampus, and striatum of L61 ASYN transgenic mice after i.p. administration of Compound 1 (1, 5, or 10 mg/kg per day) or a vehicle (5% DMSO + 20% Cremphor EL + 0.9% normal saline) for 1 month.
• Non-transgenic mice were used as a control group and were administered (i.p.) with a vehicle (5% DMSO + 20% Cremphor EL + 0.9% normal saline) for 1 month.
• FIGs. 14A-C show the optical density of insoluble alpha-synuclein deposits (PK + resistant) in the (14A) cortex, (14B) hippocampus, and (14C) striatum of L61 ASYN transgenic mice after i.p. administration of Compound 1 (1, 5, or 10 mg/kg per day) or a vehicle (5% DMSO + 20% Cremphor EL + 0.9% normal saline) for 1 month.
• Non- transgenic mice were used as a control group and were administered (i.p.) with Compound 1 (10 mg/kg per day) or a vehicle (5% DMSO + 20% Cremphor EL + 0.9% normal saline) for 1 month.
• FIG. 15 shows the insoluble alpha-synuclein deposits (PK + resistant) in representative images of cross-sections of the cortex, hippocampus, and striatum of L61 ASYN transgenic mice after i.p. administration of Compound 1 (1, 5, or 10 mg/kg per day) or a vehicle (5% DMSO + 20% Cremphor EL + 0.9% normal saline) for 1 month.
• Non- transgenic mice were used as a control group and were administered (i.p.) with a vehicle (5% DMSO + 20% Cremphor EL + 0.9% normal saline) for 1 month.
• FIGs. 16A-B show the biochemical evaluation of brain levels of monomeric ASYN in the (16A) frontal cortex and (16B) hippocampus of L61 ASYN transgenic mice after i.p. administration of Compound 1 (1, 5, or 10 mg/kg per day) or a vehicle (5% DMSO + 20% Cremphor EL + 0.9% normal saline) for 1 month.
• Non-transgenic mice were used as a control group and were administered (i.p.) with a vehicle (5% DMSO + 20% Cremphor EL + 0.9% normal saline) for 1 month.
• FIGs. 17A-C show the optical density of microtubule-associated protein 1A/1B- light chain 3 (LC3) in the (17A) cortex, (17B) hippocampus, and (17C) striatum of L61 ASYN transgenic mice after i.p. administration of Compound 1 (1, 5, or 10 mg/kg per day) or a vehicle (5% DMSO + 20% Cremphor EL + 0.9% normal saline) for 1 month.
• Non- transgenic mice were used as a control group and were administered (i.p.) with Compound 1 (10 mg/kg per day) or a vehicle (5% DMSO + 20% Cremphor EL + 0.9% normal saline) for 1 month.
• FIG. 18 shows the levels of LC3 immunolabeling via IHC in representative images of cross-sections of the cortex, hippocampus, and striatum of L61 ASYN transgenic mice after i.p. administration of Compound 1 (1, 5, or 10 mg/kg per day) or a vehicle (5% DMSO + 20% Cremphor EL + 0.9% normal saline) for 1 month.
• Non-transgenic mice were used as a control group and were administered (i.p.) with a vehicle (5% DMSO + 20% Cremphor EL + 0.9% normal saline) for 1 month.
• FIG. 19 shows the grip strength evaluation of L61 ASYN transgenic mice after administration with Compound 1 (5 or 10 mg/kg) or a vehicle (5% DMSO + 20% Cremphor EL + 0.9% normal saline) for 3 months.
• Non-transgenic mice were used as a control group and were administered (i.p.) with Compound 1 (10 mg/kg per day) or a vehicle (5% DMSO + 20% Cremphor EL + 0.9% normal saline) for 3 months.
• FIG. 20A shows the levels of Translocator Protein (18 kDa) (TSPO) in representative images of cross-sections of the frontal cortex of L61 ASYN transgenic mice after administration with Compound 1 (5 or 10 mg/kg) or a vehicle (5% DMSO + 20% Cremphor EL + 0.9% normal saline) for 3 months.
• Non-transgenic mice were used as a control group and were administered (i.p.) with Compound 1 (10 mg/kg per day - data not shown) or a vehicle (5% DMSO + 20% Cremphor EL + 0.9% normal saline) for 3 months.
• FIG. 20B shows the quantification of the TSPO images from FIG. 20A.
• FIG. 21 shows the IHC staining for GFAP in representative images of the hippocampus of L61 ASYN transgenic mice after i.p. administration of Compound 1 (1, 5, or 10 mg/kg per day) or a vehicle (5% DMSO + 20% Cremphor EL + 0.9% normal saline) for 1 month.
• Non-transgenic mice were used as a control group and were administered (i.p.) with Compound 1 (10 mg/kg per day - data not shown) or a vehicle (5% DMSO + 20% Cremphor EL + 0.9% normal saline) for 3 months.
• FIG. 22 shows the optical density in IHC staining for GFAP in the hippocampus of L61 ASYN transgenic mice after i.p. administration of Compound 1 (1, 5, or 10 mg/kg per day) or a vehicle (5% DMSO + 20% Cremphor EL + 0.9% normal saline) for 3 months.
• Non-transgenic mice were used as a control group and were administered (i.p.) with Compound 1 (10 mg/kg per day - data not shown) or a vehicle (5% DMSO + 20%
• FIG. 23 shows IHC staining of DAT in representative images of cross-sections of the striatum of L61 ASYN transgenic mice after administration with Compound 1 (5 or 10 mg/kg) or a vehicle (5% DMSO + 20% Cremphor EL + 0.9% normal saline) for 3 months.
• Non-transgenic mice were used as a control group and were administered (i.p.) with Compound 1 (10 mg/kg per day - data not shown) or a vehicle (5% DMSO + 20% Cremphor EL + 0.9% normal saline -data not shown) for 3 months.
• FIG. 24 shows the striatal-to-reference ratio from optical density of IHC staining of DAT in representative images of cross-sections of the striatum and reference region (cortex) of L61 ASYN transgenic mice after administration with Compound 1 (5 or 10 mg/kg) or a vehicle (5% DMSO + 20% Cremphor EL + 0.9% normal saline) for 3 months.
• Non-transgenic mice were used as a control group and were administered (i.p.) with Compound 1 (10 mg/kg per day) or a vehicle (5% DMSO + 20% Cremphor EL + 0.9% normal saline) for 1 month.
• FIG. 25 shows quantitation in TSPO immunofluorescence staining in
• FIG. 26 shows quantitation in immunofluorescence staining of amyloid beta using 6E10 antibodies in representative brain sections of L41 APP transgenic mouse after daily i.p. injections of vehicle or Compound 1 at 5mg/kg or vehicle for 70 days. Data for non-transgenic mouse administered with daily ip injections of vehicle was also shown.
• the present disclosure relates to therapeutic agents that may be useful in the treatment and prophylaxis of neurodegenerative disorders and/or neural inflammation.
• the transport of bioactive molecules across the blood-brain barrier is tightly regulated in order to afford precise control of their levels in the brain interstitial space.
• the BBB is formed by a tight monolayer of endothelial cells and is an interface for exchange of compounds, allowing passive diffusion of water, some gases and certain lipid- soluble molecules. Nevertheless, other molecules, such as organic anions, are selectively transported across the BBB.
• An active efflux system in the BBB controls the unbound concentrations of exogenous compounds in the brain interstitial space and inactivates neuroactive compounds by transferring them into the blood.
• the organic anion transporter (OAT) family of proteins includes members that transport organic ions across various membranes.
• OAT3 Organic anion transporter 3
• DHEA dehydroepiandrosterone
• DHEAS DHEA sulfate
• uric acid has neuroprotective actions that are mediated via astroglial cells in co-culture with neuronal cells and directly on dopaminergic cell lines (Bakshi et al., 2015; Du et al., 2007; Zhang et al., 2014). This neuroprotective action is likely the result of Nrf2 stability and nuclear translocation with consequent upregulation of glutathione and other antioxidant gene products (Bakshi et al., 2015; Zhang et al., 2014).
• beneficial effects on inflammatory and neuropathology endpoints have been demonstrated by a number of different investigators using either 6-OHDA or MPTP lesion models for Parkinson’s disease (Crotty et al., 2017; Chen et al., 2013; Gong et al., 2012; Huang et al., 2017).
• Some of the beneficial effects are exemplified by decreased levels of inflammatory markers such as glial fibrillary acidic protein (GFAP), improved dopamine system integrity and an associated upregulation of phosphorylated Akt (pAkt) in these toxin based models of Parkinson’s disease.
• GFAP glial fibrillary acidic protein
• pAkt phosphorylated Akt
• DHEA and DHEAS are the most abundant circulating steroid hormones in humans. In the brain, DHEA is synthesized by neurons and astrocytes, and is therefore considered a neurosteroid. Unlike the lipophilic DHEA, DHEAS is hydrophilic and does not readily cross the BBB. It has been shown that OAT3 plays a major role in the efflux of DHEAS from the brain interstitial space into the blood (Miyajima et ah, 2011).
• Age-related decline of circulating DHEAS has been associated with declining levels of circulating DHEAS (Maninger et ah, 2009, Callier et ah, 2003, Belanger et ah, 2006, Li et ah, 2001, Charalampopoulos et ah, 2004, Gravanis et ah, 2012, Charalampopoulos et ah, 2008). It has been shown that DHEA treatment inhibits acute microglia-mediated neuroinflammation through activation of the TrkA-Aktl/2-CREB-Jmjd3 pathway.
• DHEAS anti-inflammatory action conferred by DHEAS is thus associated with an increase in pAkt, activation of Jmjd3, promotion of anti-inflammatory microglia phenotype, and inhibition of pro- inflammatory microglia phenotype, among other resultant phenotypes (Alexaki et ah, 2016).
• OAT3 may be a primary efflux transporter for uric acid and DHEAS from the brain interstitial space into the blood, while in other organs its function (such as urate secretion in kidney) could be largely compensated by structurally similar anion transporters (such as OAT1) (Riedmaier et ah, 2012, Wu et ah, 2017, Eraly et ah, 2008), the selective blockade of OAT3 would elevate the levels of neuroprotectants in the brain interstitial space without significantly changing the corresponding plasma levels.
• Such a selective OAT3 blockade would also avail the option of treating a subject with systemic administration instead of being restricted to targeted delivery. Therefore there exists a need to utilize a selective inhibitor that blocks OAT3 -mediated efflux without significantly changing the transport mediated by other anion transporters such as OAT1. While there are molecules such as probenecid or taurocholate that block OAT3 to increase levels of DHEAS and presumably uric acid in the brain interstitial space , these molecules will also inhibit structurally similar anion transporters such as OAT1 (Yin and Wang 2016, Wu et ah, 2017).
• probenecid and taurocholate in addition to blocking OAT3, can block other anion transporters (Miyajima et ah, 2011), and can also alter plasma levels of certain therapeutic agents, leading to the concerns for drug-drug interactions (Yin and Wang 2016, Klatt et al., 2011).
• in vitro substrates such as para-aminohippurate (PAH) that are used to competitively inhibit OAT3 (Miyajima et al., 2011), are also substrates for OAT1 (Nigam et al., 2015, Nozaki et al., 2007) and have long been used to decrease the clearance of drugs from the body by the kidney (Beyer et al., 1944).
• One aspect of the current disclosure involves compounds that selectively block the efflux of bioactive endogenous metabolites from the brain interstitial space into the blood.
• the blockade is mediated by inhibition of ion transporter- mediated efflux across the BBB.
• the compounds in the present application selectively inhibit the ion transporters that mediate the efflux of bioactive endogenous compounds across the BBB.
• the ion transporters comprise OAT3.
• the bioactive endogenous metabolites comprise molecules that exhibit neuroprotective and/or anti-neuroinflammatory activities.
• the bioactive endogenous metabolites comprise DHEA, DHEAS and/or uric acid.
• the presently disclosed compounds are inhibitors of organic anion transporter 3 (OAT3).
• OAT3 organic anion transporter 3
• the presently disclosed compounds have an IC50 for OAT3 of about 1 mM or less.
• the potency of the presently disclosed compounds to inhibit OAT3 is about 20-fold higher than that for the structurally similar OAT1.
• the potent inhibitory function of the presently disclosed compounds on OAT3 are harnessed to block the OAT3-mediated efflux across the BBB, therefore increasing the local levels of bioactive molecules in the brain interstitial space which confer neuroprotection and/or anti-neuroinflammation.
• the bioactive molecules that confer neuroprotection and/or anti- neuroinflammation comprise one or more of dehydroepianodrosterone (DHEAS), DHEA sulfate (DHEAS), glutathione, and uric acid.
• DHEAS dehydroepianodrosterone
• DHEAS DHEA sulfate
• glutathione glutathione
• uric acid uric acid
• Line6l transgenic models when treated with certain compounds presently disclosed exhibited similar beneficial effects of reduced expression of inflammatory markers (such as GFAP) and improved dopamine system integrity, together with an associated upregulation of pAkt.
• inflammatory markers such as GFAP
• pAkt p-Akt
• these results correlate with the general effects of DHEA/DHEAS and/or uric acid administration to mouse models, and are highly similar to the phenotypes exhibited by toxin-based models of Parkinson’s diseases when treated with uric acid.
• the presently disclosed compounds could confer neuroprotection and anti-neuroinflammation without the harmful side effects brought on by systemic increases of uric acid or DHEA/DHEAS levels resulting from molecules that inhibit multiple ion transporters in addition to OAT3.
• the compounds described herein selectively block the efflux of neuroprotectants from the brain interstitial space into the blood by selectively inhibiting the active efflux by ion transporters across the blood brain barrier (BBB), thereby increasing the local concentration of neuroprotectants in the brain interstitial space.
• the ion transporters being inhibited comprise one or more ion transporters including OAT3.
• the ion transporters being inhibited comprise anion transporter OAT3.
• the ion transporter inhibitor comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein.
• a method for treating a condition associated with neurodegeneration or accumulation of proteins in the brain in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound that is an inhibitor of organic anion transporter 3 (OAT3).
• a method of treating a disease or condition associated with neuroinflammation comprising administering to a subject in need of such treatment an effective amount of a compound that is an inhibitor of organic anion transporter 3 (OAT3).
• the compound selectively inhibits OAT3.
• the compound is administered systematically.
• the compound is administered to the brain interstitial space with targeted delivery.
• One aspect of the current invention involves a compound that selectively blocks the efflux of neuroprotectants from the brain interstitial space into the blood.
• the blockade is mediated by inhibition of OAT3-mediated efflux across the BBB.
• the neuroprotectants comprise one or more of
• DHEAS dehydroepianodrosterone
• DHEA DHEA sulfate
• glutathione glutathione
• uric acid uric acid.
• Certain compounds described herein are developed by the applicant, and are potent and selective inhibitors of OAT3. It has been shown that the potency of some of these compounds to inhibit OAT3 is about 20-fold higher than that for the structurally similar OAT1.
• the potent inhibitory function of these compounds on OAT3 is harnessed to block the OAT3-mediated efflux across the BBB, therefore increasing the local levels of bioactive molecules in the brain interstitial space which confer neuroprotection and/or anti- neuroinflammation.
• the bioactive molecules that confer neuroprotection and/or anti-neuroinflammation comprise one or more of
• DHEAS dehydroepianodrosterone
• DHEA DHEA sulfate
• glutathione glutathione
• uric acid uric acid
• these compounds described herein could confer neuroprotection and anti-neuroinflammation without the harmful side effects brought on by systemic elevation of uric acid or DHEA/DHEAS levels resulting from inhibition of multiple ion transporters in addition to OAT3.
• the compounds described herein selectively block the efflux of neuroprotectants from the brain interstitial space into the blood by selectively inhibiting the active efflux by ion transporters across the blood brain barrier (BBB), thereby increasing the local concentration of neuroprotectants in the brain interstitial space.
• the ion transporters being inhibited comprise one or more ion transporters including OAT3.
• the ion transporters being inhibited comprise anion transporter OAT3.
• the ion transporter inhibitor comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
• the compound or the pharmaceutically acceptable salt thereof comprises compound 1.
• a method for treating a condition associated with neurodegeneration or accumulation of proteins in the brain in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound that is an inhibitor of organic anion transporter 3 (OAT3).
• a method of treating a disease or condition associated with neuroinflammation comprising administering to a subject in need of such treatment an effective amount of a compound that is an inhibitor of organic anion transporter 3 (OAT3).
• the compound selectively inhibits OAT3.
• the ion transporter inhibitor e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof
• the compound is administered systematically.
• the compound is administered to the brain interstitial space with targeted delivery.
• OAT3 inhibitors that enhance the action of other drugs that are eliminated by OAT3.
• potent and selective inhibitors of OAT3 may augment cancer chemotherapy for certain cancers, such as brain cancers.
• Certain therapeutic agents used to treat brain cancers or viral infections in the brain are eliminated from the brain by the OAT3 transporter located in the choroid plexus. This active transport of these therapeutic agents out of the brain limits their efficacy.
• blockade of OAT3 transporters in the choroid plexus will slow the efflux of these therapeutic agents from the brain and thereby increase their efficacy in treating cancers and infections in the brain.
• OAT3 inhibitors such as compounds described herein enhance the action of other drugs that are eliminated by OAT3 from the brain.
• OAT3 inhibitors such as compounds described herein enhances the action of drugs including, but not limited to, cancer chemotherapeutic agents (e.g., methyltrexate) and anti-viral agents (e.g., HIV therapeutics).
• OAT3 inhibitors that prevent renal toxicity of cancer chemotherapeutic s and other OAT3 substrates by blocking the uptake of such agents into kidney cells.
• the dose limiting toxicity that precludes achieving full efficacy is renal toxicity (caused by their accumulation in the renal proximal tubule cells).
• Certain cytotoxic drugs e.g., cisplatin and methotrexate
• the uptake of these cancer therapeutic agents into the renal proximal tubule cells is mediated by OAT3.
• the drugs are eliminated from the blood into the urine by active transport (as opposed to passive filtration).
• the path from blood to urine for these drugs includes active transport across the renal tubular basolateral membrane (blood side) into the kidney cell and then transport out of the kidney cell by different transporters on the apical (urine) side. If the drugs are cytotoxic and if the drugs accumulate in the renal tubule cell (more basolateral transport than apical transport), then they can cause renal toxicity. A blocker of the basolateral transport of these drugs would slow the uptake into the renal tubule cell and so prevent its accumulation in these cells and thus prevent renal toxicity.
• One of the basolateral transporters for these cytotoxic drugs is OAT3.
• an OAT3 inhibitor may slow uptake of these toxic drugs into the kidney proximal tubule cell and thereby prevent their renal toxicity.
• OAT3 inhibitors would act to spare the kidney from damage while allowing for higher and more prolonged dosing with cytotoxic drugs (e.g., cancer chemotherapeutic agents).
• the term“effective amount” used herein refers to an amount of a compound or composition sufficient to treat a specified disorder, condition or disease, such as a disease or condition associated with neurodegeneration or neuroinflammation, so as to ameliorate, palliate, lessen, and/or delay one or more of its symptoms.
• “treatment” is an approach for obtaining beneficial or desired clinical results.“Treatment” as used herein, covers any administration or application of a therapeutic for disease in a mammal, including a human.
• beneficial or desired clinical results include, but are not limited to, any one or more of: alleviation of one or more symptoms, diminishment of extent of disease, delay or slowing of disease progression, amelioration of the disease state, inhibiting the disease or progression of the disease, inhibiting or slowing the disease or its progression, arresting its development, and remission (whether partial or total).
• “treatment” is a reduction of pathological consequence of a proliferative disease.
• the methods of the invention contemplate any one or more of these aspects of treatment.
• the term “prevention” is an approach that includes but is not limited to preventing or delaying the occurrence or spread of disease, preventing or delaying recurrence of disease, or preventing or delaying the progression of the disease.
• the term“inhibit” may refer to the act of blocking, reducing, eliminating, or otherwise antagonizing the presence, or an activity of, a particular target. Inhibition may refer to partial inhibition or complete inhibition.
• inhibiting an ion transporter protein may refer to any act leading to a blockade, reduction, elimination, or any other antagonism of the activity of the ion transporter protein.
• activity of a target e.g., a protein
• a substrate such as a small molecule.
• inhibition of a target by a substrate is competitive. In other
• inhibition of the target by a substrate is noncompetitive.
• inhibition of the target by a substrate is reversible. In other embodiments, inhibition of the target by a substrate is non-reversible.
• modulate may refer to the act of changing, altering, varying, or otherwise modifying the presence, or an activity of, a particular target.
• modulating the efflux of certain molecules may refer to any act leading to changing, altering, varying, or otherwise modifying the efflux of the molecules.
• modulating the local concentration of neuroprotectants may refer to any act leading to changing, altering, varying, or otherwise modifying the local concentration of neuroprotectants.
• “modulate” refers to enhancing the presence or activity of a particular target.
• “modulate” refers to suppressing the presence or activity of a particular target.
• modulating the efflux of certain molecules may refer to any act leading to increasing the efflux of the molecules. In other examples, modulating the efflux of certain molecules may refer to any act leading to decreasing the efflux of the molecules.
• a“subject” as used herein intends a mammal, including but not limited to a primate, human, bovine, horse, feline, canine, or rodent. In one variation, the subject is a human.
• endogenous metabolites are products of metabolism that are formed via chemical reactions that occur within the cells of a subject.
• uric acid is an endogenous metabolite that can be produced from the chemical reactions in the breakdown of purine nucleotides within cells of the subject.
• DHEA is an endogenous metabolite that can be produced as an intermediate metabolite in the chemical reactions in the chemical synthesis of androgen and estrogen in the adrenal glands and the brains of the subject.
• Other examples of endogenous metabolites are known in the art.
• “pharmaceutically acceptable carrier” or“pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
• the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
• the half maximal inhibitory concentration is a measure of the effectiveness of a substance in inhibiting a specific biological or biochemical function.
• the IC50 is a quantitative measure that indicates how much of an inhibitor is needed to inhibit a given biological process or component of a process such as an enzyme, cell, cell receptor or microorganism by half. Methods of determining IC50 in vitro and in vivo are known in the art.
• pharmaceutically acceptable or“pharmacologically compatible” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
• alkyl refers to a straight- or branched-chain alkyl (hydrocarbon) group having from 1 to 12 carbon atoms in the chain.
• alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.
• alkyl groups are Ci- 4 alkyl.
• alkenyl refers to an unsaturated branched or straight-chain hydrocarbon group having the indicated number of carbon atoms (e.g., 2 to 8, or 2 to 6 carbon atoms) and at least one site of olefinic unsaturation (having at least one carbon-carbon double bond).
