WO2026025073A1 - Composés et utilisations pour traiter une tauopathie - Google Patents

Composés et utilisations pour traiter une tauopathie

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Publication number
WO2026025073A1
WO2026025073A1 PCT/US2025/039330 US2025039330W WO2026025073A1 WO 2026025073 A1 WO2026025073 A1 WO 2026025073A1 US 2025039330 W US2025039330 W US 2025039330W WO 2026025073 A1 WO2026025073 A1 WO 2026025073A1
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Prior art keywords
c4alkyl
alkyl
compound
certain embodiments
group
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PCT/US2025/039330
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English (en)
Inventor
Brandon LUCKE-WOLD
Henry J. ZECCA
Mikhail V. MAKAROV
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Taugen LLC
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Taugen LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
    • C07D239/10—Oxygen or sulfur atoms
    • 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
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/42—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/48—Acylated amino or imino radicals by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles 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 in position 2
    • C07D277/82—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • This invention provides compounds and uses to treat tauopathy and disorders related to tauopathies, including but not limited to traumatic brain injury (TBI), for example repetitive TBI (rTBI), as well as pharmaceutically acceptable salts and pharmaceutical compositions thereof.
  • TBI traumatic brain injury
  • rTBI repetitive TBI
  • the 15 invention also provides methods for the prevention, minimization or treatment of endoplasmic reticulum stress, including chronic traumatic encephalopathy (CTE) by administering an effective amount of a compound of this invention or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof to a patient in need thereof.
  • CTE chronic traumatic encephalopathy
  • BACKGROUND Tauopathy is a group of neurodegenerative diseases characterized by abnormal accumulation of tau protein in the brain. It is often characterized by the presence of hyperphosphorylated tau (P-tau) and increased total tau.
  • tauopathies include traumatic brain injury (TBI), Alzheimer’s disease and chronic traumatic encephalopathy.
  • TBI traumatic brain injury
  • ER Endoplasmic reticulum
  • ER stress plays a significant role in tauopathies.
  • ER stress can lead to increased tau protein levels and impaired degradation.
  • the ER is a cellular organelle involved in protein folding and processing. Markers of ER stress have been shown to be elevated in models of Alzheimer’s disease. These markers have been shown to co-localize, or be in the same cell, with hyperphosphorylated tau prior to the development of neurofibrillary tangles.
  • One such ER stress 30 marker is eukaryotic translation initiation factor (eIF2 ⁇ ). Phosphorylated eIF2 ⁇ reduces global 1
  • TBI is an injury that can result from impact to the head. TBI can occur, for example, after 5 a motor vehicle collision, a fall, or on the battlefield or sports field. Over 200,000 people were hospitalized for TBI in America in 2020, or more than 500 people per day (Centers for Disease Control, TBI Data in the United States).
  • a single mild TBI (mTBI, commonly referred to as a concussion) can induce a pro- inflammatory environment mediated by ER stress, oxidative stress, and neuroinflammation, which 10 are conserved mechanisms of homeostasis that dictate cell survival.
  • ER stress oxidative stress
  • neuroinflammation which 10 are conserved mechanisms of homeostasis that dictate cell survival.
  • the body For a mild injury, the body’s homeostatic mechanisms facilitate recovery, as the brain heals over several weeks following a single injury event. This is the process that normally occurs during recovery from a single sports- related injury or from a minor accident causing mTBI.
  • mTBI can lead to a post-concussion syndrome. Symptoms of post- 15 concussion syndrome include dizziness, sensitivity to light or noise, blurred vision, irritability, anxiety, depression or change in personality.
  • ER Persistent endoplasmic reticulum
  • tau oligomers 5 derived from brains exposed to single versus repetitive TBI differentially affect the expression levels of synaptic proteins crucial for synaptic transmission.
  • single versus repetitive mTBI brain-derived tau oligomers represent different polymorphisms.
  • rTBI is considered a significant risk factor for the development of neurodegenerative diseases, including chronic traumatic encephalopathy (CTE).