• the alkenyl group may be in either the cis or trans configuration (Z or E configuration) about the double bond(s).
• Alkenyl groups include, but are not limited to, ethenyl, propenyl (e.g., prop-l-en-l-yl, prop-l-en-2-yl, prop-2-en-l-yl (allyl), prop-2-en-2-yl), and butenyl (e.g., but-l-en-l-yl, but-l-en-2-yl, 2-methyl-prop- l-en-l-yl, but-2-en-l-yl, but-2-en-l-yl, but-2- en-2-yl, buta-l,3-dien-l-yl, buta-l,3-dien-2-yl).
• propenyl e.g., prop-l-en-l-yl, prop-l-en-2-yl, prop-2-en-l-yl (allyl), prop-2-en-2-yl
• butenyl e.g., but-l-en-l-y
• Alkynyl refers to an unsaturated branched or straight-chain hydrocarbon group having the indicated number of carbon atoms (e.g., 2 to 8 or 2 to 6 carbon atoms) and at least one site of acetylenic unsaturation (having at least one carbon-carbon triple bond).
• Alkynyl groups include, but are not limited to, ethynyl, propynyl (e.g., prop-l-yn-l-yl, prop-2-yn-l-yl) and butynyl (e.g., but-l-yn-l-yl, but-l-yn-3-yl, but-3-yn-l-yl).
• Aryl or“Ar” as used herein refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl), which condensed rings are carbocyclic and may or may not be aromatic, provided at least one ring in the multiple condensed ring structure is aromatic.
• Particular aryl groups are those having from 6 to 14 annular carbon atoms (a“C6-C14 aryl”).
• An aryl group having more than one ring where at least one ring is non-aromatic is connected to the parent structure at either an aromatic ring position or at a non-aromatic ring position.
• an aryl group having more than one ring where at least one ring is non-aromatic is connected to the parent structure at an aromatic ring position.
• Alkoxy refers to the group -O-alkyl, wherein alkyl is as defined herein.
• Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t- butoxy, sec-butoxy, n-pentoxy, and the like.
• alkoxy also refers to the groups alkenyl-O-, cycloalkyl-O-, cycloalkenyl-O-, and alkynyl-O-, where alkenyl, cycloalkyl, cycloalkenyl, and alkynyl are as defined herein.
• Cycloalkyl refers to and includes, unless otherwise stated, saturated or partially unsaturated nonaromatic cyclic univalent hydrocarbon structures, having the number of carbon atoms designated ( i.e ., C3-C10 means three to ten carbon atoms). Cycloalkyl can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantyl. A cycloalkyl comprising more than one ring may be fused, spiro or bridged, or combinations thereof. Particular cycloalkyl groups are those having from 3 to 12 annular carbon atoms.
• a preferred cycloalkyl is a cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a "C3-C8 cycloalkyl"), having 3 to 6 annular carbon atoms (a“C3-C6 cycloalkyl”), or having from 3 to 4 annular carbon atoms (a "C3-C4 cycloalkyl”).
• Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbomyl, and the like.
• Halo or“halogen” refers to fluoro, chloro, bromo, and iodo.
• “Hydroxy” or“hydroxyl” refers to the group -OH.
• Heterocycloalkyl or“heterocyclyl” refers to a saturated or partially
• unsaturated group having a single ring or multiple condensed rings, including fused, bridged, or spiro ring systems, and having from 3 to 20 ring atoms, including 1 to 10 hetero atoms.
• ring atoms are selected from the group consisting of carbon, nitrogen, sulfur, and oxygen, wherein, in fused ring systems, one or more of the rings can be cycloalkyl, aryl, or heteroaryl, provided that the point of attachment is through the non-aromatic ring.
• the nitrogen and/or sulfur atom(s) of the heterocyclic group are oxidized to provide for N-oxide, -S(O)-, or -S(0) 2 - moieties.
• heterocycloalkyls include, but are not limited to, azetidine, oxetane, tetrahydrofuran, pyrrolidine, piperazine, piperidine, morpholine, thiomorpholine, l,l-dioxothiomorpholinyl, dihydroindole, indazole, quinolizine, imidazolidine, imidazoline, indoline, l,2,3,4-tetrahydroisoquinoline, thiazolidine, and the like.
• heterocycloalkyl groups are 4-, 5-, or 6- membered rings.
• the heterocycloalkyl comprises a fused phenyl ring.
• Hetero aryl refers to an unsaturated aromatic cyclic group having from 1 to 14 annular carbon atoms and at least one annular heteroatom, including but not limited to heteroatoms such as nitrogen, oxygen and sulfur.
• a heteroaryl group may have a single ring (e.g ., pyridyl, furyl) or multiple condensed rings (e.g., indolizinyl, benzo thienyl), which condensed rings may be carbocyclic or may contain one or more annular heteroatom and which may or may not be aromatic, provided at least one ring in the multiple condensed ring structure is both aromatic and contains at least one annular heteroatom, and provided that the point of attachment is through the aromatic ring containing at least one annular heteroatom.
• a heteroaryl group may be connected to the parent structure at a ring carbon atom or a ring heteroatom. Particular heteroaryl groups are 5 to l4-membered rings having 1 to 12 annular carbon atoms and 1 to 6 annular
• heteroatoms independently selected from nitrogen, oxygen and sulfur
• 5 to lO-membered rings having 1 to 8 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, or 5, 6 or 7-membered rings having 1 to 5 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur.
• particular heteroaryl groups are monocyclic aromatic 5- , 6- or 7-membered rings having from 1 to 6 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur.
• particular heteroaryl groups are polycyclic aromatic rings having from 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur.
• substituted when used to modify a specified group or radical, can also mean that one or more hydrogen atoms of the specified group or radical are each, independently of one another, replaced with the same or different substituent groups as defined below.
• substituent groups for substituting for one or more hydrogens are, unless otherwise specified, -R 60 , halo,
• R 60 is selected from the group consisting of optionally substituted alkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, each R 70 is independently hydrogen or R 60 ; each R 80 is independently R 70 or alternatively, two R 80 s, taken together with the nitrogen atom to which they are bonded, form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl which may optionally include from 1 to 4 of the same or different additional heteroatoms selected from the group consisting of O, N and S, of which N may have -H, Ci-C 4 alkyl, -C(0)Ci- 4 alkyl, - C(0)OCi- 4 alkyl, or -S(0) 2 Ci- 4 alkyl substitution; and each M + is a counter ion with
• Each M + may independently be, for example, an alkali ion, such as K + , Na + , Li + ; an ammonium ion, such as + N(R 60 ) 4 ; or an alkaline earth ion, such as [Ca 2+ ]o . s, [Mg 2+ ]o .
• -NR 80 R 80 is meant to include -NH 2 , -NH-alkyl, /V-pyrrolidinyl, N- piperazinyl, 4- /V-mcthyl-pipcrazin- 1 -yl and /V-morpholinyl.
• heterocycloalkyl group is“substituted,” unless otherwise constrained by the definition for the heterocycloalkyl substituent, such groups can be substituted with 1 to 5, or from 1 to 3 substituents, selected from alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl,
• a group when a group is indicated as“substituted”, it may be substituted with 1 or more substituents, and that the substituents may be present at any or all of the valency-allowed position(s) on the system.
• a group that is substituted has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents, 1 or 2 substituents, or 1 substituent.
• Optionally substituted unless otherwise specified means that a group may be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4 or 5) of the substituents listed for that group in which the substituents may be the same of different.
• an optionally substituted group has one substituent.
• an optionally substituted group has two substituents.
• an optionally substituted group has three substituents.
• an optionally substituted group has four substituents.
• an optionally substituted group has 1 to 2, 2 to 5,
• the “optionally substituted” group is not substituted.
• any of the groups disclosed herein which contain one or more substituents it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible.
• the subject compounds include all stereochemical isomers arising from the substitution of these compounds.
• pharmaceutically acceptable salt means a salt which is acceptable for administration to a patient, such as a mammal (salts with counterions having acceptable mammalian safety for a given dosage regime). Such salts can be derived from
• “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts of a compound, which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, formate, tartrate, besylate, mesylate, acetate, maleate, oxalate, and the like.
• solvent refers to a complex formed by combination of solvent molecules with molecules or ions of the solute.
• the solvent can be an organic compound, an inorganic compound, or a mixture of both.
• Some examples of solvents include, but are not limited to, methanol, /V,/V-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water. When the solvent is water, the solvate formed is a hydrate.
• Stereoisomer and“stereoisomers” refer to compounds that have same atomic connectivity but different atomic arrangement in space. Stereoisomers include cis-trans isomers, E and Z isomers, enantiomers, and diastereomers. Compounds that have asymmetric centers can exist as one or more enantiomeric forms, one or more
• diastereomeric forms one or more atropisomeric forms, and mixtures thereof in any ratio.
• any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
• Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
• isotopes that can be incorporated into the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 3 ⁇ 4, 3 H, U C, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, 36 Cl, and 125 I, respectively.
• Such isotopically labeled compounds are useful in metabolic studies (e.g., with 14 C), reaction kinetic studies (with, for example 3 ⁇ 4 or 3 H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
• PET positron emission tomography
• SPECT single-photon emission computed tomography
• 18 F or n C labeled compounds are used for PET or SPECT studies.
• PET and SPECT studies may be performed as described, for example, by Brooks, D.J.,“Positron Emission Tomography and Single-Photon Emission Computed Tomography in Central Nervous System Drug Development,” NeuroRx 2005, 2(2), 226-236, and references cited therein.
• isotopically labeled compounds and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
• ChemBioDraw Ultra 13.0.2.3021 Commercially-available ChemBioDraw Ultra 13.0.2.3021 (CambridgeSoft, Cambridge, Mass.).
• ion transporter inhibitor e.g., an inhibitor of organic anion transporter 3 (OAT3)
• OAT3 organic anion transporter 3
• BBB blood brain barrier
• Neurodegenerative disorders may refer to disorders characterized by a loss of neurons and may or may not include a
• Neurodegenerative disorders include stroke, head trauma, cerebral hypoxia, spinal cord injury, senile dementia, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS) and other motor neuron diseases, cerebral amyloid angiopathy, HIV- related dementia, Parkinson’s disease, Huntington’s disease, prion diseases, myasthenia gravis, Down’s syndrome, Creutzfeldt- Jakob disease, Friedreich’s ataxia, Fergusson and Critchley’s ataxia and other ataxias, Leber’s hereditary optic neuropathy diabetic neuropathy, neuropathic pain, encephalitis, meningitis, and Duchenne’s muscular dystrophy, fronto-temporal dementia, dementia with Lewy Bodies, PD dementia, multiple system atrophy, progressive supranuclear palsy, or neuroinflammation.
• ALS amyotrophic lateral sclerosis
• prion diseases myasthenia gravis
• Down’s syndrome Creutzfeldt- Jako
• the condition associated with neurodegeneration is Alzheimer’s Disease, Parkinson’s Disease, fronto-temporal dementia, dementia with Lewy Bodies, PD dementia, multiple system atrophy, Huntington’s disease, Amyotrophic lateral sclerosis, progressive supranuclear palsy, or neuroinflammation.
• ion transporter inhibitor e.g., an inhibitor of organic anion transporter 3 (OAT3)
• Neuroprotection may refer to actions, mechanisms, functions or characteristics that counteract neurodegenerative disorders or diseases and can be any one or more of: alleviation of one or more symptoms, diminishment of extent of disease, preventing or delaying spread of disease, preventing or delaying recurrence of disease, delay or slowing of disease progression, amelioration of the disease state, inhibiting the disease or progression of the disease, inhibiting or slowing the disease or its progression, arresting its development, and remission (whether partial or total). Also encompassed by “neuroprotection” is a reduction of pathological consequence of a neurodegenerative or neurological disease.
• A“neuroprotectant” comprises an agent that can
• neuroprotection or possesses neuroprotective properties comprising administering to the subject an effective amount of an ion transporter inhibitor (e.g., an inhibitor of organic anion transporter 3 (OAT3)) that modulates the concentration of one or more bioactive endogenous metabolites in the brain interstitial space.
• an ion transporter inhibitor e.g., an inhibitor of organic anion transporter 3 (OAT3)
• OAT3 organic anion transporter 3
• the term“neuroinflammation” or“neuroinflammatory diseases, disorders or conditions” may refer to diseases, disorders or conditions characterized by large numbers of reactive microglia in postmortem brain samples, indicative of an active inflammatory process (McGeer E. G. and McGeer P.
• Neuroinflammation refers to inflammation which occurs in response to brain injury or autoimmune disorders, and has been shown to cause destruction of healthy neuronal and/or cerebral tissue.
• Neuroinflammation relates to mechanisms implicated in a broad range of acute and chronic neurodegenerative disorders, including stroke, head trauma, cerebral amyloid angiopathy, HIV-related dementia, Huntington’s disease, prion diseases, meningitis, myelin degradation, epilepsy, Down’s syndrome, post-ischemic brain injury, encephalopathy, Parkinson’s disease, senile dementia, Alzheimer’s disease, amyotrophic lateral sclerosis, multiple sclerosis and certain disorders involving the peripheral nervous system, such as myasthenia gravis and Duchenne’s muscular dystrophy.
• stroke head trauma, cerebral amyloid angiopathy, HIV-related dementia, Huntington’s disease, prion diseases, meningitis, myelin degradation, epilepsy, Down’s syndrome, post-ischemic brain injury, encephalopathy, Parkinson’s disease, senile dementia, Alzheimer’s disease, amyotrophic lateral sclerosis, multiple sclerosis and certain disorders involving the peripheral nervous system, such as
• the ion transporter inhibitor has an IC50 of about 1 mM or less. In some embodiments, the ion transporter inhibitor has an IC50 of between about 0.1 mM and about 1 pM. In some embodiments, the ion transporter inhibitor has an IC50 of between about 1 nM and about 10 pM, such as between about 0.5 pM and about 5 pM, between about 0.1 pM and about 2 pM, between about 50 nM and about 1 pM, between about 10 nM and about 500 nM, between about 5 nM and about 100 nM, or between about 1 nM and about 50 nM.
• the ion transporter inhibitor has an IC50 of less than about 1 nM. In some embodiments of any of the methods described herein, the ion transporter inhibitor selectively inhibits OAT3 compared with other ion transporter proteins. In some embodiments of any of the methods described herein, the ion transporter inhibitor has an IC50 for OAT3 of about 1 pM or less.
• the ion transporter inhibitor has an IC50 for OAT3 of between about 0.1 pM and about 1 pM. In some embodiments, the ion transporter inhibitor has an IC50 for OAT3 of between about 1 nM and about 10 pM, such as between about 0.5 pM and about 5 pM, between about 0.1 pM and about 2 pM, between about 50 nM and about 1 pM, between about 10 nM and about 500 nM, between about 5 nM and about 100 nM, or between about 1 nM and about 50 nM. In some embodiments, the ion transporter inhibitor has an IC50 for OAT3 of less than about 1 nM.
• the ion transporter inhibitor is an inhibitor of organic anion transporter 3 (OAT3).
• OAT3 organic anion transporter 3
• the ion transporter inhibitor has an IC50 for OAT3 of about 500 nM or less.
• the ion transporter inhibitor has an IC50 for OAT3 of about 1 mM or less.
• the ion transporter inhibitor selectively inhibits OAT3 compared with other ion transporter proteins.
• the ion transporter inhibitor has an IC50 for OAT3 that is lower than its IC50 for one or more other ion transporter proteins (e.g., OAT1, OAT2, OAT3, OAT4, OAT6, OAT7, OAT9, OAT 10, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K, BCRP, PBP, or URAT1).
• the ion transporter inhibitor has an IC50 for OAT3 that is at least about 10 fold lower compared with its IC50 for one or more other ion transporter proteins (e.g., OAT1, OAT2, OAT3, OAT4, OAT6, OAT7, OAT9, OAT10, OCT2, OATP1B1,
• the ion transporter inhibitor has an IC50 for OAT3 that is at least about 10 fold lower compared with its IC50 for organic anion transporter 1 (OAT1). In certain embodiments, the ion transporter inhibitor has an IC50 for OAT3 that is at least about 10-20 fold lower compared with its IC50 for organic anion transporter 1 (OAT1). In certain embodiments, the ion transporter inhibitor has an IC50 for OAT3 that is at least about 20 fold lower compared with its IC50 for organic anion transporter 1 (OAT1). In certain embodiments, the ion transporter inhibitor has an IC50 for OAT3 that is at least about 20-50 fold lower compared with its IC50 for organic anion transporter 1 (OAT1).
• the ion transporter inhibitor has an IC50 for OAT3 that is at least about 10 fold lower compared with its IC50 for organic cation transporter 2 (OCT2). In some embodiments, the ion transporter inhibitor has an IC50 for OAT3 that is at least about 10-50 fold lower compared with its IC50 for organic cation transporter 2 (OCT2). In certain embodiments, the ion transporter inhibitor has an IC50 for OAT3 that is at least about 50 fold lower compared with its IC50 for organic cation transporter 2 (OCT2).
• the ion transporter inhibitor has an IC50 for OAT3 that is at least about 100- 500 fold lower compared with its IC50 for organic cation transporter 2 (OCT2). In some embodiments, the ion transporter inhibitor has an IC 50 for OAT3 that is at least about 100 fold lower compared with its IC 50 for organic cation transporter 2 (OCT2).
• the ion transporter inhibitor has an IC 50 for OAT3 that is at least about 10 fold lower compared with its IC 50 for organic anion transporting
• the ion transporter inhibitor has an IC 50 for OAT3 that is at least about 10-20 fold lower compared with its IC 50 for organic anion transporting polypeptide 1B1 (OATP1B1). In certain embodiments, the ion transporter inhibitor has an IC 50 for OAT3 that is at least about 20 fold lower compared with its IC 50 for organic anion transporting polypeptide 1B1 (OATP1B1). In some embodiments,
• the ion transporter inhibitor has an IC 50 for OAT3 that is at least about 20- 100 fold lower compared with its IC 50 for organic anion transporting polypeptide 1B1 (OATP1B 1). In some embodiments, the ion transporter inhibitor has an IC 50 for OAT3 that is at least about 100 fold lower compared with its IC 50 for organic anion transporting polypeptide 1B1 (OATP1B1).
• the ion transporter inhibitor has an IC 50 for OAT3 that is at least about 10 fold lower compared with its IC 50 for organic anion transporting
• the ion transporter inhibitor has an IC 50 for OAT3 that is at least about 10-20 fold lower compared with its IC 50 for organic anion transporting polypeptide 1B3 (OATP1B3). In certain embodiments, the ion transporter inhibitor has an IC 50 for OAT3 that is at least about 20 fold lower compared with its IC 50 for organic anion transporting polypeptide 1B3 (OATP1B3). In some embodiments, the ion transporter inhibitor has an IC 50 for OAT3 that is at least about 20-100 fold lower compared with its IC 50 for organic anion transporting polypeptide 1B3 (OATP1B3). In some embodiments, the ion transporter inhibitor has an IC 50 for OAT3 that is at least about 100 fold lower compared with its IC 50 for organic anion transporting polypeptide 1B3 (OATP1B3).
• the ion transporter inhibitor has an IC50 for OAT3 that is at least about 10 fold lower compared with its IC50 for multidrug and toxic compound extrusion protein- 1 (MATE1 /SLC47A1). In some embodiments, the ion transporter inhibitor has an IC50 for OAT3 that is at least about 10-20 fold lower compared with its IC50 for multidrug and toxic compound extrusion protein-l (MATE1 /SLC47A1). In certain embodiments, the ion transporter inhibitor has an IC50 for OAT3 that is at least about 20 fold lower compared with its IC50 for multidrug and toxic compound extrusion protein- 1 (MATE1 /SLC47A1).
• the ion transporter inhibitor has an IC50 for OAT3 that is at least about 20-100 fold lower compared with its IC50 for multidrug and toxic compound extrusion protein-l (MATE1 /SLC47A1). In some embodiments, the ion transporter inhibitor has an IC50 for OAT3 that is at least about 100 fold lower compared with its IC50 for multidrug and toxic compound extrusion protein-l (MATE1 /SLC47A1).
• the ion transporter inhibitor has an IC 50 for OAT3 that is at least about 10 fold lower compared with its IC 50 for multidrug and toxic compound extrusion protein 2-K (MATE2-K). In some embodiments, the ion transporter inhibitor has an IC 50 for OAT3 that is at least about 10-20 fold lower compared with its IC 50 for multidrug and toxic compound extrusion protein 2-K (MATE2-K). In certain embodiments, the ion transporter inhibitor has an IC 50 for OAT3 that is at least about 20 fold lower compared with its IC 50 for multidrug and toxic compound extrusion protein 2-K (MATE2- K).
• the ion transporter inhibitor has an IC 50 for OAT3 that is at least about 20-100 fold lower compared with its IC 50 for multidrug and toxic compound extrusion protein 2-K (MATE2-K). In some embodiments, the ion transporter inhibitor has an IC 50 for OAT3 that is at least about 100 fold lower compared with its IC 50 for multidrug and toxic compound extrusion protein 2-K (MATE2-K).
• the ion transporter inhibitor has an IC 50 for OAT3 that is at least about 10 fold lower compared with its IC 50 for breast cancer resistance protein (BCRP). In some embodiments, the ion transporter inhibitor has an IC 50 for OAT3 that is at least about 10-20 fold lower compared with its IC 50 for breast cancer resistance protein (BCRP). In certain embodiments, the ion transporter inhibitor has an IC 50 for OAT3 that is at least about 20 fold lower compared with its IC 50 for breast cancer resistance protein (BCRP). In some embodiments, the ion transporter inhibitor has an IC 50 for OAT3 that is at least about 20-100 fold lower compared with its IC 50 for breast cancer resistance protein (BCRP). In some embodiments, the ion transporter inhibitor has an IC 50 for OAT3 that is at least about 100 fold lower compared with its IC 50 for breast cancer resistance protein (BCRP).
• BCRP breast cancer resistance protein
• the ion transporter inhibitor has an IC50 for OAT3 that is at least about 10 fold lower compared with its IC50 for p-glycoprotein (PGP). In some embodiments, the ion transporter inhibitor has an IC50 for OAT3 that is at least about 10-20 fold lower compared with its IC50 for p-glycoprotein (PGP). In certain embodiments, the ion transporter inhibitor has an IC50 for OAT3 that is at least about 20 fold lower compared with its IC50 for p-glycoprotein (PGP).
• the ion transporter inhibitor has an IC50 for OAT3 that is at least about 20-100 fold lower compared with its IC50 for p- glycoprotein (PGP). In some embodiments, the ion transporter inhibitor has an IC50 for OAT3 that is at least about 100 fold lower compared with its IC50 for p-glycoprotein (PGP).
• the ion transporter inhibitor has an IC50 for OAT3 that is at least about 10 fold lower compared with its IC50 for uric acid transporter 1 (URAT1). In some embodiments, the ion transporter inhibitor has an IC50 for OAT3 that is at least about 2-10 fold lower compared with its IC50 for uric acid transporter 1 (URAT1). In some embodiments, the ion transporter inhibitor has an IC50 for OAT3 that is at least about 10-20 fold lower compared with its IC50 for uric acid transporter 1 (URAT1).
• the ion transporter inhibitor has an IC50 for OAT3 that is at least about 20 fold lower compared with its IC50 for uric acid transporter 1 (URAT1). In some embodiments, the ion transporter inhibitor has an IC50 for OAT3 that is at least about 20- 100 fold lower compared with its IC50 for uric acid transporter 1 (URAT1). In some embodiments, the ion transporter inhibitor has an IC50 for OAT3 that is at least about 100 fold lower compared with its IC50 for uric acid transporter 1 (URAT1).
• the ion transporter inhibitor has an IC50 for OAT3 that is at least about 5 fold, at least about 10 fold, at least about 20 fold, at least about 30 fold, at least about 40 fold, at least about 50 fold, at least about 60 fold, at least about 70 fold, at least about 80 fold, at least about 90 fold, or at least about 100 fold, at least about 200 fold, at least about 300 fold, at least about 400 fold, at least about 500 fold, at least about 600 fold, at least about 700 fold, at least about 10 fold, at least about 800 fold, at least about 900 fold, at least about 10000 fold, at least about 5000 fold, or at least about 10000 fold lower compared with its IC50 for one or more other ion transporter proteins (e.g.,OATl, OAT2, OAT3, OAT4, OAT6, OAT7, OAT9, OAT10, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K, BCRP, PBP, or URAT1).
• ion transporter proteins
• bioactive endogenous metabolites e.g., OAT3 substrates
• CSF cerebrospinofluid
• bioactive molecules may refer to molecules that exhibit biological activity.
• a bioactive molecule can inhibit the interaction between an enzyme or receptor and its respective substrate(s) or endogenous ligand(s), or inhibit cell growth of a microorganism, by at least 15% at a solution concentration of 10 3 molar or lower (i.e., it has inhibitory activity).
• the bioactive molecule will inhibit such processes at solution concentrations of any one of 10 4 molar or lower, 10 5 molar or lower, 10 6 molar or lower, or 10 7 molar or lower.
• the one or more bioactive endogenous metabolites are selected from an anionic neurotransmitter metabolite of epinephrine, norepinephrine, dopamine, and/or serotonin.
• the one or more bioactive endogenous metabolites are selected from the group consisting of: uric acid, glutathione, dehydroepianodrosterone (DHEA), and DHEA sulfate (DHEAS).
• OAT3 inhibitors are known in the art.
• probenecid and para-aminohippurate (PAH) have long been used in blocking OAT3 (Dantzler et al. 1995).
• PAH para-aminohippurate
• the OAT 3 inhibitor comprises probenecid (Takeda et al., J
• the OAT 3 inhibitor comprises para-aminohippurate (PAH).
• the OAT 3 inhibitor comprises one or more of Ciprofloxacin, linezolid, para-aminosalicylic acid (PAS), and rifampin (Parvez et al. 2016).
• the OAT 3 inhibitor comprises one or more antituberculosis drugs and their derivatives (Parvez et al. 2016).
• the OAT3 inhibitor comprises one or more of novobiocin, steviol, and the HIV integrase inhibitor cabotegravir (Duan and You 2009, Srimaroeng 2005,
• the OAT 3 inhibitor comprises one or more of mefenamic acid, meclofenamic acid, pioglitazone, oxaprozin, nateglinide, amlexanox, ketorolac tromethamine, diflunisal, nitazoxanide, irbesartan, valsartan, telmisartan, balsalazide, and ethacrynic acid (Duan et al. 2012).
• the OAT 3 inhibitor comprises one or more of stiripentol, cortisol succinate, demeclocycline, penciclovir, ornidazole, benazepril, chlorpropamide, and artesunate (Duan et al. 2012).
• the OAT3 inhibitor comprises one or more of cephalothin (also known as keflin or cefalotin), cefamandole, cefotaxime (also known as cefotax, claforan, or kefotex), cefazolin, cefoperazone (also known as cefobid), cephaloridine (also known as aliporina, cefaloridine, ceporine, kefloridin, lloncefal, loridine, or sefacin), and ceftriaxone (also known as rocefin, rocephin, or ceftriaxone) (Takeda et al. Eur J Pharmacol.
• cephalothin also known as keflin or cefalotin
• cefamandole also known as cefotaxime
• cefazolin cefoperazone
• cephaloridine also known as aliporina, cefaloridine, ceporine, keflor
• the OAT3 inhibitor comprises rolofylline (Takeda et al. Eur J Pharmacol 2002 Apr 26;44l(3):2l5).
• the OAT3 inhibitor comprises one or more of probenecid (also known as benemid, probalan, probampicin, or probecid), piroxicam (also known as feldene), octanoic acid (also known as caprylic acid), citrinin, aminohippuric acid (also known as aminohippurate) (Jung et al. Life Sci. 2001 Sep 21;69(18):2123-35).
• the OAT3 inhibitor comprises indomethacin (also known as Indocin, Indocin SR, Indo-Lemmon, indometacin, or indometacin famesil) (Takeda et al. J Pharmacol Exp Ther. 2002 Aug; 302(2):666-7l).
• the OAT3 inhibitor comprises one or more of (lr,4r)-4-((5-(2-((4-fluorobenzyl)carbamoyl)-6- methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexane-l -carboxylic acid
• the OAT3 inhibitor is zonampanel
• the OAT3 inhibitor comprises one or more of cefadroxil (also known as cefadrops, cefatabs, or CHEMBL1644) and cefadroxil hemihydrate (Wolman et al., Drug Metab Dispos. 2013 Apr;4l(4):79l-800).
• the OAT3 inhibitor comprises one or more of betamipron (CHEMBL1231530) and pravastatin (also known as pravachol or CHEMBL1144) (Khamdang et al., J Pharmacol Sci. 2004 Feb;94(2): 197-202).
• the OAT3 inhibitor is hippuric acid (CHEMBL461) (Deguchi et al., Kidney Int. 2004 Jan;65(l): 162-74).
• the OAT 3 inhibitor comprises an OAT3 -inhibitory antibody or a binding protein specific to OAT3.
• the efflux of the one or more bioactive endogenous metabolites across the blood brain barrier is reduced.
• the efflux of the one or more bioactive endogenous metabolites from the brain interstitial space across the blood brain barrier to the blood stream is reduced.
• the ion transporter inhibitor increases the concentration of one or more bioactive endogenous metabolites in the brain. In some embodiments, the ion transporter inhibitor increases the concentration of one or more bioactive endogenous metabolites in the brain by at least about 50%.
• the ion transporter inhibitor increases the concentration of one or more bioactive endogenous metabolites in the brain by at least about 50%, such as by at least about 75%, by at least about 100%, by at least about 150%, by at least about 200%, by at least about 300%, by at least about 400%, by at least about 500%, by at least about 600%, by at least about 700%, by at least about 800%, by at least about 900%, by at least about 1000%, or by at least about 2000%.
• the ion transporter inhibitor increases the concentration of one or more bioactive endogenous metabolites in the brain by at least 5 fold. In some embodiments, the ion transporter inhibitor increases the concentration of one or more bioactive endogenous metabolites in the brain by at least about 0.5 fold, by at least about 0.75 fold, by at least about 1 fold, by at least about 1.5 fold, by at least about 1.75 fold, by at least about 2 fold, by at least about 3 fold, by at least about 4 fold, by at least about 5 fold, by at least about 6 fold, by at least about 7 fold, by at least about 8 fold, by at least about 9 fold, by at least about 10 fold, by at least about 20 fold, by at least about 30 fold, by at least about 40 fold, by at least about 50 fold, by at least about 100 fold, by at least about 500 fold, or by at least about 1000 fold.
• the ion transporter inhibitor does not alter (e.g., does not increase or decrease) the plasma level of the bioactive endogenous metabolites by more than 5 fold.
• the compound does not alter the plasma level of the bioactive endogenous metabolites by more than 0.5 fold, by more than 0.75 fold, by more than 1 fold, by more than 2 fold, by more than 3 fold, by more than 4 fold, by more than 5 fold, by more than 6 fold, by more than 7 fold, by more than 8 fold, by more than 9 fold, by more than 10 fold, by more than 20 fold, by more than 30 fold, by more than 40 fold, by more than 50 fold, by more than 100 fold, by more than 500 fold, or by more than 1000 fold.
• the ion transporter inhibitor does not alter (e.g., does not increase or decrease) the plasma level of the bioactive endogenous metabolites by more than 500%.
• the compound does not alter the plasma level of the bioactive endogenous metabolites by more than 50%, by more than 75%, by more than 100%, by more than 200%, by more than 300%, by more than 400%, by more than 500%, by more than 600%, by more than 700%, by more than 800%, by more than 900%, by more than 1000%, by more than 2000%, by more than 3000%, by more than 4000%, by more than 5000%, by more than 10,000%, by more than 50,000%, or by more than 100,000% .
• the compound does not increase the plasma level of the bioactive endogenous metabolites by more than 5 fold. In some embodiments, the compound does not increase the plasma level of the bioactive endogenous metabolites by more than 0.5 fold, by more than 0.75 fold, by more than 1 fold, by more than 2 fold, by more than 3 fold, by more than 4 fold, by more than 5 fold, by more than 6 fold, by more than 7 fold, by more than 8 fold, by more than 9 fold, by more than 10 fold, by more than 20 fold, by more than 30 fold, by more than 40 fold, by more than 50 fold, by more than 100 fold, by more than 500 fold, or by more than 1000 fold.
• the compound does not increase the plasma level of the bioactive endogenous metabolites by more than 500%. In some embodiments, the compound does not alter the plasma level of the bioactive endogenous metabolites by more than 50%, by more than 75%, by more than 100%, by more than 200%, by more than 300%, by more than 400%, by more than 500%, by more than 600%, by more than 700%, by more than 800%, by more than 900%, by more than 1000%, by more than 2000%, by more than 3000%, by more than 4000%, by more than 5000%, by more than 10,000%, by more than 50,000%, or by more than 100,000% .
• the ion transporter inhibitor increases or elevates one or more bioactive endogenous metabolites in the brain. In some embodiments, the ion transporter inhibitor alters the plasma level of the bioactive metabolites by about 5 fold or less.
• the ion transporter inhibitor alters the plasma level of the bioactive endogenous metabolites by more than 0.5 fold, by more than 0.75 fold, by more than 1 fold, by more than 2 fold, by more than 3 fold, by more than 4 fold, by more than 5 fold, by more than 6 fold, by more than 7 fold, by more than 8 fold, by more than 9 fold, by more than 10 fold, by more than 20 fold, by more than 30 fold, by more than 40 fold, by more than 50 fold, by more than 100 fold, by more than 500 fold, or by more than 1000 fold. In some embodiments, the ion transporter inhibitor does not increase the plasma level of the bioactive endogenous metabolites by more than 5 fold.
• the compound does not increase the plasma level of the bioactive endogenous metabolites by more than 0.5 fold, by more than 0.75 fold, by more than 1 fold, by more than 2 fold, by more than 3 fold, by more than 4 fold, by more than 5 fold, by more than 6 fold, by more than 7 fold, by more than 8 fold, by more than 9 fold, by more than 10 fold, by more than 20 fold, by more than 30 fold, by more than 40 fold, by more than 50 fold, by more than 100 fold, by more than 500 fold, or by more than 1000 fold.
• the ion transporter inhibitor increases or elevates one or more bioactive endogenous metabolites in the brain.
• the ion transporter inhibitor alters the plasma level of the bioactive metabolites by about 5000% or less. In some embodiments, the ion transporter inhibitor alters the plasma level of the bioactive endogenous metabolites by more than 50%, by more than 75%, by more than 100%, by more than 200%, by more than 300%, by more than 400%, by more than 500%, by more than 600%, by more than 700%, by more than 800%, by more than 900%, by more than 1000%, by more than 2000%, by more than 3000%, by more than 4000%, by more than 5000%, by more than 10,000%, by more than 50,000%, or by more than 100,000%.
• the ion transporter inhibitor does not increase the plasma level of the bioactive endogenous metabolites by more than 500%.
• the compound does not increase the plasma level of the bioactive endogenous metabolites by more than 50%, by more than 75%, by more than 100%, by more than 200%, by more than 300%, by more than 400%, by more than 500%, by more than 600%, by more than 700%, by more than 800%, by more than 900%, by more than 1000%, by more than 2000%, by more than 3000%, by more than 4000%, by more than 5000%, by more than 10,000%, by more than 50,000%, or by more than 100,000%.
• the compound does not alter uric acid secretion from blood into urine by more than 5 fold. In some embodiments, the compound does not alter uric acid secretion from blood into urine by more than 0.5 fold, by more than 0.75 fold, by more than 1 fold, by more than 2 fold, by more than 3 fold, by more than 4 fold, by more than 5 fold, by more than 6 fold, by more than 7 fold, by more than 8 fold, by more than 9 fold, by more than 10 fold, by more than 20 fold, by more than 30 fold, by more than 40 fold, by more than 50 fold, by more than 100 fold, by more than 500 fold, or by more than 1000 fold.
• the compound does not reduce uric acid secretion from blood into urine by more than 5 fold. In some embodiments, the compound does not reduce uric acid secretion from blood into urine by more than 0.5 fold, by more than 0.75 fold, by more than 1 fold, by more than 2 fold, by more than 3 fold, by more than 4 fold, by more than 5 fold, by more than 6 fold, by more than 7 fold, by more than 8 fold, by more than 9 fold, by more than 10 fold, by more than 20 fold, by more than 30 fold, by more than 40 fold, by more than 50 fold, by more than 100 fold, by more than 500 fold, or by more than 1000 fold.
• the compound does not alter uric acid secretion from blood into urine by more than 500%. In some embodiments, the compound does not alter uric acid secretion from blood into urine by more than 50%, by more than 75%, by more than 100%, by more than 200%, by more than 300%, by more than 400%, by more than 500%, by more than 600%, by more than 700%, by more than 800%, by more than 900%, by more than 1000%, by more than 2000%, by more than 3000%, by more than 4000%, by more than 5000%, by more than 10,000%, by more than 50,000%, or by more than
• the compound does not reduce uric acid secretion from blood into urine by more than 500%. In some embodiments, the compound does not reduce uric acid secretion from blood into urine by more than 50%, by more than 75%, by more than 100%, by more than 200%, by more than 300%, by more than 400%, by more than 500%, by more than 600%, by more than 700%, by more than 800%, by more than 900%, by more than 1000%, by more than 2000%, by more than 3000%, by more than 4000%, by more than 5000%, by more than 10,000%, by more than 50,000%, or by more than
• a method for treating a condition associated with neurodegeneration or accumulation of proteins in the brain in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound that upregulates one or more bioactive endogenous metabolites in the brain, wherein the concentration of the one or more bioactive endogenous metabolites is increased or elevated in the brain.
• the one or more bioactive endogenous metabolite is selected from the group consisting of uric acid, glutathione, and dehydroepianodrosterone (DHEA), and DHEA sulfate (DHEAS).
• DHEA dehydroepianodrosterone
• DHEAS DHEA sulfate
• the condition associated with neurodegeneration is Alzheimer’s Disease, Parkinson’s Disease, fronto temporal dementia, dementia with Lewy Bodies, PD dementia, multiple system atrophy, Huntington’s disease, Amyotrophic lateral sclerosis, progressive supranuclear palsy, or neuroinflammation .
• a method of decreasing neuroinflammation in a subject comprising administering to the subject an effective amount of a compound that is an inhibitor of organic anion transporter 3 (OAT3).
• OAT3 organic anion transporter 3
• a method of treating a disease or condition associated with neuroinflammation comprising administering to a subject in need of such treatment an effective amount of a compound that is an inhibitor of organic anion transporter 3 (OAT3).
• OAT3 organic anion transporter 3
• the compound increases the expression of anti-inflammatory markers.
• the compound reduces pro-inflammatory response.
• the reduction in pro-inflammatory response comprises reduction in gene expression one or more of TNF, IL6, IL12/23p40 or MCP1.
• the compound activates TrkA/Akt/CREB/Jmjd3 pathway.
• the compound increases the level of pTrkA.
• the compound increases the level of pAkt.
• the compound increases the activation of CREB.
• the compound increases the expression of Jmjd3.
• the compound promotes anti-inflammatory phenotype of microglia.
• the anti-inflammatory phenotype of microglia comprises increased gene expression of one or more of M2 polarization markers comprising arginase 1, Yml (chitinase-like protein 3), Fizzl, Klf4 (Kruppel like factor 4) or IL10.
• M2 polarization markers comprising arginase 1, Yml (chitinase-like protein 3), Fizzl, Klf4 (Kruppel like factor 4) or IL10.
• the compound inhibits pro-inflammatory phenotype of microglia.
• One aspect of the invention provides a method of preventing aggregation or accumulation or enhancing clearance of protease-resistant protein, comprising contacting the protease-resistant protein with an effective amount of a compound that is an inhibitor of organic anion transporter 3 (OAT3), wherein the contacting is in vitro, ex vivo, or in vivo.
• OAT3 organic anion transporter 3
• the protease-resistant protein is selected from alpha synuclein, a- beta, tau, Huntingtin, and TAR DNA binding protein 43 (TDP43) proteins.
• protease-resistant protein comprising contacting the protease-resistant protein with an effective amount of a compound that is an inhibitor of organic anion transporter 3 (OAT3), wherein the contacting is in vitro, ex vivo, or in vivo.
• OAT3 organic anion transporter 3
• the protease-resistant protein is selected from alpha synuclein, a-beta, tau, Huntingtin, and TAR DNA binding protein 43 (TDP43) proteins.
• ion transporter inhibitors e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein
• the ion transporter inhibitor modulates the efflux of one or more bioactive endogenous metabolites across the blood brain barrier (BBB) of the subject.
• BBB blood brain barrier
• the disease or condition associated with neurodegeneration is Alzheimer’s Disease, Parkinson’s Disease, fronto temporal dementia, dementia with Lewy Bodies, PD dementia, multiple system atrophy, Huntington’s disease, Amyotrophic lateral sclerosis, progressive supranuclear palsy, or neuroinflammation .
• ion transporter inhibitors e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein
• ion transporter inhibitors for use in a method of modulating efflux of one or more bioactive endogenous metabolites across the blood brain barrier (BBB) in a subject in need thereof.
• ion transporter inhibitors e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein
• ion transporter inhibitors for use in a method of improving neuroprotection in subject in need thereof.
• ion transporter inhibitors e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein
• the ion transporter inhibitor modulates the concentration of one or more bioactive endogenous metabolites in the brain interstitial space.
• ion transporter inhibitors e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein
• the ion transporter inhibitor modulates the efflux of one or more bioactive endogenous metabolites across the blood brain barrier (BBB) of the subject.
• BBB blood brain barrier
• the disease or condition associated with neurodegeneration is
• ion transporter inhibitors e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein
• a medicament for improving neuroprotection in subject e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein
• ion transporter inhibitors e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein
• the ion transporter inhibitor modulates the concentration of one or more bioactive endogenous metabolites in the brain interstitial space.
• the present disclosure provides a compound of Formula (I):
• R 1 , R 2 , and R 3 are each independently hydrogen, hydroxy, halogen, optionally substituted Ci- 4 alkyl, optionally substituted Ci- 4 alkoxy, -CN, -C(0)R x , -C(0)0R x , - S(0) 2 R x , or -NR y R z ;
• R x , R y , and R z are each independently H or optionally substituted Ci- 4 alkyl, or R y and R z taken together with the nitrogen to which they are attached form an optionally substituted monocyclic heterocycloalkyl ring;
• R 5 and R 6 are each independently hydrogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C6-C14 aryl, 5-6-membered heteroaryl or 3-6 membered heterocyclyl, wherein the Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 - C 6 cycloalkyl, C6-C14 aryl, 5-6-membered heteroaryl and 3-6 membered heterocyclyl are each independently unsubstituted or substituted by halogen, oxo, -CN, -OR 9 , -NR
• R 1 , R 2 , and R 3 are each independently hydrogen, hydroxy, halogen, optionally substituted C alkyl, optionally substituted C alkoxy, or -NR y R z .
• the CM alkyl or CM alkoxy groups are substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, -NR f R g , cyano, nitro, CM alkoxy, and CM haloalkoxy, wherein R f and R g are each independently H, Ci- 4 alkyl, -C(0)Ci- 4 alkyl, -C(0)OCi- 4 alkyl, or -S(0) 2 Ci- 4 alkyl.
• R 4 is independently hydrogen, Ci-C 6 alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, C 3 -C 6 cycloalkyl, C 6 -C 14 aryl, 5-6-membered heteroaryl or 3-6- membered heterocyclyl, wherein the Ci-C 6 alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, C 3 -C 6 cycloalkyl, C6-C14 aryl, 5-6-membered heteroaryl and 3-6-membered heterocyclyl are independently optionally substituted by halogen, oxo, -CN, -OR 9 , -NR 9 R 10 ,
• R 5 and R 6 are each independently hydrogen, Ci-C 6 alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, C 3 -C 6 cycloalkyl, C 6 -C 14 aryl, 5-6-membered heteroaryl or 3-6 membered heterocyclyl, wherein the Ci-C 6 alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, C 3 - C 6 cycloalkyl, C6-C14 aryl, 5-6-membered heteroaryl and 3-6 membered heterocyclyl are independently optionally substituted by halogen, oxo, -CN, -OR 9 , -NR 9 R 10 or Ci-C 6 alkyl optionally substituted by halogen,
• R 1 is hydrogen, hydroxy, halogen, optionally substituted C 1-4 alkyl, optionally substituted C 1-4 alkoxy, or -NR y R z .
• R 1 is hydrogen.
• R 1 is hydroxyl.
• R 1 is halogen.
• R 1 is chloro.
• R 1 is fluoro.
• R 1 is bromo or iodo.
• R 1 is optionally substituted C alkyl.
• R 1 is C alkyl substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, -NR f R g , cyano, nitro, CM alkoxy, and CM
• R 1 is CM alkyl substituted with one or more halogen groups.