  • CTE can lead to progressive 10 impairments of memory and cognition, as well as depression, anxiety, and motor abnormalities. Athletes exposed to sub-concussive and concussive injury are at risk of developing CTE, as are military personnel exposed to even a single blast (Lucke-Wold, B., et al., “Linking Traumatic Brain Injury to Chronic Traumatic Encephalopathy: Identification of Potential Mechanisms Leading to Neurofibrillary Tangle Development”. J. Neurotrauma. 2014, 31, 1129-1138). Most 15 documented cases have occurred in athletes involved in striking-based combat sports, such as boxing, kickboxing, and contact sports such as American football, rugby, soccer, professional wrestling, and ice hockey.
  • NFTs tau neurofibrillary tangles
  • Tau protein is a microtubule-associated protein that helps to stabilize the structure of nerve cells. Hyperphosphorylation of tau protein can result in the development of NFTs. Tau NFTs have been associated with CTE as well as other 25 neurodegenerative diseases such as Alzheimer’s disease.
  • compositions to minimize, prevent, or treat a tauopathy including but not limited to traumatic brain injury, CTE, Alzheimer’s disease or Parkinson’s disease in a human. It is yet another object of the present invention to provide compounds, uses, methods and compositions to treat ER stress in a human in need thereof.
  • the present invention provides a compound or a pharmaceutically acceptable salt and/or a pharmaceutical composition or use thereof to treat, minimize, prevent or ameliorate a tauopathy disease or related disease characterized by endoplasmic reticulum stress, including but not limited 10 to traumatic brain injury (TBI), including repetitive traumatic brain injury (rTBI), chronic traumatic encephalopathy (CTE), Alzheimer’s Disease, or Parkinson’s Disease in a patient, typically a human, in need thereof.
  • TBI traumatic brain injury
  • rTBI repetitive traumatic brain injury
  • CTE chronic traumatic encephalopathy
  • Alzheimer’s Disease or Parkinson’s Disease in a patient, typically a human, in need thereof.
  • the invention is also directed to uses and methods of treatment or amelioration of a tauopathy or related disease such as TBI, CTE, Alzheimer’s, or Parkinson’s Disease by 15 administering an effective amount of a compound of the invention or a pharmaceutically acceptable salt, and/or a pharmaceutical composition thereof to a patient in need thereof.
  • a compound of the present invention exerts potent cell protective effects by inhibiting endoplasmic reticulum (ER) stress, for example endoplasmic reticulum stress caused by any of the disorders described above.
  • ER endoplasmic reticulum
  • 20 There are known compounds which are potent inhibitors of ER stress but many of them have poor chemical properties which limit their ability to be used in the treatment of human patients to prevent ER stress in the central nervous system.
  • salubrinal has been used in animal models to treat traumatic brain injuries but has poor solubility and metabolic stability which prevents its potential therapeutic use in human patients (see Logsdon, A.F. et al. Brain 25 Research.2016, 1643, 140-151 and Long et al. Bioorg. Med. Chem. Lett. 2005, 15, 3849-3852).
  • the present invention includes compounds that are significantly more soluble than salubrinal. As nonlimiting examples, see Example 13, Table 5.
  • the present invention also includes compounds that exhibit cell protective effects in an ER stress assay (see Example 12, Table 4) and many of these compounds are more metabolically stable than salubrinal (see Example 14, Table 6). 4
  • an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof can be used in an oral, parenteral, sublingual, buccal, intravenous, or other dosage form to treat a human with a tauopathy or TBI as described further herein.
  • an effective amount of a compound of the present invention or a 5 pharmaceutically acceptable salt thereof can be used in an intranasal spray dosage form to treat a human with a tauopathy or TBI.