• R 1 is -CF3, -(CH 2 )F, - CHF 2 , CFFBr, -CH2CF3, - CH2CHF2, or -CH2CH2F.
• R 1 is CF 3 .
• R 1 is unsubstituted CM alkyl.
• R 1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl, or tertbutyl.
• R 1 is -NR y R z , wherein R y and R z taken together with the nitrogen to which they are attached form an optionally substituted monocyclic
• R 1 is -NR y R z , wherein R y and R z taken together with the nitrogen to which they are attached form an optionally substituted 5- to 12- membered heterocycloalkyl ring. In some embodiments, R 1 is -NR y R z , wherein R y and R z taken together with the nitrogen to which they are attached form an optionally substituted 5- to 6- membered heterocycloalkyl ring. In some embodiments, R 1 is morpholinyl.
• R 1 is morpholinyl substituted with one or more substituents selected from the group consisting of Ci-C 6 alkyl, C 2 -C 6 alkenyl, Ci-Ce alkynyl, hydroxyl, halogen, -NR f R g , cyano, nitro, CM alkoxy, CM haloalkoxy, -C(0)R 4 , -0C(0)R 4 , -C(0)0R 4 , -C(0)NR f R g , and -0C(0)NR f R g , wherein R 4 is H or Ci- 4 alkyl and R f and R g are each independently H, Ci- 4 alkyl, -C(0)Ci- 4 alkyl, -C(0)OCi- 4 alkyl, or -S(0) 2 C M alkyl.
• R 1 is piperazinyl. In some embodiments, R 1 is piperazinyl substituted with one or more substituents selected from the group consisting of Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 - C 6 alkynyl, hydroxyl, halogen, -NR f R g , cyano, nitro, CM alkoxy, CM haloalkoxy, -C(0)R 4 , -0C(0)R 4 , -C(0)0R 4 , -C(0)NR f R g , and -0C(0)NR f R g , wherein R 4 is H or Ci_ 4 alkyl and R f and R g are each independently H, Ci- 4 alkyl, -C(0)Ci- 4 alkyl, -C(0)OCi- 4 alkyl, or -S(0) 2 Ci- 4 alkyl.
• R 1 is piperadinyl. In some embodiments, R 1 is piperadinyl substituted with one or more substituents selected from the group consisting of Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, hydroxyl, halogen, -NR f R g , cyano, nitro, CM alkoxy, CM haloalkoxy, -C(0)R 4 , -0C(0)R 4 , -C(0)0R 4 , -C(0)NR f R g , and -0C(0)NR f R g , wherein R 4 is H or Ci- 4 alkyl and R f and R g are each independently H, Ci- 4 alkyl, -C(0)Ci- 4 alkyl, -C(0)OCi- 4 alkyl, or -S(0) 2 Ci- 4 alkyl.
• substituents selected from the group consisting of Ci-C 6 alkyl, C 2
• R 1 is pyrrolidinyl. In some embodiments, R 1 is pyrrolidinyl substituted with one or more substituents selected from the group consisting of Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, hydroxyl, halogen, -NR f R g , cyano, nitro, CM alkoxy, CM haloalkoxy, -C(0)R 4 , -0C(0)R 4 ,
• R 4 is H or Ci- 4 alkyl and R f and R g are each independently H, Ci- 4 alkyl, -C(0)Ci- 4 alkyl, -C(0)OCi- 4 alkyl, or -S(0) 2 C M alkyl.
• R 1 is -NR y R z , wherein R y and R z are each independently H or optionally substituted Ci- 4 alkyl. In some embodiments, R 1 is -NR y R z , wherein R y and R z are each H. In some embodiments, R 1 is -NR y R z , wherein R y and R z are each optionally substituted Ci- 4 alkyl.
• R 1 is -NR y R z , wherein R y and R z are each optionally Ci- 4 alkyl substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, -NR f R g , cyano, nitro, C alkoxy, Ci- 4 haloalkoxy, -C(0)R 4 , -0C(0)R 4 , -C(0)0R 4 , -C(0)NR f R g , and -0C(0)NR f R g , wherein R 4 is H or Ci- 4 alkyl and R f and R g are each independently H, Ci- 4 alkyl, -C(0)Ci- 4 alkyl, -C(0)OCi- 4 alkyl, or -S(0) 2 Ci- 4 alkyl.
• R 1 is -NR y R z , wherein R y and R z are each optionally unsubstituted Ci- 4
• R 1 is -NR y R z , wherein one of R y and R z is H and the other is unsubstituted Ci- 4 alkyl.
• R 1 is - NR y R z , wherein one of R y and R z is H and the other is Ci- 4 alkyl substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, -NR f R g , cyano, nitro, CM alkoxy, and CM haloalkoxy, wherein R f and R g are each independently H, Ci- 4 alkyl, -C(0)Ci- 4 alkyl, -C(0)OCi- 4 alkyl, or -S(0) 2 C M alkyl.
• R 1 is - NR y R z , wherein one or R y and R z is H and the other is Ci- 4 alkyl unsubstituted or substituted with hydroxyl. In certain embodiments, R 1 is -NH(CH 2 ) 2 OH.
• R 1 is optionally substituted CM alkoxy. In some embodiments, R 1 is unsubstituted CM alkoxy. In other embodiments, R 1 is CM alkoxy substituted with one or more substituents selected from the group consisting of Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, hydroxyl, halogen, -NR f R g , cyano, nitro, CM alkoxy, CM haloalkoxy, -C(0)R 4 , -0C(0)R 4 , -C(0)0R 4 , -C(0)NR f R g , and -0C(0)NR f R g , wherein R 4 is H or Ci- 4 alkyl and R f and R g are each independently H, Ci- 4 alkyl, -C(0)Ci- 4 alkyl, -C(0)OCi- 4 alkyl, or -S
• R 1 is CM alkoxy further substituted with CM alkoxy.
• R 1 is - OCH 2 CH 2 OCH 2 CH 3 or -OCH 2 CH 2 OCH 3 .
• R 1 is CM alkoxy substituted with optionally substituted CM alkoxy.
• R 1 is - (0CH 2 CH 2 ) P -0-CH 2 CH 3 , wherein p is 0-10.
• R 1 is -(0CH 2 CH 2 ) p -0- CH 3 , wherein p is 0-10.
• R 2 is hydrogen, hydroxy, halogen, optionally substituted CM alkyl, optionally substituted CM alkoxy, or -NR x R y .
• R 2 is hydrogen.
• R 2 is hydroxyl.
• R 2 is halogen.
• R 2 is chloro.
• R 2 is fluoro.
• R 2 is bromo or iodo.
• R 2 is optionally substituted C alkyl.
• R 2 is C alkyl substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, -NR f R g , cyano, nitro, CM alkoxy, and CM
• R f and R g are each independently H, Ci- 4 alkyl, -C(0)Ci- 4 alkyl, -C(0)OCi- 4 alkyl, or -S(0) 2 Ci- 4 alkyl.
• R 2 is CM alkyl substituted with one or more halogen groups.
• R 2 is -CF 3 , -(CH 2 )F, - CHF 2 , CFI 2 Br, -CH 2 CF 3 , - CH 2 CHF 2 , or -CH 2 CH 2 F.
• R 2 is CF 3 .
• R 2 is unsubstituted CM alkyl.
• R 2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl, or tertbutyl.
• R 2 is -NR y R z , wherein R y and R z taken together with the nitrogen to which they are attached form an optionally substituted monocyclic
• R 2 is -NR y R z , wherein R y and R z taken together with the nitrogen to which they are attached form an optionally substituted 5- to 12- membered heterocycloalkyl ring. In some embodiments, R 2 is -NR y R z , wherein R y and R z taken together with the nitrogen to which they are attached form an optionally substituted 5- to 6- membered heterocycloalkyl ring. In some embodiments, R 2 is morpholinyl.
• R 2 is morpholinyl substituted with one or more substituents selected from the group consisting of Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, hydroxyl, halogen, -NR f R g , cyano, nitro, CM alkoxy, CM haloalkoxy, -C(0)R 4 , -0C(0)R 4 , -C(0)0R 4 , -C(0)NR f R g , and -0C(0)NR f R g , wherein R 4 is H or Ci- 4 alkyl and R f and R g are each independently H, Ci- 4 alkyl, -C(0)Ci- 4 alkyl, -C(0)OCi- 4 alkyl, or -S(0) 2 C M alkyl.
• R 2 is piperazinyl.
• R 2 is piperazinyl substituted with one or more substituents selected from the group consisting of Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 - C 6 alkynyl, hydroxyl, halogen, -NR f R g , cyano, nitro, CM alkoxy, CM haloalkoxy, -C(0)R 4 , -0C(0)R 4 , -C(0)0R 4 , -C(0)NR f R g , and -0C(0)NR f R g , wherein R 4 is H or Ci_ 4 alkyl and R f and R g are each independently H, Ci- 4 alkyl, -C(0)Ci- 4 alkyl, -C(0)OCi- 4 alkyl, or -S(0) 2 Ci- 4 alkyl.
• R 2 is piperadinyl.
• R 2 is piperadinyl substituted with one or more substituents selected from the group consisting of Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, hydroxyl, halogen, -NR f R g , cyano, nitro, CM alkoxy, CM haloalkoxy, -C(0)R 4 , -0C(0)R 4 , -C(0)0R 4 , -C(0)NR f R g , and -0C(0)NR f R g , wherein R 4 is H or Ci- 4 alkyl and R f and R g are each independently H, Ci- 4 alkyl, -C(0)Ci- 4 alkyl, -C(0)OCi- 4 alkyl, or -S(0) 2 Ci- 4 alkyl.
• R 2 is pyrrolidinyl.
• R 2 is pyrrolidinyl substituted with one or more substituents selected from the group consisting of Ci-C 6 alkyl, C 2 -C 6 alkenyl, Ci-Ce alkynyl, hydroxyl, halogen, -NR f R g , cyano, nitro, C alkoxy, Ci- 4 haloalkoxy, -C(0)R 4 , -0C(0)R 4 ,
• R 4 is H or Ci- 4 alkyl and R f and R g are each independently H, Ci- 4 alkyl, -C(0)Ci- 4 alkyl, -C(0)OCi- 4 alkyl, or—S(0) 2 C i - 4 al kyl .
• R 2 is -NR y R z , wherein R y and R z are each independently H or optionally substituted Ci- 4 alkyl. In some embodiments, R 2 is -NR y R z , wherein R y and R z are each H. In some embodiments, R 2 is -NR y R z , wherein R y and R z are each optionally substituted Ci- 4 alkyl.
• R 2 is -NR y R z , wherein R y and R z are each optionally Ci- 4 alkyl substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, -NR f R g , cyano, nitro, C alkoxy, Ci- 4 haloalkoxy, -C(0)R 4 , -0C(0)R 4 , -C(0)0R 4 , -C(0)NR f R g , and -0C(0)NR f R g , wherein R 4 is H or Ci- 4 alkyl and R f and R g are each independently H, Ci- 4 alkyl, -C(0)Ci- 4 alkyl, -C(0)OCi- 4 alkyl, or -S(0) 2 Ci- 4 alkyl.
• R 2 is -NR y R z , wherein R y and R z are each optionally unsubstituted Ci- 4 alkyl.
• R 2 is -N(CH 2 ) 2 or - N(CH 2 CH 3 ) 2 .
• R 2 is -NR y R z , wherein R y and R z are each
• R 2 is -NR y R z , wherein one of R y and R z is H and the other is unsubstituted Ci- 4 alkyl.
• R 2 is - NR y R z , wherein one of R y and R z is H and the other is Ci- 4 alkyl substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, -NR f R g , cyano, nitro, CM alkoxy, and CM haloalkoxy, wherein R f and R g are each independently H, Ci- 4 alkyl, -C(0)Ci- 4 alkyl, -C(0)OCi- 4 alkyl, or -S(0) 2 C M alkyl.
• R 2 is - NR y R z , wherein one or R y and R z is H and the other is Ci- 4 alkyl unsubstituted or substituted with hydroxyl.
• R 2 is -NH(CH 2 ) 2 OH.
• R 2 is optionally substituted CM alkoxy. In some embodiments, R 2 is unsubstituted CM alkoxy. In other embodiments, R 2 is CM alkoxy substituted with one or more substituents selected from the group consisting of Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, hydroxyl, halogen, -NR f R g , cyano, nitro, CM alkoxy, CM haloalkoxy, -C(0)R 4 , -0C(0)R 4 , -C(0)0R 4 , -C(0)NR f R g , and -0C(0)NR f R g , wherein R 4 is H or Ci- 4 alkyl and R f and R g are each independently H, Ci- 4 alkyl, -C(0)Ci- 4 alkyl, -C(0)OCi- 4 alkyl, or -S
• R 2 is Ci- 4 alkoxy further substituted with C alkoxy.
• R 2 is - OCH2CH2OCH2CH3 or -OCH2CH2OCH3.
• R 2 is CM alkoxy substituted with optionally substituted CM alkoxy.
• R 2 is - (OCFhCFhVO-CFhCFb, wherein p is 0-10.
• R 2 is -(OCFhCFhVO- CH3, wherein p is 0-10.
• R 3 is hydrogen, hydroxy, halogen, optionally substituted CM alkyl, optionally substituted CM alkoxy, or -NR x R y .
• the CM alkyl or C M alkoxy groups are substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, -NR f R g , cyano, nitro, CM alkoxy, and CM haloalkoxy, wherein R f and R g are each independently H, Ci- 4 alkyl, -C(0)Ci- 4 alkyl, -C(0)OCi- 4 alkyl, or -S(0) 2 Ci- 4 alkyl.
• R 3 is hydrogen. In some embodiments, R 3 is hydroxyl. In some embodiments, R 3 is halogen. In some embodiments, R 3 is chloro. In some embodiments, R 3 is fluoro. In other embodiments, R 3 is bromo or iodo. In some embodiments, R 3 is optionally substituted CM alkyl.
• R 3 is CM alkyl substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, -NR f R g , cyano, nitro, CM alkoxy, and CM haloalkoxy, wherein R f and R g are each independently H, Ci- 4 alkyl, -C(0)Ci- 4 alkyl, -C(0)OCi- 4 alkyl, or -S(0) 2 C M alkyl. In some embodiments, R 3 is CM alkyl substituted with one or more halogen groups.
• R 3 is -CF 3 , -(CFh)F, -CHF 2 , CH 2 Br, -CH2CF3, - CH2CHF2, or -CH2CH2F. In some embodiments, R 3 is CF3. In some embodiments, R 3 is unsubstituted CM alkyl. For instance, in some embodiments, R 3 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl, or tertbutyl.
• R 3 is -NR y R z , wherein R y and R z taken together with the nitrogen to which they are attached form an optionally substituted monocyclic
• R 3 is -NR y R z , wherein R y and R z taken together with the nitrogen to which they are attached form an optionally substituted 5- to 12- membered heterocycloalkyl ring. In some embodiments, R 3 is -NR y R z , wherein R y and R z taken together with the nitrogen to which they are attached form an optionally substituted 5- to 6- membered heterocycloalkyl ring. In some embodiments, R 3 is morpholinyl.
• R 3 is morpholinyl substituted with one or more substituents selected from the group consisting of Ci-C 6 alkyl, C 2 -C 6 alkenyl, Ci-Ce alkynyl, hydroxyl, halogen, -NR f R g , cyano, nitro, CM alkoxy, CM haloalkoxy, -C(0)R 4 , -0C(0)R 4 , -C(0)0R 4 , -C(0)NR f R g , and -0C(0)NR f R g , wherein R 4 is H or Ci- 4 alkyl and R f and R g are each independently H, Ci- 4 alkyl, -C(0)Ci- 4 alkyl, -C(0)OCi- 4 alkyl, or -S(0) 2 C M alkyl.
• R 3 is piperazinyl.
• R 3 is piperazinyl substituted with one or more substituents selected from the group consisting of Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 - C 6 alkynyl, hydroxyl, halogen, -NR f R g , cyano, nitro, CM alkoxy, CM haloalkoxy, -C(0)R 4 , -0C(0)R 4 , -C(0)0R 4 , -C(0)NR f R g , and -0C(0)NR f R g , wherein R 4 is H or Ci_ 4 alkyl and R f and R g are each independently H, Ci- 4 alkyl, -C(0)Ci- 4 alkyl, -C(0)OCi- 4 alkyl, or -S(0) 2 Ci- 4 alkyl.
• R 3 is piperadinyl. In some embodiments, R 3 is piperadinyl substituted with one or more substituents selected from the group consisting of Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, hydroxyl, halogen, -NR f R g , cyano, nitro, CM alkoxy, CM haloalkoxy, -C(0)R 4 , -0C(0)R 4 , -C(0)0R 4 , -C(0)NR f R g , and -0C(0)NR f R g , wherein R 4 is H or Ci- 4 alkyl and R f and R g are each independently H, Ci- 4 alkyl, -C(0)Ci- 4 alkyl, -C(0)OCi- 4 alkyl, or -S(0) 2 Ci- 4 alkyl.
• R 3 is pyrrolidinyl. In some embodiments, R 3 is pyrrolidinyl substituted with one or more substituents selected from the group consisting of Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, hydroxyl, halogen, -NR f R g , cyano, nitro, CM alkoxy, CM haloalkoxy, -C(0)R 4 , -0C(0)R 4 ,
• R 4 is H or Ci- 4 alkyl and R f and R g are each independently H, Ci- 4 alkyl, -C(0)Ci- 4 alkyl, -C(0)OCi- 4 alkyl, or -S(0) 2 C M alkyl.
• R 3 is -NR y R z , wherein R y and R z are each independently H or optionally substituted Ci- 4 alkyl. In some embodiments, R 3 is -NR y R z , wherein R y and R z are each H. In some embodiments, R 3 is -NR y R z , wherein R y and R z are each optionally substituted Ci- 4 alkyl.
• R 3 is -NR y R z , wherein R y and R z are each optionally Ci- 4 alkyl substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, -NR f R g , cyano, nitro, CM alkoxy, CM haloalkoxy,
• R 4 is H or Ci- 4 alkyl and R f and R g are each independently H, Ci- 4 alkyl, -C(0)Ci- 4 alkyl, -C(0)OCi- 4 alkyl, or -S(0) 2 Ci- 4 alkyl.
• R 3 is -NR y R z , wherein R y and R z are each optionally unsubstituted Ci- 4 alkyl.
• R 3 is -N(CH 2 ) 2 or - N(CH 2 CH 3 ) 2 .
• R 3 is -NR y R z , wherein R y and R z are each
• R 3 is -NR y R z , wherein one of R y and R z is H and the other is unsubstituted Ci- 4 alkyl.
• R 3 is - NR y R z , wherein one of R y and R z is H and the other is Ci- 4 alkyl substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, -NR f R g , cyano, nitro, C alkoxy, and C haloalkoxy, wherein R f and R g are each independently H, Ci- 4 alkyl, -C(0)Ci- 4 alkyl, -C(0)OCi- 4 alkyl, or -S(0) 2 C M alkyl.
• R 3 is - NR y R z , wherein one or R y and R z is H and the other is Ci- 4 alkyl unsubstituted or substituted with hydroxyl. In certain embodiments, R 3 is -NH(CH 2 ) 2 OH.
• R 3 is optionally substituted CM alkoxy. In some embodiments, R 3 is unsubstituted CM alkoxy. In other embodiments, R 3 is CM alkoxy substituted with one or more substituents selected from the group consisting of Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, hydroxyl, halogen, -NR f R g , cyano, nitro, CM alkoxy, CM haloalkoxy, -C(0)R 4 , -0C(0)R 4 , -C(0)0R 4 , -C(0)NR f R g , and -0C(0)NR f R g , wherein R 4 is H or Ci- 4 alkyl and R f and R g are each independently H, Ci- 4 alkyl, -C(0)Ci- 4 alkyl, -C(0)OCi- 4 alkyl, or -S
• R 3 is CM alkoxy further substituted with CM alkoxy.
• R 3 is - OCH 2 CH 2 OCH 2 CH 3 or -OCH 2 CH 2 OCH 3 .
• R 3 is CM alkoxy substituted with optionally substituted CM alkoxy.
• R 3 is - (0CH 2 CH 2 ) P -0-CH 2 CH 3 , wherein p is 0-10.
• R 3 is -(0CH 2 CH 2 ) p -0- CH 3 , wherein p is 0-10.
• R 1 , R 2 , and R 3 are independently selected from the group consisting of H, -Cl, -CN, -CF 3 , methyl, methoxy, -NHCH 2 CH 2 OH, -N(CH 2 CH ) 2 , - N(CH ) 2 , -0CH 2 CH 2 -0-CH 2 CH , -OCH 2 CH 2 OCH , morpholinyl, 4-methyl-piperazin-l-yl, piperidinyl, and pyrrolidinyl.
• R 1 is selected from the group consisting of H,-NHCH 2 CH 2 OH, -N(CH 2 CH 3 ) 2 , morpholinyl, 4-methyl-piperazin-l-yl, piperidinyl, pyrrolidinyl, -0CH 2 CH 2 -0-CH 2 CH 3 , and -OCH 2 CH 2 OCH 3 .
• R 2 is selected from the group consisting of H,-CF 3 , -CN, methyl, methoxy, - 0CH 2 CH 2 -0-CH 2 CH 3 , -N(CH 3 ) 2 , and morpholinyl.
• R 3 is selected from the group consisting of FI, -Cl, -CN, methyl, methoxy, and morpholinyl.
• R 2 is optionally substituted CM alkyl and R 3 is halogen or CM alkyl.
• R 2 is CM alkyl substituted with one or more halogen, and R 3 is halogen.
• R 2 is -CF 3 and R 3 is Cl.
• R 2 is -CF 3 and R 3 is methyl.
• R 3 is optionally substituted C alkyl and R 2 is halogen or CM alkyl.
• R 3 is CM alkyl substituted with one or more halogen, and R 2 is halogen.
• R 3 is -CF 3 and R 2 is Cl.
• R 3 is -CF 3 and R 2 is methyl.
• R 2 and R 3 are each H.
• R 2 is H and R 3 is halogen, -CN, optionally substituted CM alkyl, optionally substituted C M alkoxy, or -NR y R z , wherein R y and R z are each independently H or optionally substituted Ci- 4 alkyl, or R y and R z taken together with the nitrogen to which they are attached form an optionally substituted monocyclic heterocycloalkyl ring.
• R 2 is H and R 3 is halogen.
• R 2 is H and R 3 is Cl.
• R 2 is H and R 3 is F. In some embodiments, R 2 is H and R 3 is -CN. In some embodiments, R 2 is H and R 3 is optionally substituted CM alkyl. For instance, in some embodiments, R 2 is H and R 3 is methyl. In some embodiments, R 2 is H and R 3 is -CF 3 . In some embodiments, R 2 is H and R 3 is optionally substituted CM alkoxy. For instance, in some embodiments, R 2 is H and R 3 is methoxy. In some embodiments, R 2 is H and R 3 is -NR y R z , wherein R y and R z are each independently H or optionally substituted Ci- 4 alkyl.
• R 2 is H and R 3 is -N(CH 3 ) 2 .
• R 2 is H and R 3 is -NR y R z , wherein R y and R z taken together with the nitrogen to which they are attached form an optionally substituted monocyclic heterocycloalkyl ring.
• R 2 is H and R 3 is morpholinyl.
• R 2 is CM alkyl and R 3 is halogen. For instance, in some embodiments, R 2 is methyl and R 3 is Cl. In other embodiments, R 2 is H and R 3 is -CN.
• R 3 is H and R 2 is halogen, - CN, optionally substituted C M alkyl, optionally substituted C M alkoxy, or -NR y R z , wherein R y and R z are each independently H or optionally substituted Ci- 4 alkyl, or R y and R z taken together with the nitrogen to which they are attached form an optionally substituted monocyclic heterocycloalkyl ring.
• R 3 is H and R 2 is halogen.
• R 3 is H and R 2 is Cl.
• R 3 is H and R 2 is F.
• R 3 is H and R 2 is -CN.
• R 3 is H and R 2 is -NR y R z , wherein R y and R z taken together with the nitrogen to which they are attached form an optionally substituted monocyclic heterocycloalkyl ring. In certain embodiments, R 3 is H and R 2 is morpholinyl.
• R 3 is C alkyl and R 2 is halogen.
• R 3 is methyl and R 2 is Cl. In other embodiments, R 3 is H and R 2 is -CN.
• any variable of Formula (I) may, where applicable, be combined with one or more descriptions of any other variable, the same as if each and every combination of variables were specifically and individually listed.
• every description of R 1 may be combined with every description of R 2 and R 3 the same as if each and every combination were specifically and individually listed.
• every description of R 2 may be combined with every description of R 1 and R 3 the same as if each and every description were specifically and individually listed, and every description of R 3 may be combined with every description of R 1 and R 2 the same as if each and every description were specifically and individually listed.
• the compound of Formula (I) is a compound shown in the following table.
• the present disclosure provides a compound of Formula (IIA):
• G 1 is CH or N
• G 2 is CR 2a or N
• G 3 is CR 3a or N
• G 4 is CH or N
• G 1 , G 2 , G 3 , and G 4 are N;
• G 5 is CH or N;
• G 6 is CR la or N;
• G 7 is CH or N
• G 8 is CH or N
• G 5 , G 6 , G 7 , and G 8 is N;
• R la , R 2a , and R 3a are each independently hydrogen, hydroxy, halogen, Ci- 4 alkyl, substituted C alkyl, Ci- 4 alkoxy, substituted Ci- 4 alkoxy, -CN, -C(0)R x , -C(0)0R x , - S(0) 2 R x , -NR x R y , or an optionally substituted heterocyclyl;
• R x and R y are each independently H or optionally substituted Ci- 4 alkyl; or R la and R 2a are taken together with the carbons to which they are attached to form a 5- to 16- membered heterocyclyl ring;
• X is -CR 4a R 5a -, -0-, -S-, -S(O)-, -NR 6a -, -S(0) 2 -, -NR 6a S(0) 2 -, -CR 4a R 5a S(0) 2 -, -C(O)-, - NR 6a C(0)-, or -NHNHC(O)-;
• R 4a and R 5a are independently hydrogen, hydroxy, halogen, substituted CM alkyl, CM alkoxy, or substituted CM alkoxy;
• R 4a and R 5a are taken together with the carbon to which they are attached to form a 3- to 6-membered cycloalkyl ring;
• each R 6a is independently hydrogen or CM alkyl
• G 9 is CH or N
• Z 1 and Z 2 are independently S or O;
• W and R 7a are independently hydrogen or CM alkyl
• the present disclosure provides a compound of Formula (II):
• G 1 is CH or N
• G 2 is CR 2a or N
• G 3 is CR 3a or N
• G 4 is CH or N
• G 1 , G 2 , G 3 , and G 4 are N;
• G 5 is CH or N
• G 6 is CR la or N
• G 7 is CH or N
• G 8 is CH or N
• G 5 , G 6 , G 7 , and G 8 is N;
• R la , R 2a , and R 3a are each independently hydrogen, hydroxy, halogen, C alkyl, substituted CM alkyl, Ci- 4 alkoxy, substituted Ci- 4 alkoxy, -CN, -C(0)R x , -C(0)0R x , - S(0) 2 R x , -NR x R y , or an optionally substituted heterocyclyl;
• R x and R y are each independently H or optionally substituted Ci- 4 alkyl; or R la and R 2a are taken together with the carbons to which they are attached to form a 5- to 16- membered heterocyclyl ring;
• X is -CR 4a R 5a -, -0-, -S-, -S(O)-, -NR 6a -, -S(0) 2 -, or -C(O)-;
• R 4a and R 5a are independently hydrogen, hydroxy, halogen, substituted CM alkyl, CM alkoxy, or substituted CM alkoxy;
• R 4a and R 5a are taken together with the carbon to which they are attached to form a 3- to 6-membered cycloalkyl ring;
• R 6a is hydrogen or CM alkyl
• G 9 is CH or N
• Z 1 and Z 2 are independently S or O;
• W and R 7a are independently hydrogen or C alkyl
• X is -CR 4a R 5a -, -0-, -S-, -S(0)-, -NR 6a -, -NR 6a S(0) 2 -, -CR 4a R 5a S(0) 2 -, -C(O)-, -NR 6a C(0)-, or -NHNHC(O)-;
• one or two of G 1 , G 2 , G 3 , and G 4 is N;
• one of G 5 , G 6 , G 7 , and G 8 is N;
• R la is an optionally substituted heterocyclyl, wherein when the heterocyclyl is monocyclic, the point of connection is via a carbon atom;
• R 2a is an optionally substituted heterocyclyl, wherein when the heterocyclyl is monocyclic, the point of connection is via a carbon atom;
• R 3a is an optionally substituted heterocyclyl, wherein when the heterocyclyl is monocyclic,
• R la is an optionally substituted heterocyclyl, wherein when the heterocyclyl is monocyclic, the point of connection is via a carbon atom
• R 2a is an optionally substituted heterocyclyl, wherein when the heterocyclyl is monocyclic, the point of connection is via a carbon atom
• R 3a is an optionally substituted heterocyclyl, wherein when the heterocyclyl is monocyclic, the point of connection is via a carbon atom
• R 2a and R 3a are taken together with the carbons to which they are attached to form a 5-
• G 1 is CH. In some embodiments, G 1 is N.
• G 2 is CR 2a . In some embodiments, G 2 is N. In some embodiments, G 2 is CR 2a and R 2a is selected from the group consisting of hydroxy, halogen, C alkyl, substituted CM alkyl, CM alkoxy, substituted CM alkoxy, -CN, -C(0)R x , -C(0)0R x , -S(0) 2 R x , -NR x R y , and an optionally substituted heterocyclyl.
• G 2 is CH. In some embodiments, G 2 is CR 2a and R 2a is hydroxy. In some embodiments, G 2 is CR 2a and R 2a is halogen. In certain embodiments, G 2 is CR 2a and R 2a is Cl. In certain embodiments, G 2 is CR 2a and R 2a is F. In other words,
• G 2 is CR 2a and R 2a is Br or I. In some embodiments, G 2 is CR 2a and R 2a is Ci- 4 alkyl. For example, in some embodiments, G 2 is CR 2a and R 2a is methyl. In some embodiments, G 2 is CR 2a and R 2a is ethyl. In some embodiments, G 2 is CR 2a and R 2a is n- propyl or isopropyl. In other embodiments, G 2 is CR 2a and R 2a is n-butyl, isobutyl, secbutyl, or tertbutyl.
• G 2 is CR 2a and R 2a is CM alkyl substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, -NR f R g , cyano, nitro, CM alkoxy, and CM haloalkoxy, wherein R f and R g are each independently H, Ci- 4 alkyl, -C(0)Ci- 4 alkyl, -C(0)OCi- 4 alkyl, or -S(0) 2 C M alkyl.
• G 2 is CR 2a and R 2a is CM alkoxy.
• G 2 is CR 2a and R 2a is methoxy.
• G 2 is CR 2a and R 2a is ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, secbutoxy, or tertbutoxy.
• G 2 is CR 2a and R 2a is CM alkoxy substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, -NR f R g , cyano, nitro, CM alkoxy, and CM haloalkoxy, wherein R f and R g are each independently H, Ci- 4 alkyl, -C(0)Ci- 4 alkyl, -C(0)OCi- 4 alkyl, or -S(0) 2 Ci- 4 alkyl.
• G 2 is CR 2a and R 2a is -CN. In some embodiments, G 2 is CR 2a and R 2a is -C(0)R x , wherein R x is H or optionally substituted Ci- 4 alkyl. In some
• G 2 is CR 2a and R 2a is -C(0)H, -C(0)CH 3 , - C(0)CH 2 CH 3 , -C(0)CH 2 CH 2 CH , -C(0)CH(CH ) 2 , -C(0)CH 2 CH 2 CH 2 CH , - C(0)CH(CH )CH 2 CH , -C(0)CH 2 CH(CH ) 2 , or -C(0)C(CH ) .
• G 2 is CR 2a and R 2a is -C(0)0R x , wherein R x is H or optionally substituted C M alkyl.
• G 2 is CR 2a and R 2a is -C(0)0H, -C(0)0CH 3 , - C(0)0CH 2 CH , -C(0)0CH 2 CH 2 CH , -C(0)0CH(CH ) 2 , -C(0)0CH 2 CH 2 CH 2 CH , - C(0)0CH(CH )CH 2 CH , -C(0)0CH 2 CH(CH ) 2 , or -C(0)0C(CH ) .
• R 2a is -C(0)0H, -C(0)0CH 3 , - C(0)0CH 2 CH , -C(0)0CH 2 CH 2 CH , -C(0)0CH(CH ) 2 , -C(0)0CH 2 CH(CH ) 2 , or -C(0)0C(CH ) .
• G 2 is CR 2a and R 2a is -S(0) 2 R x , wherein R x is H or optionally substituted Ci- 4 alkyl.
• G 2 is CR 2a and R 2a is -S(0) 2 H, - S(0) 2 CH , -S(0) 2 CH 2 CH , -S(0) 2 CH 2 CH 2 CH , -S(0) 2 CH(CH ) 2 , -S(0) 2 CH 2 CH 2 CH 2 CH , - S(0) 2 CH(CH3)CH 2 CH3, -S(0) 2 CH 2 CH(CH 3 ) 2 , or -S(0) 2 C(CH 3 ) 3 .
• G 2 is CR 2a and R 2a is -NR x R y , wherein R x and R y are each independently H or optionally substituted Ci- 4 alkyl. In some embodiments, G 2 is CR 2a and R 2a is -NH 2 .
• G 2 is CR 2a and R 2a is -NH(Ci- 4 alkyl), such as -NHCH 3 , -NHCH 2 CH 3 , - NHCH 2 CH 2 CH 3 , -NHCH(CH 3 ) 2 , -NHCH 2 CH 2 CH 2 CH 3 , -NHCH(CH 3 )CH 2 CH 3 , - NHCH 2 CH(CH 3 ) 2 , or -NHC(CH 3 ) 3 .
• G 2 is CR 2a and R 2a is -N(Ci- 4 alkyl) 2 , including, but not limited to -N( ⁇ 3 ⁇ 4) 2 , -N(CH 2 CH 3 ) 2, - N(CH(CH 3 ) 2 ) 2 , and - N(CH(CH 3 ) 2 ) 2 .
• G 2 is CR 2a and R 2a is an optionally substituted heterocyclyl containing one or more heteroatoms selected from N, O, and S.
• G 2 is CR 2a and R 2a is an optionally substituted 5- to 12- membered
• G 2 is CR 2a and R 2a is an optionally substituted monocyclic heterocycloalkyl ring. In some embodiments, G 2 is CR 2a and R 2a is an optionally substituted bicyclic heterocycloalkyl ring. In some embodiments, G 2 is CR 2a and R 2a is an optionally substituted 5- to 6- membered heterocycloalkyl ring.
• G 3 is CR 3a .
• G 3 is N.
• G 3 is CR 3a and R 3a is selected from the group consisting of hydroxy, halogen, C 1-4 alkyl, substituted C 1-4 alkyl, C 1-4 alkoxy, substituted C 1-4 alkoxy, -CN, -C(0)R x , -C(0)0R x , -S(0) 2 R x , -NR x R y , and an optionally substituted heterocyclyl.
• G 3 is CH.
• G 3 is CR 3a and R 3a is hydroxy.
• G 3 is CR 3a and R 3a is halogen.
• G 3 is CR 3a and R 3a is Cl.
• G 3 is CR 3a and R 3a is F.
• G 3 is CR 3a and R 3a is Br or I. In some embodiments, G 3 is CR 3a and R 3a is Ci- 4 alkyl. For example, in some embodiments, G 3 is CR 3a and R 3a is methyl. In some embodiments, G 3 is CR 3a and R 3a is ethyl. In some embodiments, G 3 is CR 3a and R 3a is n- propyl or isopropyl. In other embodiments, G 3 is CR 3a and R 3a is n-butyl, isobutyl, secbutyl, or tertbutyl.
• G 3 is CR 3a and R 3a is C 1-4 alkyl substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, -NR f R g , cyano, nitro, C i - 4 alkoxy, and C 1-4 haloalkoxy, wherein R f and R g are each independently H, Ci- 4 alkyl, -C(0)Ci- 4 alkyl, -C(0)OCi- 4 alkyl, or -S(0) 2 Ci ⁇ alkyl.
• G 3 is CR 3a and R 3a is C 1-4 alkoxy.
• G 3 is CR 3a and R 3a is methoxy.
• G 3 is CR 3a and R 3a is ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, secbutoxy, or tertbutoxy.
• G 3 is CR 3a and R 3a is C 1-4 alkoxy substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, -NR f R g , cyano, nitro, Ci- 4 alkoxy, and C haloalkoxy, wherein R f and R g are each independently H, Ci- 4 alkyl, -C(0)Ci- 4 alkyl, -C(0)OCi- 4 alkyl, or -S(0) 2 Ci- 4 alkyl.
• G 3 is CR 3a and R 3a is -CN. In some embodiments, G 3 is CR 3a and R 3a is -C(0)R x , wherein R x is H or optionally substituted Ci- 4 alkyl. In some
• G 3 is CR 3a and R 3a is -C(0)H, -C(0)CH 3 , - C(0)CH 2 CH 3 , -C(0)CH 2 CH 2 CH , -C(0)CH(CH ) 2 , -C(0)CH 2 CH 2 CH 2 CH , - C(0)CH(CH )CH 2 CH , -C(0)CH 2 CH(CH ) 2 , or -C(0)C(CH ) .
• G 3 is CR 3a and R 3a is -C(0)0R x , wherein R x is H or optionally substituted C M alkyl.
• G 3 is CR 3a and R 3a is -C(0)0H, -C(0)0CH 3 , - C(0)0CH 2 CH , -C(0)0CH 2 CH 2 CH , -C(0)0CH(CH ) 2 , -C(0)0CH 2 CH 2 CH 2 CH , - C(0)0CH(CH )CH 2 CH , -C(0)0CH 2 CH(CH ) 2 , or -C(0)0C(CH ) .
• R 3a is -C(0)0H, -C(0)0CH 3 , - C(0)0CH 2 CH , -C(0)0CH 2 CH 2 CH , -C(0)0CH(CH ) 2 , -C(0)0CH 2 CH(CH ) 2 , or -C(0)0C(CH ) .
• G 3 is CR 3a and R 3a is -S(0) 2 R x , wherein R x is H or optionally substituted Ci- 4 alkyl.
• G 3 is CR 3a and R 3a is -S(0) 2 H, - S(0) 2 CH , -S(0) 2 CH 2 CH , -S(0) 2 CH 2 CH 2 CH , -S(0) 2 CH(CH ) 2 , -S(0) 2 CH 2 CH 2 CH 2 CH , - S(0) 2 CH(CH )CH 2 CH , -S(0) 2 CH 2 CH(CH ) 2 , or -S(0) 2 C(CH ) .
• G 3 is CR 3a and R 3a is -NR x R y , wherein R x and R y are each independently H or optionally substituted Ci- 4 alkyl. In some embodiments, G 3 is CR 3a and R 3a is -NH 2 .
• G 3 is CR 3a and R 3a is -NH(Ci- 4 alkyl), such as -NHCH 3 , -NHCH 2 CH 3 , - NHCH 2 CH 2 CH , -NHCH(CH ) 2 , -NHCH 2 CH 2 CH 2 CH , -NHCH(CH )CH 2 CH , - NHCH 2 CH(CH ) 2 , or -NHC(CH ) .
• G 3 is CR 3a and R 3a is -N(Ci- 4 alkyl) 2 , including, but not limited to -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2, - N(CH(CH 3 ) 2 ) 2 , and - N(CH(CH 3 ) 2 ) 2 .
• G 3 is CR 3a and R 3a is an optionally substituted heterocyclyl containing one or more heteroatoms selected from N, O, and S.
• G 3 is CR 3a and R 3a is an optionally substituted 5- to 12- membered heterocycloalkyl ring.
• G 3 is CR 3a and R 3a is an optionally substituted monocyclic heterocycloalkyl ring. In some embodiments, G 3 is CR 3a and R 3a is an optionally substituted bicyclic heterocycloalkyl ring. In some embodiments, G 3 is CR 3a and R 3a is an optionally substituted 5- to 6- membered heterocycloalkyl ring.
• G 4 is CH. In some embodiments, G 4 is N.
• G 2 is CR 2a
• G 3 is CR 3a
• R 2a and R 3a are taken together with the carbons to which they are attached to form a 5- to 16- membered heterocyclyl ring.
• G 2 is CR 2a
• G 3 is CR 3a
• R 2a and R 3a are taken together with the carbons to which they are attached to form a 5- to 16- membered heterocyclyl ring comprising one or more heteroatoms selected from N, O, and S.
• G 2 is CR 2a
• G 3 is CR 3a
• R 2a and R 3a are taken together with the carbons to which they are attached to form a 6- to l2-membered heterocyclyl ring comprising one or more O atoms.
• G 2 is CR 2a
• G 3 is CR 3a
• R 2a and R 3a are taken together with the carbons to which they are attached to form a 9- to 12- membered heterocyclyl ring comprising one or more O atoms.
• the compound of Formula (IIA) or Formula (II) is a compound of Formula (II- 1):
• G 1 , G 4 , G 5 , G 6 , G 7 , G 8 , X and A are as defined for Formula (IIA) or Formula (II), and t is 1, 2, or 3.
• the compound of Formula (IIA) or Formula (II) is a compound of Formula (II-2):
• R la , R 2a , R 3a , X and A are as defined for Formula (IIA) or Formula (II).
• one of G 1 , G 2 , G 3 , and G 4 is N.
• G 1 is N
• G 2 is CR 2a
• G 3 is CR 3a
• G 4 is CH.
• G 1 is CH
• G 2 is N
• G 3 is CR 3a
• G 4 is CH.
• G 1 is CH
• G 2 is CR 2a
• G 3 is N
• G 4 is CH.
• G 1 is CH
• G 2 is CR 2a
• G 3 is N
• G 4 is CH.
• G 1 is CH
• G 2 is CR 2a
• G 3 is CR 3a
• G 4 is N.
• G 1 , G 2 , G 3 , and G 4 are N.
• G 1 is N
• G 2 is N
• G 3 is CR 3a
• G 4 is CH
• G 1 is N
• G 2 is CR 2a
• G 3 is N
• G 4 is CH
• G 1 is N
• G 2 is CR 2a
• G 3 is CR 3a
• G 4 is N.
• G 1 is CH
• G 2 is N
• G 3 is N
• G 4 is CH
• G 1 is CH
• G 2 is N
• G 3 is CR 3a
• G 4 is N.
• G 1 is CH
• G 2 is CR 2a
• G 3 is N
• G 4 is N
• G 1 is CH
• G 2 is CR 2a
• G 3 is CR 3a
• G 4 is CH.
• no more than one of G 1 , G 2 , G 3 , and G 4 is N.
• no more than two of G 1 , G 2 , G 3 , and G 4 is N.
• G 5 is CH. In some embodiments, G 5 is N. In some embodiments of Formula (IIA) or Formula (II), G 6 is CR la . In some embodiments, G 6 is CR la and R la is selected from the group consisting of hydrogen, hydroxy, halogen, Ci- 4 alkyl, Ci- 4 haloalkyl, Ci- 4 alkoxy, and Ci- 4 haloalkoxy. In some embodiments, G 6 is N. In some embodiments of Formula (IIA) or Formula (II), G 7 is CH. In some embodiments, G 7 is N. In some embodiments of Formula (IIA) or Formula (II), G 8 is CH. In some embodiments, G 8 is N.
• one of G 5 , G 6 , G 7 , and G 8 is N.
• G 5 is N
• G 6 is CR la
• G 7 is CH
• G 8 is CH.
• G 5 is CH
• G 6 is N
• G 7 is CH
• G 8 is CH.
• G 5 is CH
• G 6 is CR la
• G 7 is N
• G 8 is CH.
• G 5 is CH
• G 6 is CR la
• G 7 is CH
• G 8 is CH.
• G 5 is CH
• G 6 is CR la
• G 7 is CH
• G 8 is N.
• no more than one of G 5 , G 6 , G 7 , and G 8 is N.
• G 6 is CR la and R la is selected from the group consisting of hydroxy, halogen, Ci- 4 alkyl, substituted Ci- 4 alkyl, Ci- 4 alkoxy, substituted Ci- 4 alkoxy, -CN, -C(0)R x , -C(0)OR x , - S(0) 2 R x , -NR x R y , and an optionally substituted heterocyclyl.
• G 6 is CH.
• G 6 is CR la and R la is hydroxy.
• G 6 is CR la and R la is halogen.
• G 6 is CR la and R la is Cl. In certain embodiments, G 6 is CR la and R la is F. In other embodiments, G 6 is CR la and R la is Br or I. In some embodiments, G 6 is CR la and R la is Ci- 4 alkyl. For example, in some embodiments, G 6 is CR la and R la is methyl. In some embodiments, G 6 is CR la and R la is ethyl. In some embodiments, G 6 is CR la and R la is n-propyl or isopropyl. In other embodiments, G 6 is CR la and R la is n-butyl, isobutyl, secbutyl, or tertbutyl.