  • the invention provides a compound of Formula A, Formula B, Formula C, Formula D, Formula E, or Formula F: 10 ), ); o wherein: m is 1 or 2; 15 or m is 1, 2, 3, or 4; Z 1 is O, S, N-OR 20 , or N-NHR 21 ; Z 2 is O or S; R 20 is H or -C 1 -C 4 alkyl; R 21 is H or -C1-C4alkyl; 20 is aryl, heteroaryl, cycloalkyl, or heterocyclyl each of which is optionally substituted with 1, 2, or 3 R 18 substituents; 5
  • each R 18 and each R 19 is independently selected from the group consisting of F, Cl, Br, -C 1 -C 4 alkyl, -S-C 1 -C 4 alkyl, -S(O)-C 1 -C 4 alkyl, -S(O) 2 -C 1 -C 4 alkyl, -S(O) 2 NH 2 , -C 1 -C 4 haloalkyl, -O-C1-C4alkyl, -C1-C4
  • each R 43 is independently selected from F, Cl, Br, -C 1 -C 4 alkyl, -S-C1-C4alkyl, -C1-C4haloalkyl, -O-C1-C4alkyl, -C1-C4alkyl-OH, -O-C1-C4haloalkyl, -S-C1- C4haloalkyl, -NH2, -NH(C1-C4alkyl), and -N(C1-C4alkyl)2;
  • R 33 , R 34 , R 35 , and R 36 are independently selected at each instance from the group consisting 5 of hydrogen, F, Cl, Br, -R 40 -R 41 , -C1-C4alkyl-R 40 -R 41 , -C2-C4alkenyl-R 40 -R 41 , -C2-C4alkynyl-R 40 -R 41 , -C1-C4hal
  • Non-limiting examples of compounds of the present invention include compounds of 15 Formula: , ; or
  • a compound described herein, or a pharmaceutically acceptable 20 salt thereof, optionally in a pharmaceutically acceptable carrier can be used in an effective amount to treat or ameliorate a tauopathy.
  • a compound described herein, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier can be used in an effective amount to treat or ameliorate a traumatic brain injury such as mild traumatic brain injury, chronic traumatic 25 brain injury, repetitive traumatic brain injury or recurring traumatic brain injury. 7
  • a compound described herein, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier can be used to treat, prevent, or ameliorate chronic traumatic encephalopathy (CTE).
  • CTE chronic traumatic encephalopathy
  • any of the compounds described herein, or a pharmaceutically 5 acceptable salt thereof, optionally in a pharmaceutically acceptable carrier can be used to treat, prevent or ameliorate a disease characterized by endoplasmic reticulum stress, for example CTE, Alzheimer’s disease, Parkinson’s disease, prion disease, amyotrophic lateral sclerosis (ALS), motor neuron disease (MND), frontotemporal dementia, progressive supranuclear palsy, or corticobasal degeneration. 10
  • the compound of the present invention is selected from: ), ), ), 15 8
  • Z 1 is O, S, N-OR 20 , or N-NHR 21 ;
  • Z 2 is O or S;
  • Z 3 is O, NH, or S;
  • Z 4 is O, NH, or S;
  • R 20 is H or -C1-C4alkyl;
  • R 21 is H or -C1-C4alkyl;
  • X is selected from O, S, and NR B ;
  • R B is H, C1-C4alkyl, C3-C6cycloalkyl, OH, OC1-C4alkyl, -C(O)-C1-C4alkyl, or -C(O)-OC1- C4alkyl;
  • Ring A is selected from the group consisting of aryl and heteroaryl each of which is substituted with 1, 2, or 3 R 1 substituents; or Ring A is cycloalkyl or heterocyclyl each of which is optionally substituted with 1, 2, or 3 R 1 substituents;
  • Ring H is 3-, 4-, 5-, 8-, 9-, or 10-membered cycloalkyl optionally substituted with 1, 2, or 3 R 8 substituents; or Ring H is cyclohexyl or cycloheptyl each of which is substituted with 1, 2, or 3 R 8 substituents; 5 Ring I is heteroaryl optionally substituted with 1, 2, or 3 R 9 substituents; Ring J is phenyl; or Ring J is naphthyl or indanyl each of which is optionally substituted with 1, 2, or 3 R 10 substituents; Ring K is cycloalkyl optionally substituted with 1, 2, or 3 R 11 substituents; 10 or Ring K is phenyl; Ring L is furyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,
  • each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 19 is independently selected from the group consisting of F, Cl, Br, -C1-C4alkyl, -S-C1-C4alkyl, -S(O)-C1-C4alkyl, -S(O)2-C1-C4alkyl, -S(O)2NH2, -C1-C4haloalkyl, -O-C1-C4alkyl, -C 1 -C 4 alkyl-OH, -O-C 1 -C 4 haloalkyl, -S-C 1 -C 4 haloalkyl, -COOC 1 -C 4 alkyl, -COC 1 -C 4 alkyl, 5
  • the compound of the invention is selected from the group consisting of 5 10 13
  • the invention provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a 5 pharmaceutically acceptable carrier.