• G 6 is CR la and R la is Ci-4 alkyl substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, -NR f R g , cyano, nitro, Ci- 4 alkoxy, and Ci- 4 haloalkoxy, wherein R f and R g are each independently H, Ci- 4 alkyl, -C(0)Ci- 4 alkyl, -C(0)OCi- 4 alkyl, or -S(0) 2 Ci- 4 alkyl.
• G 6 is CR la and R la is Ci- 4 alkoxy.
• G 6 is CR la and R la is methoxy.
• G 6 is CR la and R la is ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, secbutoxy, or tertbutoxy.
• G 6 is CR la and R la is C alkoxy substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, -NR f R g , cyano, nitro, CM alkoxy, and CM haloalkoxy, wherein R f and R g are each independently H, Ci- 4 alkyl, -C(0)Ci- 4 alkyl, -C(0)OCi- 4 alkyl, or -S(0) 2 Ci- 4 alkyl.
• G 6 is CR la and R la is - CN. In some embodiments, G 6 is CR la and R la is -C(0)R x , wherein R x is H or optionally substituted Ci- 4 alkyl. In some embodiments, In some embodiments, G 6 is CR la and R la is - C(0)H, -C(0)CH 3 , -C(0)CH 2 CH 3 , -C(0)CH 2 CH 2 CH , -C(0)CH(CH ) 2 , - C(0)CH 2 CH 2 CH 2 CH , -C(0)CH(CH )CH 2 CH , -C(0)CH 2 CH(CH ) 2 , or -C(0)C(CH ) .
• G 6 is CR la and R la is -C(0)0R x , wherein R x is H or optionally substituted Ci- 4 alkyl. In some embodiments, In some embodiments, G 6 is CR la and R la is - C(0)0H, -C(0)0CH , -C(0)0CH 2 CH , -C(0)0CH 2 CH 2 CH , -C(0)0CH(CH ) 2 , - C(0)0CH 2 CH 2 CH 2 CH , -C(0)0CH(CH )CH 2 CH , -C(0)0CH 2 CH(CH ) 2 , or - C(0)0C(CH 3 ) 3 .
• G 6 is CR la and R la is -S(0) 2 R x , wherein R x is H or optionally substituted C M alkyl. In some embodiments, In some embodiments, G 6 is CR la and R la is -S(0) 2 H, -S(0) 2 CH , -S(0) 2 CH 2 CH , -S(0) 2 CH 2 CH 2 CH , -S(0) 2 CH(CH ) 2 , - S(0) 2 CH 2 CH 2 CH 2 CH , -S(0) 2 CH(CH )CH 2 CH , -S(0) 2 CH 2 CH(CH ) 2 , or -S(0) 2 C(CH ) . In some embodiments, G 6 is CR la and R la is -NR x R y , wherein R x and R y are each
• G 6 is CR la and R la is -NH 2 .
• G 6 is CR la and R la is -NH(Ci- 4 alkyl), such as -NHCH 3 , -NHCH 2 CH , -NHCH 2 CH 2 CH , -NHCH(CH ) 2 , -NHCH 2 CH 2 CH 2 CH , - NHCH(CH )CH 2 CH , -NHCH 2 CH(CH ) 2 , or -NHC(CH ) .
• G 6 is CR la and R la is -N(C M alkyl) 2 , including, but not limited to -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2, - N(CH(CH 3 ) 2 ) 2 , and -N(CH(CH 3 ) 2 ) 2 .
• G 6 is CR la and R la is an optionally substituted heterocyclyl containing one or more heteroatoms selected from N, O, and S.
• G 6 is CR la and R la is an optionally substituted 5- to 12- membered heterocycloalkyl ring.
• G 6 is CR la and R la is an optionally substituted monocyclic heterocycloalkyl ring. In some embodiments, G 6 is CR la and R la is an optionally substituted bicyclic heterocycloalkyl ring. In some embodiments, G 6 is CR la and R la is an optionally substituted 5- to 6- membered heterocycloalkyl ring.
• R 4 is independently hydrogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3-C6 cycloalkyl, C6-C14 aryl, 5-6-membered heteroaryl or 3-6- membered heterocyclyl, wherein the Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3-C6 cycloalkyl, C6-C14 aryl, 5-6-membered heteroaryl and 3-6-membered heterocyclyl are independently optionally substituted by halogen, oxo, -CN, -OR 9 , -NR 9 R 10 ,
• R 5 and R 6 are each independently hydrogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -C 14 aryl, 5-6-membered heteroaryl or 3-6 membered heterocyclyl, wherein the Ci-C 6 alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, C 3 - C 6 cycloalkyl, C 6 -C 14 aryl, 5-6-membered heteroaryl and 3-6 membered heterocyclyl are independently optionally substituted by halogen, oxo, -CN, -OR 9 , -NR 9 R 10 or Ci-C 6 alkyl optionally substituted by
• Z 1 is S or O, G 9 is N, and W is H or C alkyl.
• Z 1 is S, G 9 is N, and W is H.
• Z 1 is O, G 9 is N, and W is H.
• Z 1 is S, G 9 is N, and W is C M alkyl.
• Z 1 is O, G 9 is N, and W is C M
• Z 1 is S or O
• G 9 is CH, and W is H or C M alkyl.
• Z 1 is S, G 9 is CH, and W is H.
• Z 1 is O, G 9 is CH, and W is H.
• Z 1 is S, G 9 is CH, and W is C M alkyl.
• Z 1 is O, G 9 is CH, and W is C M alkyl.
• A is
• Z 1 is S or O
• G 9 is CH or N
• W is H.
• Z 1 is S or O
• G 9 is CH or N
• W is CM alkyl.
• Z 2 is S or O, G 9 is N, and R 7a is H or C alkyl. In some embodiments, Z 2 is S, G 9 is N, and R 7a is H. In some embodiments, Z 2 is O, G 9 is N, and R 7a is H. In some embodiments,
• Z 2 is S, G 9 is N, and R 7a is C alkyl. In some embodiments, Z 2 is O, G 9 is N,
• R 7a is C alkyl.
• G 9 is
• Z 2 is S, G 9 is CH, and R 7a is H or CM alkyl.
• Z 2 is S, G 9 is CH, and R 7a is H.
• Z 2 is O, G 9 is CH, and R 7a is H.
• Z 2 is S, G 9 is CH, and R 7a is CM alkyl.
• Z 2 is O, G 9 is CH, and R 7a is CM alkyl.
• Z 2 is S
• G y is CH or N
• R 7a is H or CM
• X is -CR 4a R 5a -, wherein R 4a and R 5a are each independently hydrogen, hydroxy, halogen, substituted Ci- 4 alkyl, Ci- 4 alkoxy, or substituted C alkoxy.
• X is -CR 4a R 5a -; wherein R 4a and R 5a , are each independently hydrogen, hydroxy, halogen, or R 4a and R 5a are taken together with the carbon to which they are attached to form a 3- to 6-membered cycloalkyl ring.
• X is -CH 2 -.
• X is -CR 4a R 5a -, wherein one of R 4a and R 5a is hydrogen and the other is hydroxy, halogen, substituted Ci- 4 alkyl, Ci- 4 alkoxy, or substituted Ci- 4 alkoxy.
• X is -CR 4a R 5a -, wherein each of R 4a and R 5a is independently hydroxy, halogen, substituted Ci- 4 alkyl, Ci- 4 alkoxy, or substituted Ci- 4 alkoxy.
• X is -CR 4a R 5a -, wherein R 4a and R 5a are each independently hydrogen, hydroxy, halogen, Ci- 4 alkyl substituted with one or more halogen, Ci- 4 alkoxy, or Ci-4 alkoxy substituted with one or more halogen.
• R 4a and R 5a are each independently hydrogen, hydroxy, halogen, Ci- 4 alkyl substituted with one or more halogen, Ci- 4 alkoxy, or Ci-4 alkoxy substituted with one or more halogen.
• X is -CR 4a R 5a -, and one of R 4a and R 5a is hydroxy.
• X is -CH(OH)-.
• X is -CR 4a R 5a -, and one or both R 4a and R 5a is F, Cl, Br, or I.
• X is -C(F) 2 -.
• X is -CR 4a R 5a -, and one or both R 4a and R 5a is C alkyl substituted with halogen, including, but not limited to - CF 3 , -(CH2)F, -CHF 2 , CFI 2 Br, -CH 2 CF 3 , - CH 2 CHF 2 , and -CH 2 CH 2 F.
• halogen including, but not limited to - CF 3 , -(CH2)F, -CHF 2 , CFI 2 Br, -CH 2 CF 3 , - CH 2 CHF 2 , and -CH 2 CH 2 F.
• X is -CR 4a R 5a -, and one or both R 4a and R 5a is Ci- 4 alkoxy, including, but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, and sec-butoxy.
• X is -CR 4a R 5a -, and one or both R 4a and R 5a is Ci- 4 alkoxy substituted with halogen, including, but not limited to -OCF 3 , -0(CH2)F, -OCHF 2 , -OCH 2 Br, - OCH 2 CF , -OCH 2 CHF 2 , and -OCH 2 CH 2 F.
• X is -CR 4a R 5a -, wherein R 4a and R 5a are taken together with the carbon to which they are attached to form a 3- to 6-membered cycloalkyl ring. In some embodiments, X is -CR 4a R 5a -, wherein R 4a and R 5a are taken together with the carbon to which they are attached to form a cyclopropyl ring. In some embodiments, X is - CR 4a R 5a -, wherein R 4a and R 5a are taken together with the carbon to which they are attached to form a cyclobutyl ring.
• X is -CR 4a R 5a -, wherein R 4a and R 5a are taken together with the carbon to which they are attached to form a cyclopentyl ring. In some embodiments, X is -CR 4a R 5a -, wherein R 4a and R 5a are taken together with the carbon to which they are attached to form a cyclohexyl ring.
• X is -0-. In some embodiments, X is -S-. In some embodiments, X is -S(O)-. In some embodiments, X is -NR 6a -, wherein R 6a is hydrogen or Ci-4 alkyl. For instance, in some embodiments, X is -NH-. In some embodiments, X is - NR 6a -, wherein R 6a is C alkyl. For instance, in some embodiments, X is -N(CH 3 )-. In some embodiments, X is -S(0) 2 - ⁇ In other embodiments, X is or -C(O)-.
• X is -NR 6a S(0) 2 -, wherein R 6a is hydrogen or Ci- 4 alkyl.
• X is -NHS(0) 2 -.
• X is -CR 4a R 5a S(0) 2 -, wherein R 4a and R 5a are each independently hydrogen, hydroxy, halogen.
• X is -CF 2 S(0) 2 -.
• X is -CH 2 S(0) 2 -.
• X is so -NR 6a C(0)-, wherein R 6a is hydrogen or Ci- 4 alkyl.
• X is -NHC(O)-.
• X is -NHNHC(O)-.
• the compound of Formula (IIA) or Formula (II) is a compound of Formula (Ila) or (lib):
• R la , R 2a , and R 3a are as defined for Formula (IIA) or Formula (II).
• the compound of Formula (IIA) or Formula (II) is a compound of Formula (lie), (lid), (He), (Ilf), or (Ilg):
• R la , R 2a , and R 3a are as defined for Formula (IIA) or Formula (II).
• the compound of Formula (IIA) or Formula (II) is a compound of Formula (Ilh), (Hi), (Ilj), (Ilk), (III), (Ilm), (Iln), (IIo), or (Up):
• R la , R 2a , R 3a , and R 6a are as defined for Formula (IIA) or Formula (II).
• the compound of Formula (IIA) or Formula (II) is a compound of Formula (Ilq), (Ilr), (IIs), (lit), (IIu), (IIv), or (IIw):
• R la , R 2a , and R 3a are as defined for Formula (IIA) or Formula (II).
• R 2a is selected from the group consisting of hydrogen, hydroxy, halogen, Ci- 4 alkyl, substituted Ci- 4 alkyl, Ci- 4 alkoxy, substituted Ci- 4 alkoxy, -CN, -NR x R y , and optionally substituted heterocyclyl.
• R 2a is selected from the group consisting of hydrogen, Ci- 4 alkyl, Ci- 4 haloalkyl, Ci- 4 alkoxy, and substituted Ci- 4 alkoxy.
• R 2a is hydrogen.
• R 2a is methyl, ethyl, n-propyl, isopropyl, n-butyl, seebutyl, or tertbutyl. In some embodiments, R 2a is methyl, ethyl, n-propyl, isopropyl, n-butyl, seebutyl, or tertbutyl. In some embodiments,
• R 2a is methyl. In some embodiments, R 2a is CF 3 . In some embodiments, R 2a is methoxy, ethoxy, propoxy, isopropoxy, butoxy, or tertbutoxy. In some embodiments, R 2a is a 5- to 12- membered heterocyclyl. In some embodiments, R 2a is a 5- to 6- membered heterocyclyl.
• R 3a is selected from the group consisting of hydrogen, hydroxy, halogen, C alkyl, substituted CM alkyl, CM alkoxy, substituted CM alkoxy, -CN, -NR x R y , and optionally substituted heterocyclyl. In some embodiments, R 3a is selected from the group consisting of hydrogen, CM alkyl, Ci- 4 haloalkyl, CM alkoxy, and substituted CM alkoxy. In some embodiments, R 3a is hydrogen.
• R 3a is methyl, ethyl, n-propyl, isopropyl, n-butyl, secbutyl, or tertbutyl. In some embodiments, R 3a is methyl, ethyl, n-propyl, isopropyl, n-butyl, secbutyl, or tertbutyl. In some
• R 3a is methyl. In some embodiments, R 3a is CF 3 . In some embodiments, R 3a is methoxy, ethoxy, propoxy, isopropoxy, butoxy, or tertbutoxy. In some embodiments, R 3a is a 5- to 12- membered heterocyclyl. In some embodiments, R 3a is a 5- to 6- membered heterocyclyl.
• R 2a and R 3a are taken together with the carbons to which they are attached to form a 5- to 16- membered heterocyclyl ring.
• R 2a and R 3a are taken together with the carbons to which they are attached to form a 5- to 16- membered heterocyclyl ring comprising one or more heteroatoms selected from N, O, and S. In some embodiments, R 2a and R 3a are taken together with the carbons to which they are attached to form a 9- to l2-membered heterocyclyl ring comprising one or more O atoms.
• R 2a is CM alkyl or substituted CM alkyl and R 3a is halogen or CM alkyl. In some embodiments, R 2a is CM alkyl substituted with one or more halogen, and R 3a is halogen.
• R 2a is -CF 3 and R 3a is Cl. In certain embodiments, R 2a is -CF 3 and R 3a is methyl. In some embodiments, R 3a is CM alkyl or substituted CM alkyl and R 2a is halogen or CM alkyl. In some embodiments, R 3a is CM alkyl substituted with one or more halogen, and R 2a is halogen. In some embodiments, R 3a is -CF 3 and R 2a is Cl. In some embodiments, R 3a is -CF 3 and R 2a is methyl. In some embodiments, R 2a and R 3a are each H.
• R 2a is H and R 3a is halogen, -CN, CM alkyl, substituted CM alkyl, CM alkoxy, substituted CM alkoxy, -NR x R y , wherein R x and R y are each independently H or optionally substituted Ci- 4 alkyl, or an optionally substituted heterocyclyl.
• R 2a is H and R 3a is halogen.
• R 2a is H and R 3a is Cl.
• R 2a is H and R 3a is F.
• R 2a is H and R 3a is -CN.
• R 2a is H and R 3a is optionally substituted C alkyl.
• R 2a is H and R 3a is methyl.
• R 2a is H and R 3a is -CF 3 .
• R 2a is H and R 3a is optionally substituted Ci- 4 alkoxy.
• R 2a is H and R 3a is methoxy.
• R 2a is H and R 3a is -N(CH 3 ) 2 .
• R 2a is H and R 3a is an optionally substituted heterocyclyl.
• R 2a is H and R 3a is morpholinyl.
• R 2a is C alkyl and R 3a is halogen.
• R 2a is methyl and R 3a is Cl.
• R 2a is H and R 3a is -CN.
• R 3a is H and R 2a is halogen, -CN, C alkyl, substituted CM alkyl, CM alkoxy, substituted CM alkoxy, -NR x R y , wherein R x and R y are each independently H or optionally substituted Ci- 4 alkyl, or an optionally substituted heterocyclyl.
• R 3a is H and R 2a is halogen.
• R 3a is H and R 2a is Cl. In other some embodiments, R 3a is H and R 2a is F. In some embodiments, R 3a is H and R 2a is -CN. In some embodiments, R 3a is H and R 2a is optionally substituted CM alkyl. For instance, in some embodiments, R 3a is H and R 2a is methyl. In some embodiments, R 3a is H and R 2a is -CF 3 . In some embodiments, R 3a is H and R 2a is optionally substituted CM alkoxy. For instance, in some embodiments, R 3a is H and R 2a is methoxy.
• R 3a is H and R 2a is -N(CH 3 ) 2 . In some embodiments, R 3a is H and R 2a is an optionally substituted heterocyclyl. In certain embodiments, R 3a is H and R 2a is morpholinyl. In some embodiments, R 3a is CM alkyl and R 2a is halogen. For instance, in some embodiments, R 3a is methyl and R 2a is Cl. In other embodiments, R 3a is H and R 2a is -CN.
• R la is selected from the group consisting of hydrogen, hydroxy, halogen, CM alkyl, substituted CM alkyl, CM alkoxy, substituted CM alkoxy, -CN, -NR x R y , and optionally substituted heterocyclyl.
• R la is selected from the group consisting of hydrogen, CM alkyl, Ci- 4 haloalkyl, CM alkoxy, and substituted CM alkoxy. In some embodiments, R la is hydrogen. In some embodiments, R la is methyl, ethyl, n-propyl, isopropyl, n-butyl, seebutyl, or tertbutyl. In some embodiments, R la is methyl, ethyl, n-propyl, isopropyl, n-butyl, seebutyl, or tertbutyl. In some embodiments,
• R la is methyl. In some embodiments, R la is CF 3 . In some embodiments, R la is methoxy, ethoxy, propoxy, isopropoxy, butoxy, or tertbutoxy. In some embodiments, R la is a 5- to 12- membered heterocyclyl. In some embodiments, R la is a 5- to 6- membered heterocyclyl.
• any variable of Formula (IIA) or Formula (II) may, where applicable, be combined with one or more descriptions of any other variable, the same as if each and every combination of variables were specifically and individually listed.
• every description of A may be combined with every description of G 1 , G 2 , G 3 , G 4 , G 5 , G 6 , G 7 , G 8 , G 8 , G 9 , R la , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , X, Z, and W the same as if each and every combination were specifically and individually listed.
• every description of X may be combined with every description of A, G 1 , G 2 , G 3 , G 4 , G 5 , G 6 , G 7 , G 8 , G 8 , G 9 , R la , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , Z, and W the same as if each and every description were specifically and individually listed
• every description of G 1 may be combined with every description of A, G 2 , G 3 , G 4 , G 5 , G 6 , G 7 , G 8 , G 8 , G 9 , R la , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , X, Z, and W the same as if each and every description were specifically and individually listed.
• the compound of Formula (IIA) or Formula (II) is a compound shown in the following table.
• compositions of Formula (I), Formula (IIA), and Formula (II) may be prepared and/or formulated as pharmaceutically acceptable salts.
• pharmaceutically acceptable salts include acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid and the like. These salts may be derived from inorganic or organic acids.
• Non-limiting examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen- phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-l,4-dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsul
• pharmaceutically acceptable salts are formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base.
• Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine,
• Examples of pharmaceutically acceptable base addition salts include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
• the organic non-toxic bases are L-amino acids, such as L-lysine and L- arginine, tromethamine, N-ethylglucamine and N-methylglucamine.
• Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. Lists of other suitable pharmaceutically acceptable salts are found in Remington's Pharmaceutical Sciences, l7th Edition, Mack Publishing Company, Easton, Pa., 1985.
• pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as mandelic acid, citric acid, or tartaric acid, an amino acid, such as aspartic acid or glutamic acid,
• the embodiments also relate to pharmaceutically acceptable prodrugs of the compounds described herein, and treatment methods employing such pharmaceutically acceptable prodrugs.
• prodrug means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to the compound of Formula (I), Formula (IIA), or Formula (II).
• a "pharmaceutically acceptable prodrug” is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject. Illustrative procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in“Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.
• the embodiments also relate to pharmaceutically active metabolites of compounds described herein, and uses of such metabolites in the methods provided herein.
• A“pharmaceutically active metabolite” means a pharmacologically active product of metabolism in the body of a compound described herein or salt thereof.
• Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertolini et ah, J. Med. Chem. 1997, 40, 2011-2016; Shan et ah, J.
• the ion transporter inhibitor comprises one or more of compounds 1-23, or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the ion transporter inhibitor does not comprise compounds 1-23, or a pharmaceutically acceptable salt thereof.
• a pharmaceutical composition according to the present disclosure comprises at least one compound of Formula (I), Formula (IIA), or Formula (II), or a pharmaceutically acceptable salt thereof.
• the pharmaceutical compositions may further comprise one or more pharmaceutically-acceptable excipients.
• a pharmaceutically- acceptable excipient is a substance that is non-toxic and otherwise biologically suitable for administration to a subject. Such excipients facilitate administration of the compounds described herein and are compatible with the active ingredient. Examples of
• compositions according to the embodiments are sterile compositions.
• Pharmaceutical compositions may be prepared using
• compositions are also contemplated by the embodiments, including compositions that are in accord with national and local regulations governing such compositions.
• compositions and compounds described herein may be formulated as solutions, emulsions, suspensions, dispersions, or inclusion complexes such as cyclodextrins in suitable pharmaceutical solvents or carriers, or as pills, tablets, lozenges, suppositories, sachets, dragees, granules, powders, powders for reconstitution, or capsules along with solid carriers according to conventional methods known in the art for preparation of various dosage forms.
• Pharmaceutical compositions provided herein may be
• the compositions are formulated for intravenous or oral administration.
• a suitable route of delivery such as oral, parenteral, rectal, nasal, topical, or ocular routes, or by inhalation.
• the compositions are formulated for intravenous or oral administration.
• the compounds the embodiments may be provided in a solid form, such as a tablet or capsule, or as a solution, emulsion, or suspension.
• the compounds provided herein may be formulated to yield a dosage of, e.g., from about 0.01 to about 50 mg/kg daily, or from about 0.05 to about 20 mg/kg daily, or from about 0.1 to about 10 mg/kg daily.
• Oral tablets may include the active ingredient(s) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents.
• suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like.
• Exemplary liquid oral excipients include ethanol, glycerol, water, and the like.
• Starch, polyvinyl pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are exemplary disintegrating agents.
• Binding agents may include starch and gelatin.
• the lubricating agent if present, may be magnesium stearate, stearic acid, or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.
• Capsules for oral administration include hard and soft gelatin capsules.
• active ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent.
• Soft gelatin capsules may be prepared by mixing the active ingredient with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.
• Liquids for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use.
• Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose,
• non-aqueous vehicles e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.
• compositions described herein may be formulated for rectal administration as a suppository.
• parenteral use including intravenous, intramuscular, intraperitoneal, intranasal, or subcutaneous routes, the agents provided herein may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil.
• Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride.
• Such forms may be presented in unit-dose form such as ampoules or disposable injection devices, in multi-dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation.
• Illustrative infusion doses range from about 1 to 1000 pg/kg/minute of agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.
• the compounds or pharmaceutical compositions described herein may be administered using, for example, a spray formulation also containing a suitable carrier.
• the compounds of the present embodiments are formulated as creams or ointments or a similar vehicle suitable for topical administration.
• the compounds or pharmaceutical compositions described herein may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle.
• Another mode of administering the agents provided herein may utilize a patch formulation to effect transdermal delivery.
• beneficial or desired clinical results include, but are not limited to, one or more of the following: decreasing one or more symptoms resulting from the condition, diminishing the extent of the condition, stabilizing the condition (e.g., preventing or delaying the worsening of the condition), ameliorating a disease state, providing a remission (whether partial or total) of a disease, decreasing the dose of one or more other medications required to treat the condition, enhancing the effect of another medication used to treat the condition, increasing the quality of life of an individual having the condition, and/or prolonging survival.
• a method of treating a disease or condition encompasses a reduction of the pathological consequence of the disease or condition. The methods described herein contemplate any one or more of these aspects of treatment.
• the term“prevent,”“preventing” or“prevention” of a condition, disease, or disorder refers in one embodiment, to delay or avoidance of onset of the disease or disorder (i.e., slowing or preventing the onset of the disease or disorder in a patient susceptible to development of the disease or disorder). In some embodiments,“prevent,” “preventing” or“prevention” refers in to delaying or slowing the progression of the condition, disease, or disorder.
• subject refers to a mammalian patient in need of such treatment, such as a human.
• Exemplary diseases that may be therapeutic targets for such compounds include, but are not limited to, central neurodegenerative disorders such as Alzheimer’s Disease, Parkinson’s Disease, Huntington Disease and other central neurodegenerative disorders and peripheral degenerative disorders where there is evidence of accumulated neurotoxic proteins.
• the compounds and pharmaceutical compositions of the present disclosure specifically target the accumulation of neurotoxic proteins or their aggregated species.
• these compounds and pharmaceutical compositions can treat degenerative neurological diseases related to or caused by mis-regulation of protein homeostasis
• proteostasis e.g., such as inadequate clearance of protein aggregates and/or damaged organelles, insufficient activation of a survival pattern of gene expression, and/or deficiencies in cell energetics.
• the methods of the present disclosure target neurodegenerative diseases associated with the accumulation of neurotoxic misfolded and aggregated proteins.
• methods of treatment target Parkinson’s disease, Alzheimer’s disease, Lewy body disease, multiple system atrophy, or Huntington’s disease.
• the compounds, compositions, and methods of the present disclosure are also used to mitigate deleterious effects of impaired protein homeostasis including impairments of various forms of macro autophagy and other protein clearance mechanisms.
• dysregulation of autophagy is thought to be caused by alpha synuclein beta amyloid and other proteins that accumulate and aggregate in neurodegenerative disorders.
• Many pathologies in Parkinson’s disease including oxidative stress, mitochondrial dysfunction, and protein aggregation (such as alpha- synuclein aggregation) are linked to autophagy, which is also dysregulated in Parkinson’s disease.
• an“effective amount” means an amount or dose sufficient to generally bring about the desired therapeutic benefit in subjects needing such treatment.
• Effective amounts or doses of the compounds provided herein may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the infection, the subject’s health status, condition, and weight, and the judgment of the treating physician.
• An exemplary dose is in the range of about 1 pg to 2 mg of active agent per kilogram of subject’s body weight per day, such as about 0.05 to 100 mg/kg/day, or about 1 to 35 mg/kg/day, or about 0.1 to 10 mg/kg/day.
• the total dosage may be given in single or divided dosage units (e.g., BID, TID, QID).
• the dose may be adjusted for preventative or maintenance treatment.
• the dosage or the frequency of administration, or both may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained.
• treatment may cease.
• Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms. Patients may also require chronic treatment on a long-term basis.
• additional active ingredients are those that are known or discovered to be effective in treating neurodegenerative disorders, including those active against another target associated with the disease, such as but not limited to, a) compounds that address protein misfolding (such as drugs which reduce the production of these proteins, which increase their clearance or which alter their aggregation and/or propagation); b) compounds that treat symptoms of such disorders (e.g., dopamine replacement therapies, cholinesterase inhibitors and precognitive glutamatergic drugs); and c) drugs that act as neuroprotectants by complementary mechanisms (e.g., those targeting autophagy, those that are anti-oxidants, and those acting by other mechanisms such as adenosine A2A antagonists).
• a) compounds that address protein misfolding such as drugs which reduce the production of these proteins, which increase their clearance or which alter their aggregation and/or propagation
• compounds that treat symptoms of such disorders e.g., dopamine replacement therapies, cholinesterase inhibitors and precognitive glutamatergic drugs
• additional active ingredients are those that are known or discovered to be effective in treating neurodegenerative disorders, including those active against another target associated with the disease, such as but not limited to, a) compounds that target different mechanisms of protein misfolding (such as aggregation and/or propagation); b) compounds that treat symptoms of such disorders (e.g., dopamine replacement therapies); and c) drugs that act as neuroprotectants by complementary mechanisms (e.g., those targeting autophagy, anti-oxidants, and adenosine A2A
• compositions and formulations provided herein, as well as methods of treatment can further comprise other drugs or pharmaceuticals, e.g., other active agents useful for treating or palliative for a degenerative neurological disease related to or caused by protein aggregation, e.g., synuclein, beta-amyloid, tau, Huntingtin, or TDP43 protein aggregation, e.g., Parkinson's disease, Alzheimer's Disease (AD), Lewy body disease (LBD) and multiple system atrophy (MSA), or related symptoms or conditions.
• other drugs or pharmaceuticals e.g., other active agents useful for treating or palliative for a degenerative neurological disease related to or caused by protein aggregation, e.g., synuclein, beta-amyloid, tau, Huntingtin, or TDP43 protein aggregation, e.g., Parkinson's disease, Alzheimer's Disease (AD), Lewy body disease (LBD) and multiple system atrophy (MSA), or related symptoms or conditions.
• compositions and formulations of the generic and specific compounds described herein are useful in methods of treatment for Alzheimer’s Disease, Parkinson’s Disease, fronto temporal dementia, dementia with Lewy Bodies, PD dementia, multiple system atrophy, Huntington’s disease, Amyotrophic lateral sclerosis, cancer, infection, Crohn’s disease, heart disease, aging, or traumatic brain injury (TBI).
• the pharmaceutical compositions provided herein may additionally comprise one or more of such active agents, and methods of treatment may additionally comprise administering an effective amount of one or more of such active agents.
• the one or more additional active agents is a compound that is used to treat the symptoms or progression of a neurodegenerative disorder (e.g., Alzheimer’s Disease, Parkinson’s Disease, Huntington’s disease).
• additional active agents may be cytokines, immunoregulatory agents, anti inflammatory agents, complement activating agents, such as peptides or proteins comprising collagen-like domains or fibrinogen-like domains (e.g., a ficolin), carbohydrate -binding domains, and the like and combinations thereof.
• the additional active agent is an anti-inflammatory agent.
• Additional active agents include those useful in such compositions and methods include dopamine therapy drugs, catechol-O-methyl transferase (COMT) inhibitors, monoamine oxidase inhibitors, cognition enhancers (such as acetylcholinesterase inhibitors or memantine), adenosine 2A receptor antagonists, beta- secretase inhibitors, or gamma-secretase inhibitors.
• dopamine therapy drugs catechol-O-methyl transferase (COMT) inhibitors, monoamine oxidase inhibitors, cognition enhancers (such as acetylcholinesterase inhibitors or memantine), adenosine 2A receptor antagonists, beta- secretase inhibitors, or gamma-secretase inhibitors.
• CCT catechol-O-methyl transferase
• monoamine oxidase inhibitors such as acetylcholinesterase inhibitors or memantine
• adenosine 2A receptor antagonists such as
• At least one compound of the present embodiments may be combined in a pharmaceutical composition or a method of treatment with one or more drugs selected from the group consisting of: tacrine (Cognex), donepezil (Aricept), rivastigmine (Exelon) galantamine (Reminyl), physostigmine, neostigmine, Icopezil (CP-l 18954, 5,7-dihydro-3-[2-[l-(phenylmethyl)-4- piperidinyl]ethyl]-6H-pyrrolo-[4,5-f- ]-l,2-benzisoxazol-6-one maleate), ER-127528 (4- [(5,6-dimethoxy-2-fluoro-l-indanon)-2-yl]methyl-l-(3-fluorobenzyl)piperidine
• Such a combination may serve to increase efficacy, ameliorate other disease symptoms, decrease one or more side effects, or decrease the required dose of the compounds or compositions described herein.
• the additional active ingredients may be administered in a separate pharmaceutical composition from a compound provided herein or may be included with a compound provided herein in a single pharmaceutical composition.
• the additional active ingredients may be administered simultaneously with, prior to, or after administration of a compound of Formula (I),
• kits comprising an ion transporter inhibitor (e.g., an OAT inhibitor).
• the kits further include instructions for use, e.g. for administering an effective amount of the ion transporter inhibitor for treatment of disease or condition associated with neurodegeneration to an subject in need thereof according to a method as described herein.
• the disease or condition associated with neurodegeneration is Alzheimer’s Disease, Parkinson’s Disease, fronto-temporal dementia, dementia with Lewy Bodies, PD dementia, multiple system atrophy, Huntington’s disease, Amyotrophic lateral sclerosis, progressive supranuclear palsy, or neuroinflammation.
• kits containing a compound or composition described herein (e.g., compounds of Formula (I), (IIA), or (II), or a pharmaceutically acceptable salt thereof) and instructions for use.
• the kits may contain instructions for use in the treatment of a condition in an individual in need thereof.
• the condition is a neurodegenerative disease or condition.
• the ion transporter inhibitor can be in its free form or in the form of a stereoisomer, pharmaceutically acceptable salt, solvate, hydrate, co-crystal, polymorph, or prodrug.
• the ion transporter inhibitor can be in its free form or in the form of a stereoisomer, pharmaceutically acceptable salt, solvate, hydrate, co-crystal, or polymorph.
• the hydrate is a monohydrate form, dihydrate form, or trihydrate form.
• kits may additionally contain any materials or equipment that may be used in the administration of the compound or composition, such as vials, syringes, or IV bags.
• a kit may also contain sterile packaging.
• the embodiments are also directed to processes and intermediates useful for preparing subject compounds or a salt or solvate thereof.
• Many general references providing commonly known chemical synthetic schemes and conditions useful for synthesizing the disclosed compounds are available (see, e.g., Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, 2001.)
• Compounds as described herein can be purified by any of the means known in the art, including chromatographic means, such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reversed phases as well as ionic resins. Most typically the disclosed compounds are purified via silica gel and/or alumina chromatography. See, e.g., Introduction to Modern Liquid Chromatography, 2nd ed., ed. L. R. Snyder and J. J. Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, E. Stahl (ed.), Springer- Verlag, New York, 1969.
• HPLC high performance liquid chromatography
• Any suitable stationary phase can be used, including normal and reversed phases as well as ionic resins.
• Most typically the disclosed compounds are purified via silica gel and/or alumina chromatography. See, e.g.,
• R 1 , R 2 , and R 3 are as defined herein. Starting materials may be obtained from commercial sources or via well-established synthetic procedures.
• Scheme 3 shows the general synthesis for compounds of an embodiment of Formula (I).
• R 1 , R 2 , R 3 , R y , and R z are as defined herein.
• Example 1 In vitro ion transport assays
• Radio-labeled para-aminohippurate [3H]-PAH) was used as a substrate for measuring OAT1 and OAT3 mediated transport, where the transport of the substrate was determined by radiometric detection.
• OAT 1 -mediated transport was assayed using 2 mM of [3H]-PAH;
• OAT3-mediated transport was assayed using 10 mM of [3H]-PAH.
• the probe substrate for OAT1 was 2 pM [3H]-p-aminohippurate.
• the probe substrate for OAT3 was 10 pM [3H]p-aminohippurate.
• the reference inhibitor for both assays was 100 pM probenecid.
• [3H]- PAH was added at the concentrations described above. Wells were then treated with either reference inhibitor probeneic acid or with the test compound. Cells transfected with empty vector served as an additional control. Experiments were performed under the same conditions for the cells expressing the transporter or those treated with the control vector.
• FIG. 1 shows the dose response curve of Compound 1 in its inhibition against organic anion transporter 3 (OAT3) in the uptake of [3H]-PAH.
• FIG. 2 shows the dose response curve of Compound 1 in its inhibition against organic anion transporter 1 (OAT1) in the uptake of [3H]-PAH.
• the potency of compound 1 against OAT3 was observed to be about 20-fold lower compared with its potency against OAT1. While Compound 1 inhibited OAT3 with an IC50 value of 0.62 pM (FIG. 1), its IC50 against OAT1 was 12.9 pM (FIG. 2).
• Compound 1 was also assessed against several other ion transporter proteins, including organic anion transporter 1 (OAT1), organic cation transporter 2 (OCT2), organic anion transporting polypeptide 1B1 (OATP1B1), organic anion transporting polypeptide 1B3 (OATP1B3), multidrug and toxic compound extrusion protein-l (MATE1 /SLC47A1), multidrug and toxic compound extrusion protein 2-K (MATE-2K), breast cancer resistance protein (BCRP), p-glycoprotein (PGP), and uric acid transporter 1 (URAT1).
• OAT1 organic anion transporter 1
• OCT2 organic cation transporter 2
• OATP1B1 organic anion transporting polypeptide 1B1
• OATP1B3 organic anion transporting polypeptide 1B3
• MATE1 /SLC47A1 multidrug and toxic compound extrusion protein-l
• MATE-2K multidrug and toxic compound extrusion protein 2-K
• BCRP
• Compound 1 was studied in the concentration range of 0.1 - 100 mM for its potency against transport mediated by various transporter proteins.
• the experimental conditions for the in vitro transport assay 1 are summarized in the table below.
• Table 1A summarizes the inhibitory activity of Compound 1 against each of these ion transporter proteins in assay 1.
• Compound 1 was studied in the concentration range of 0.1 - 10 mM for its potency against transport mediated by various transporter proteins.
• the experimental conditions for the in vitro transport assay 2 are summarized in the table below.
• Table 1B summarizes the inhibitory activity of Compound 1 against each of these ion transporter proteins in assay 2.
• the effects of several other compounds were assessed against OAT3.
• the assay was carried out using a similar procedure as described above, using para-aminohippurate (PAH) and estrone-3-sulfate (E3S) as the substrates for measuring OAT3-mediated transport.
• Transport studies were conducted using cells expressing the transporter of interest (MDCK-II cells expressing human transporter OAT3) and control cells which do not express the transporter (MDCK-II transfected with a control vector (GFP)).
• MDCK-II cells were grown in 96-well cell culture plates, and the cell plates are maintained at 37° C in 5% C0 2 atmosphere prior to initiation of the transport experiment.
• MDCK-II cells were maintained in DMEM with low glucose and 10% FBS. Cells passages up to 40 are seeded at 60K+10K cells/well on 96-well, transwell membrane plates approximately 24 hours before transfection. Transport assays were carried out approximately 48 hours after transfection. Radio-labeled para- aminohippurate ([3H]-PAH) and estrone-3 -sulfate (E3S) were used as substrates for measuring OAT3-mediated transport, where the transport of the substrate was determined by radiometric detection. Probenecid was used as a reference inhibitor. Transport study samples were run in triplicate.
• V the net transporter-mediated uptake rate of the substrate by each SLC transporter
• Percent inhibition was calculated by dividing the transporter-mediated uptake rate in presence of the test article or the reference inhibitor by the transporter-mediated uptake rate in presence of vehicle control:
• Percent inhibition 100 - (100 x (transporter-mediated uptake rate) with inhibitor /
• Table 2 summarizes the inhibitory activity of these compounds against OAT3 in the uptake of probe substrate PAH (p-aminohippurate) or E3S (estrone-3-sulfate).
• the percent inhibition values were determined by testing compounds at a single concentration of 1 mM with a PAH concentration of 10 mM. Data represent the mean and standard deviation of triplicate samples.
• the IC50 values were calculated by means of a concentration response curve with a compound concentration range of 0.03 - 10 pM and a probe substrate concentration of 10 pM PAH or 0.1 pM E3S. The percent inhibition at the various concentrations was run in triplicate and the IC50 value was determined by non-linear regression using GraphPad Prism.
• Example 2 Effect of QAT3 inhibitor on levels of bioactive endogenous metabolites in brain and plasma
• FIG. 3A shows the concentration of uric acid in whole brain homogenates of mice administered (p.o.) with 50 mg/kg of compound 1.
• FIG. 3B shows the concentration of uric acid in blood plasma of mice administered (p.o.) with 50 mg/kg of compound 1.
• FIG. 4A shows the concentration of DHEAS in the brain of mice administered (p.o.) with 50 mg/kg of compound 1.
• FIG. 4B shows the concentration of DHEAS in blood plasma of mice administered (p.o.) with 50 mg/kg of compound 1.
• FIG. 5A shows the concentration of DHEA in the brain of mice administered (p.o.) with 50 mg/kg of compound 1.
• FIG. 5B shows the concentration of DHEA in blood plasma of mice administered (p.o.) with 50 mg/kg of compound 1.
• Stepl To a mixture of 4-chloro-3-(trifluoromethyl)aniline (500 g, 2.56 mol) in HC1 (750 mL) and H 2 0 (750 mL) was added a solution of NaN0 2 (194 g, 2.81 mol) in 250 mL water, dropwise while keeping the temperature below 5°C. The mixture was stirred at 0- 5°C for 30 min. A solution of ethoxycarbothioyl-sulfanyl potassium (492 g, 3.07 mol) in 1 L water was added dropwise at 0-5 °C, and the mixture was stirred at 20°C for 12 hrs. The mixture was extracted with ethyl acetate (1 L, 3 times). The organic layers were washed with brine (1 L), dried over Na 2 S0 4, and evaporated to give o-ethyl [4-chloro-3
• Sten.2 To the mixture of 4-chloro-3-(trifluoromethyl)benzenethiol (480 g, 2.26 mol) in DML (3 L) was added Cs 2 C0 3 (1.15 kg, 3.53 mol) and l-fluoro-4-nitro-benzene (300 g, 2.12 mol). The mixture was stirred at 80 °C for 3 hrs. The mixture was filtered and the solvent was added to 3 L water and extracted with ethyl acetate (1 L x 3).
• Step 3a To the mixture of A-3 (640 g, 1.93 mol) in DCM (3.5 L) was added mCPBA (822 g, 4.05 mol, 80% purity) at 20°C. The mixture was stirred at 20°C for 12 hrs. The mixture was added to a solution of Na 2 S0 3 (100 g, 0.79 mol) and Na 2 C0 3 (250 g, 2.36 mol) in 4 L H 2 0, and stirred at 20°C for 2 hrs. The mixture was filtered, and the solid was collected as the desired compound.
• mCPBA 822 g, 4.05 mol, 80% purity
• Step 4 To the mixture of A-4 (450 g, 1.23 mol) in EtOH (1.25 L) and H 2 0 (1.25 L) was added HC1 (15 mL). The mixture was heated to 70°C. Fe (140 g, 2.46 mol) was added, and the mixture was stirred at 70°C for 3 hrs. The mixture was filtered, and EtOH was evaporated. The remaining aqueous solution was extracted with DCM (0.5 L x 3), and the organic layers were evaporated to give a solid (the crude product). The solid was dissolved in DCM (1 L x 3) and filtered. The solvent was evaporated to give the desired compound. The combined A-5 (200 g, 48% yield) was obtained as an earth yellow solid.
• Step 5 To the mixture of A-5 (100 g, 298 mmol) in isopropanol (1.20 L) was added 2-bromo-l,3,4-thiadiazole (49.2 g, 298 mmol) and TsOH H 2 0 (8.50 g, 44.7 mmol). The mixture was stirred at 80°C for 4 hrs. The mixture was filtered, and the filtrate was evaporated to give a crude product. The crude product was purified by column
• Step 1 i In a 1 L round-bottom flask equipped with a mechanical stirrer and thermometer was added 60 mL of concentrated hydrochloric acid, 60 mL of water, and 4- chloro-3-(trifluoromethyl)benzene amine (19.5 g, 0.1 mol). The mixture was heated to promote dissolution and then cooled down to below 0 °C in an ice-water bath. A solution of sodium nitrite (7.6 g, 0.11 mol) in 10 mL of water was added in dropwise while the internal temperature was kept below 5 °C, and the mixture was stirred at 5 °C for 30 min.
• the mixture was then added into a mixture of potassium ethyl xanthate (19.2 g, 0.12 mol) in 30 mL of water over 2 hours.
• the organic phase in the reaction mixture was separated, and the aqueous layer was extracted twice with diethyl ether.
• the combined organic layers were washed with 30 mL of 10% sodium hydroxide solution followed by several portions of water until the aqueous phase that separated was pH neutral.
• the organic phase was dried over Na 2 S0 4 and concentrated, and the crude residue was dissolved in 95% ethanol (100 mL). The solution heated to reflux to aid dissolution.
• Sten.2 To a solution of 4-chloro-3-(trifluoromethyl)benzenethiol (19.2 g, 0.091 mol) in N,N-d ⁇ methyl formamidc (250 mL) was added l-fluoro-4-nitrobenzene (12.8 g, 0.091 mol) and Cs 2 C0 3 (59.4 g, 0.182 mol), and the reaction mixture was stirred at 80 °C under thin layer chromatography monitoring (1:30 ethyl acetate/petroleum ether). Upon the completion of the reaction, the mixture was cooled to room temperature and diluted with water (500 mL).
• Step 3b To a solution of 4-chloro-3-(trifluoromethyl)phenyl)(4- nitrophenyl)sulfane (25 g, 0.075 mol) in acetic acid (100 mL) was added 30% H 2 0 2 dropwise (20 g, 0.3 mol) at room temperature. The reaction mixture was stirred at 85 °C with thin layer chromatography monitoring (1:5 ethyl acetate/petroleum ether). Upon the completion of reaction, water was added to quench the reaction.
• Sten.4 Five drops of concentrated HC1 was added into a mixture of iron power (16 g, 0.29 mol) in water (100 mL) and ethanol (100 mL). The mixture was heated to reflux while l-chloro-4-(4-nitrophenylsulfonyl)-2-(trifluoromethyl)benzene (26.4g, 0.072 mol) was added. The reaction mixture was kept under reflux for an additional hour with thin layer chromatography monitoring (1:5 ethyl acetate/petroleum ether). Upon the completion of reaction, the hot mixture was filtered, and the filter cake was washed with ethanol.
• Step 6 Thiophosgene (6.6 g, 0.057 mol) was added into a two phase solution of 4-((4-chloro-3-(trifluoromethyl)phenyl)sulfonyl) aniline (19.2 g, 0.057 mol)in
• Step 7 Hydrazine monohydrate (5.2 g, 0.058 mol) was added into a solution of l-chloro-4-(4-isothiocyanatophenylsulfonyl)-2-(trifluoromethyl)benzene (11 g, 0.029 mol) in ethanol (60 mL) dropwise at 0 °C. After 4 hours, the reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (50 mL x 3).
• Step 8 A/-(4-((4-Chloro-3-(trifluoromethyl)phenyl)sulfonyl)
• phenyl)hydrazinecarbothioamide (8.2 g, 0.02 mol) was treated with triethoxymethane (50 mL) at 145 °C for 3 hours. Water (100 mL) was added, and the mixture was extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with brine, dried over Na 2 S0 4 , filtered and concentrated to give the crude product, which was purified by column chromatography (0 to 10% ethyl acetate/petroleum ether) to give the title compound (5.4 g, 64%) as a white solid.
• 1H NMR 300 MHz, DMSO -d 6 ) d 14.07 (s, 1H), 8.77 (s,
• FIG. 6B shows a 2D NOESY spectrum of Compound 1 in DMSO-d6 (400 MHz) as synthesized via Route B.
• FIG. 6C shows an expansion of the 2D NOESY spectrum of compound 1 in DMSO-d6 (500 mHz) as synthesized via Route B.
• the NOESY spectra show nOe coupling between the triazole thione CH and the phenyl CH, corresponding to R 1 in Formula 1.
• Step 1 A 250 mL jacketed flask was equipped with a magnetic stirrer. The flask was charged with concentrated HC1 (25 mL, 0.30 mol, 3.0 eq) and water (98.2 mL). 4- Chloro-3-(trifluoromethyl)aniline (20.0 g, 0.10 mol, 1.0 eq) was melted and added to the flask at 25°C. The mixture was heated to 50°C and stirred at 50°C for 30 min. After cooling the mixture to 0-5°C, a solution of NaN0 2 (7.6g, O.l lmol, l.leq) in 12mL water was added dropwise over 30min while maintaining a temperature between 0-5°C. After completing addition of NaN0 2 , the mixture was stirred at 0-5°C for 1 h.
• a second reaction flask was charged with potassium ethyl xanthate (20.8 g, 0.13 mol, 1.3 eq) followed by water (80 mL). After stirring for 20 minutes, toluene (80 mL) was added followed by dropwise addition of the diazonium salt from the first reaction flask at 19-23°C over 3 h. After complete addition, the mixture was stirred at 20°C for 2 h. The aqueous phase was separated from the organic phase and extracted with 20 mL toluene, three times. The organic phases were combined and washed with water (10 mL, 4 times) and then degassed by bubbling nitrogen through for 30 min.
• a third flask was charged with EtOH (63.2 g), water (10 mL) and KOH (23.0 g, 0.41 mol, 4.1 eq).
• EtOH 63.2 g
• water 10 mL
• KOH 23.0 g, 0.41 mol, 4.1 eq
• the ethanolic KOH solution was degassed by bubbling nitrogen through the mixture 30 minutes.
• the KOH solution was heated to 75-82°C under and inert nitrogen atmosphere.
• the toluene solution from the second reaction vessel was added to the degassed ethanolic KOH solution at 75-82°C over the course of 2 hours under an inert nitrogen atmosphere. After addition, the mixture was stirred at 78°C for 3.5 hours.
• the mixture was distilled to 1.5-2 V at 45 °C. Additional toluene was added (60 mL, N 2 purged) to the mixture before distilling again to 1.5-2 V at 45°C and adding toluene (20 mL, N 2 purged). Water (80 mL, N 2 purged) was added into the reaction flask and the aqueous phase was separated from the toluene. The aqueous phase was washed with 20 mL toluene 3 times. The aqueous phase was cooled to 10 °C and the pH was adjusted pH ⁇ 1 with cone. HCI (32.0 mL) at 10-15 °C. The mixture was purged with nitrogen for 20 minutes and warmed to 20 °C.
• Sten.2 To a mixture of 60.0 g of 4-chloro-3-(trifluoromethyl)benzenethiol (0.285 mol, l.Oeq.) in MeCN (1116 mL) was added Cs 2 C0 3 (195.0 g, 0.60 mol, 2.1 eq.) and l-fluoro-4-nitro-benzene (52.3 g, 0.37 mol, 1.3 eq.). The mixture was stirred at 80°C for 11 h, cooled to 25-30°C and filtered. The filter cake was rinsed with acetonitrile (120 mL x2).
• the acetonitrile solution was concentrated to 60-120 mL under reduced pressure, keeping the temperature below 45 °C.
• Dichloromethane (1116 mL) and 15% NaCl (1600 mL) were added to the solution.
• the mixture was stirred at 20-30 °C for 30 minutes and the organic layer was separated.
• the organic layer was washed with 5 wt% NaCl solution 2 more times.
• the organic layer was concentrated to 480-600 mL under reduced pressure while keeping the temperature below 45°C.
• Step 3 Additional DCM (340 mL, 20 vol.) was added to a DCM (8.5 vol.) solution of (4-chloro-3-(trifluoromethyl)phenyl)(4-nitrophenyl)sulfane (17.0 g, 50.9 mmol, 1.0 eq.) from step 2.
• the mixture was heated to 33-37°C and stirred for 0.5 h before portion wise addition of m-CPBA (31.0 g, 152.8 mmol, 3.0 eq, 85 wt%) at 33-37°C.
• m-CPBA 3.0 mmol, 3.0 eq, 85 wt
• the mixture was stirred at 33-37°C for 4 h and then cooled to 20-30°C. To the mixture, 16% wt Na 2 S0 3 aq.
• IPAc 28vol.
• IPAc 28vol.
• the solution was heated to 60°C with stirring to provide a clear solution.
• the solution was cooled to 55°C with stirring for 1-2 h.
• the solution was distilled to 3-5 vol. under reduced pressure below 55°C.
• the mixture was cooled down to 45°C for 2 h.
• MTBE 11 vol. was added to the mixture and the mixture stirred at 45°C for an additional l-2h.
• the mixture was cooled to -l0°C in 11 h and aged at - l0°C for an additional 4.5 h.
• Step 4 1 -Chloro-4-((4-nitrophenyl)sulfonyl)-2-(trifluoromethyl)benzene (20.0 g, 54.7 mmol) and IPAc (200 mL) were added to a 1.0 L high-pressure vessel.
• the vessel was purged and degassed with Ar 2 , charged with 5% Pt/C (800 mg) under N 2 protection, purged and degassed with H 2 and the mixture was stirred at 0.5 MPa (72.5 psi) H 2 atmosphere at 65 °C for 18 h. Over that period the hydrogen pressure was depleted to 0 MPa, so the vessel was recharged with H 2 to 0.5 MPa and kept at 65 °C for 14 h. The mixture was cooled, filtered through celite, washed with IPAc (50 mL x 2) and the solvent was distilled to obtain a light yellow solid (18.0 g, 98.5% crude yield).
• JL N 1 -Chloro-4-
• Step 5 i To a flask containing l,3,4-thiadiazol-2-amine (5.0 g, 49.4 mmol) at 30 °C was added 30 mL of HC1 (30 g, 36.5% aq, 300 mmol) followed by 25 mL of H 2 0. The solution was cooled to 0°C to give a suspension. CuCl (0.5 g, 4.9 mmol) was added at 0°C. A solution of NaN0 2 (3.4 g, 49.4 mmol) in H 2 0 (50 mL) was added slowly at 0°C over a period of 30 min. and the reaction mixture was stirred for 2.5 h at 0-5°C.
• Step 6 4-((4-Chloro-3-(trifluoromethyl)phenyl)sulfonyl)aniline (7.0 g, 20.9 mmol) and IPA (93 mL) was added to a reaction vessel at 30 °C to give a suspension.
• p-TSA.H20 (595 mg) was added and the reaction mixture was heated to 80-85°C.
• 2-Chloro- 1,3,4- thiadiazole (4.6 g, 38.2 mmol) in IPA (20 mL) was added at 80-85°C over a period of 5 h and the mixture was stirred for 1 h after the addition was complete. The mixture was cooled to 30°C and stood for 15 h.
• reaction mixture was concentrated to dryness.
• MTBE 50 mL was added and the mixture was stirred for 2 h at 30 °C and filtered.
• FIG. 6A shows a 2D NOESY spectrum of Compound 1 in DMSO-d6 (400 MHz) as synthesized from Route C.
• the NOESY spectrum shows nOe coupling between the triazole thione CH and the phenyl CH, corresponding to R 1 in Formula 1.
• FIG. 6E shows the HMBC of Compound 1 in DMSO-d6 (400 MHz) showing a correlation between the triazole thione CH, and the aromatic carbon connected to the triazole thione.
• Step 1 Purified water (178 kg) was charged into a reaction vessel followed by concentrated HC1 (216 kg) and 4-chloro-3-(trifluoromethyl)aniline (60.55 kg, l.Oeq). The mixture was heated to 45-55°C, stirred for 5h and then cooled -5 ⁇ 5°C. A solution of NaN0 2 (25.65 kg) in 38kg water was added drop-wise over 1-2 h at -5 ⁇ 5°C. After addition, the mixture was stirred at 0-5°C for 2 h.
• the solution (528.2 kg) and an aqueous solution of potassium O-ethyl carbonodithioate (63.5 kg potassium O-ethyl carbonodithioate and 242 kg purified water) were added at 15-25 °C simultaneously over 2-6 h into a reactor containing toluene (211.6kg, 4V) and 0.5 volumes of purified water.
• the resultant mixture was stirred at 20 °C for 5-12 h.
• the layers were separated, and the aqueous phase was extracted with toluene (1 l2kg).
• the organic layers were combined and washed with purified water 3 times.
• Ethanol (208 kg) and water (32kg) were charged into a second reaction vessel followed by KOH (7lkg).
• the mixture was heated to 75-82°C under N 2 protection.
• the toluene solution from the extraction was added at 75-82°C under N 2 protected over 5 h.
• the mixture was stirred at 78°C for 5 h.
• the mixture was then distilled to 2-4 volumes at an inner temperature not more than 45 °C and distilled again with toluene (l69kg) to remove EtOH.
• Purified water (250 kg) was charged into the vessel with stirring; the toluene phase was separated and the aqueous layer was washed with 2 volumes of toluene 2 times to give a product rich aqueous layer.
• the product was a mixture of monomer and dimer with a yield of 55.5%.
• Step 2 The mixture of D-2 and dimer (34.1 kg, 158.8 kg x 2l.5wt %, l.Oeq.) in MTBE (3 vol.) was charged into a reaction vessel. Acetonitrile (482 kg, 18.6 vol.) was added followed by Cs 2 C0 3 (157 kg, 3.0 eq.) and l-fluoro-4-nitro-benzene (29.6 kg, 1.3 eq.). The mixture was heated to 60-65 °C and stirred at that temperature for 57 h. The mixture was cooled to 20-30°C. Celite (37 kg) was added and, after stirring for 1-3 h, the mixture was filtered and washed with acetonitrile (163 kg). The acetonitrile solution was
• Step 3 i DCM (1480 kg) was charged into a reaction vessel followed by 40.4 kg of D-3. The mixture was heated to 33-37°C. MCPBA (3 x 20.6 kg) was added portion-wise at 33-37°C and stirred for 20-30 minutes between additions. After the addition was complete, the reaction was stirred for 3-5 hours at 33-37°C. After cooling to 20-30°C, 16 wt% Na 2 S0 3 aq. (344 kg) and 16% Na 2 C0 3 aq. (342 kg) were added. The mixture was stirred for 1-2 h and then extracted with DCM (342 kg).
• the organic layer was separated and washed with an aqueous solution of 7 wt% Na 2 S0 4 (134 kg) 2 times.
• the organic layer was concentrated to 3-4 vol. under reduced pressure below 35°C, while keeping the walls of the reaction vessel clean by rinsing down the sides with DCM (1 l4kg).
• MTBE (322kg) was added, and the mixture was stirred at 40-50°C for 1-2 h, cooled to 5-l0°C, and stirred at 5- l0°C for 4-6 h.
• the precipitate was filtered and washed with solvent (DCM:
• Sten.4 Pt/V/C (2.9 kg) was added to a reaction vessel containing D-4 (38.4 kg) in THF (198 kg) and MeOH (126 kg). The reaction vessel was evacuated and back-filled with nitrogen 3 times and then evacuated and back-filled with hydrogen 3 times. The temperature was adjusted to 60°C, and the reaction was stirred under H 2 (0.3-0.4MPa) for 17 hours. The reaction mixture was filtered and washed with THF (97 kg). The filtrate was concentrated to 2-3 volumes. The solvent was exchanged by methanol addition (120 kg) and concentrated to 2-3 volumes (repeated 3 times). Methanol (64 kg) was added to the reaction vessel and the temperature was adjusted to 60°C with stirring for 0.5-1 hour.
• Step 5 i To a reaction vessel containing a solution of NaHC0 3 (23.4 kg) and water (293 kg), D-5 (28.5 kg) was added followed by 361 kg of DCM. After stirring at 15- 25°C for 0.5 h, the reaction vessel was cooled to -5 ⁇ 5°C. Sequential addition of
• thiophosgene (12.3 kg, 6 kg) added dropwise with stirring at -5 ⁇ 5°C for 4 hours followed by NaHC0 3 (3.7 kg, 2.9) was repeated twice.
• a final portion of thiophosgene (6.0 kg) was added, and the reaction was stirred at -5 ⁇ 5°C for 2-10 h, warmed to 15-25 °C and stirred for an additional 1-2 h.
• the organic layer was separated and washed with water (112 kg). The organic layer was concentrated to 2-3 volumes under vacuum below 25 °C.
• DCM 185 kg
• concentration to 2-3 volumes under vacuum below 25°C was repeated 3 times with a final DCM concentration of 4-5 volumes.
• Solvent exchange was accomplished by portion- wise addition of the DCM solution of D-6 to a second reaction vessel charged with 180 kg of methylcyclohexane with stirring at 20-25 °C for 2-4 hours and concentrated to 7.5-8.5 volumes under vacuum at a temperature below 25 °C between additions.
• Methylcyclohexane (2 x 100 kg) was added to the vessel, and the mixture was concentrated to 4.0-4.5 volumes under vacuum below 35 °C twice. Additional methylcyclohexane (135 kg) was added, and the mixture was stirred at 55-65 °C for 3-4 h, cooled slowly (10-12 h) to 0-5°C and stirred for 6-10 h. The suspension was filtered, washed with 68 kg
• Step 6 To a reaction vessel charged with D-6 (30.95 kg) and DABCO (11.4 k g) was added THF (268 kg) under nitrogen. The reaction vessel was cooled to 10-20 °C and stirred for 30-60 min and before adding formohydrazide (5.6 kg) under nitrogen. The reaction was stirred at l0 ⁇ 20°C for 1.5 h, warmed to 35-45 °C, then stirred for 17 hours, and then warmed to 45 ⁇ 55°C and stirred 9 hours. The reaction was cooled to 20-40 °C and transferred to a second reaction vessel through a fine filter. The mixture was concentrated to -2 volumes while keeping the temperature below 40°C.
• Step 1 Synthesis of sodium benzenesulfinate:
• Phenyl sulfonyl chloride (3.5 g, 19.9 mmol, 1 eq.) was added to a solution of sodium sulfite (5 g, 39.8 mmol, 2 eq.) and sodium bicarbonate (3.3 g, 39.8 mmol, 2 eq.) in water (50 mL). The reaction was stirred for 2 hours at rt. The water was removed in vacuo and the residue was suspended in methanol and filtered. The residue was washed with methanol 3 more times and filtered. The methanol filtrates were combined and
• Step 2 Synthesis of 4,4,5,5-Tetramethyl-2-(4-nitrophenyl)-l,3,2-dioxaborolane:
• Step 3 Synthesis of l-nitro-4-(phenylsulfonyl)benzene
• Step 5 Synthesis of l-isothiocyanato-4-(phenylsulfonyl)benzene:
• Step 6 Synthesis of 4-(4-(phenylsulfonyl)phenyl)-2,4-dihydro-3H- 1,2,4- triazole-3-thione
• Example 7 4-(4-((4-Chloro-3-methylphenyl)sulfonyl)phenyl)-2,4-dihydro-3H- 1,2,4- triazole-3-thione (Compound 5)
• Step 1 N,N-dimethyl-3-(4-nitrophenylthio)aniline:
• Sten.2 N,N-dimethyl-3-(4-nitrophenylsulfonyl)aniline:
• N,N-dimethyl-3-(4-nitrophenylsulfonyl)aniline 400 mg, 1.3 mmol, 1 eq.
• acetic acid 10 mL
• Fe 7.28 mg, 13.0 mmol, 10 eq.
• the reaction was heated at 60 °C for 2 h.
• the mixture was cooled to rt, diluted with ethyl acetate, filtered, and the cake was washed with ethyl acetate.
• the filtrate was washed with brine.
• Step 4 3-(4-isothiocyanatophenylsulfonyl)-N,N-dimethylaniline:
• Step 5 4-(4-(3-(dimethylamino)phenylsulfonyl)phenyl)-lH- 1,2, 4-triazole- 5(4H)-thione
• Example 14 4-(4-((4-chloro-3-(trifluoromcthyl )phcnyl Isulfonyl )-2-(pipcridin- 1 -yl )phcnyl )-
• Step 1 Synthesis of l-(5-bromo-2-nitrophenyl)piperidine
• Step 2 Synthesis of l-(2-Nitro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)piperidine :
• Step 3 Synthesis of l-(5-((4-chloro-3-(trifluoromethyl)phenyl)sulfonyl)-2- nitrophenyl)piperidine
• Step 4 Synthesis of 4-(4-Chloro-3-(trifluoromethyl)phenylsulfonyl)-2- (piperidin- 1 -yl)aniline:
• Step 5 Synthesis of l-(5-(4-Chloro-3-(trifluoromethyl)phenylsulfonyl)-2- isothiocyanatophenyl)piperidine:
• Step 6 Synthesis of 4-(4-((4-chloro-3-(trifluoromethyl)phenyl)sulfonyl)-2- (piperidin-l-yl)phenyl)-2,4-dihydro-3H-l,2,4-triazole-3-thione:
• Example 17 4-(4-((4-chloro-3-(trifluoromethyl)phenyl)sulfonyl)-2-(2- ethoxyethoxy)phenyl)-2,4-dihydro-3H- 1 ,2,4-triazole-3-thione (Compound 22)
• Step 1 1 -Chloro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene:
• Step 2 4-(4-Chloro-3-(trifluoromethvl)phenoxv)aniline:
• Step 3 1 -Chloro-4-(4-isothiocyanatophenoxy)-2-(trifluoromethyl)benzene:
• Step 4 4-(4-(4-chloro-3-(trifluoromethyl)phenoxy)phenyl)-2,4-dihydro-3H- l,2,4-triazole-3-thione (Compound 30)
• Step 1 N-(4-chloro-3-(trifluoromethyl)phenyl)-4-nitrobenzenesulfonamide:
• Step 2 _4-amino-N-(4-chloro-3-(trifluoromethyl)phenyl)benzenesulfonamide:
• Step 4 N-(4-chloro-3-(trifluoromethvl)phenvl)-4-(5-thioxo-lH-l,2,4-triazol- 4(5H)-yl)benzenesulfonamide
• Step 1 Synthesis of 2-(4-nitrophenylthio)-4-(trifluoromethyl)pyridine:
• Step 2 Synthesis of 4-(4-(trifluoromethyl)pyridin-2-ylsulfonyl)aniline:
• the nitro intermediate (550 mg, 1.66 mmol, 1 eq.) was dissolved in acetic acid (15 mL) and Fe (928 mg, 16.6 mmol, 10 eq.) was added.
• the reaction was heated at 60 °C for 1 h.
• the mixture was cooled to rt, diluted with ethyl acetate, filtered, and the cake was washed with ethyl acetate.
• the volatile solvents were removed in vacuo and the water phase was neutralized to pH 7-8 with sodium bicarbonate.
• the resulting mixture was extracted with ethyl acetate for three times.
• the organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated.
• the residue was purified
• Step 3 Synthesis of 2-(4-isothiocyanatophenylsulfonyl)-4- (trifluoromethyl)pyridine:
• Step 4 Synthesis of 4-(4-((4-(trifluoromethyl)pyridin-2-yl)sulfonyl)phenyl)-2,4- dihydro-3H- 1 ,2,4-triazole-3-thione
• Step 1 5-(4-chloro-3-(trifluoromethyl)phenylthio)-2-nitropyridine:
• Step 2 5-(4-chloro-3-(trifluoromethvl)phenvlsulfonvl)pvridin-2-amine:
• Step 4 4-(5-(4-chloro-3-(trifluoromethyl)phenylsulfonyl)pyridin-2-yl)-2,4- dihydro-3H-l,2,4-triazole-3-thione (Compound 36)
• hydrazine urea intermediate HC1 salt (-200 mg).
• the hydrazine urea intermediate HC1 salt (-200 mg) was dissolved in DMF (2 mL).
• Formamidine acetate 140 mg, 1.35 mmol, 3 eq.
• acetic acid 80 mg, 1.35 mmol, 3 eq.
• the reaction was heated at 80°C for 1 h.
• the solution was cooled to rt, diluted with water, and extracted with ethyl acetate three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated.

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