  • the invention provides a method for the treatment of a tauopathy such as CTE or a TBI in a human patient comprising administering an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, to the human patient in need thereof.
  • the invention provides a compound of the present invention, or a pharmaceutically acceptable salt thereof for use in the treatment of a tauopathy such as CTE or a TBI in a human patient by administering an effective amount of the compound or a pharmaceutically acceptable salt thereof to the human patient in need thereof.
  • the invention provides a use of a compound of the present 15 invention, or a pharmaceutically acceptable salt thereof in the treatment of a tauopathy such as CTE or a TBI in a human patient by administering an effective amount of the compound or a pharmaceutically acceptable salt thereof to the human patient in need thereof.
  • the invention provides use of a compound of the present invention, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment 20 of a tauopathy such as CTE or a TBI in a human patient in need thereof.
  • the present invention thus includes at least the following features: (a) A compound of the present invention, or a pharmaceutically acceptable salt or isotopic derivative (including a deuterated derivative) thereof or a pharmaceutically acceptable composition thereof; 25 (b) A method for treating, preventing, or ameliorating the symptoms of a tauopathy disease that may be characterized by endoplasmic reticulum stress comprising administering an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt 14
  • (l) A compound of the present invention, or a pharmaceutically acceptable salt, or isotopic derivative (including a deuterated derivative) thereof for use in the treatment, prevention, or amelioration of a traumatic brain injury in a human patient in need thereof;
  • the compound for use of (l), wherein the traumatic brain injury is a mild traumatic 5 brain injury, chronic traumatic brain injury, or recurring traumatic brain injury;
  • (n) Use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in an effective amount in the treatment, prevention, or amelioration of the symptoms of a tauopathy disease which may be characterized by endoplasmic reticulum stress in a human patient in need thereof; 10
  • (o) The use of (n), wherein the disease characterized by endoplasmic reticulum stress is a neurodegenerative disorder;
  • (p) The use of (n), wherein the disease characterized by endoplasmic reticulum stress is chronic traumatic encephalopathy;
  • (q) The use of (n),
  • the compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by 5 one of skill in the art to which this invention belongs.
  • the compound may be in the form of a racemate, enantiomer, mixture of enantiomers, diastereomer, mixture of diastereomers, tautomer, N-oxide, or isomer, such as a rotamer, as if each is specifically described unless specifically excluded by context.
  • the present invention includes compounds described herein with at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched.
  • Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons. If isotopic substitutions are used, the common replacement is at least one deuterium for hydrogen.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine such as 2H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 35 S, and 36 Cl respectively.
  • isotopically labelled compounds can be used in metabolic studies (with, for example 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques, such as positron 30 emission tomography (PET) or single-photon emission computed tomography (SPECT) including 18
  • PET positron 30 emission tomography
  • SPECT single-photon emission computed tomography
  • any hydrogen atom present in the compound of the invention may be substituted with an 18 F atom, a substitution that may be particularly desirable for PET or SPECT studies.
  • Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the 5 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.
  • isotopes of hydrogen for example, deuterium ( 2 H) and tritium ( 3 H) may be used anywhere in described structures that achieves the desired result.
  • isotopes of carbon e.g., 13 C and 14 C
  • isotopes of carbon e.g., 13 C and 14 C
  • 10 Isotopic substitutions for example deuterium substitutions, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted with deuterium.
  • the isotope is 90, 95 or 99% or more enriched in an isotope at any location of interest.
  • deuterium is 90, 95 or 99% enriched at a desired location.
  • the substitution of a hydrogen atom for a deuterium atom can be 15 provided in any compound described herein.
  • the alkyl residue may be deuterated (in non-limiting embodiments, CDH 2 , CD 2 H, CD 3, CH 2 CD 3 , CD 2 CD 3 , CHDCH 2 D, CH 2 CD 3 , CHDCHD 2 , OCDH 2 , OCD 2 H, or OCD 3 etc.).
  • the unsubstituted carbons may be deuterated when two substituents are combined to form a cycle.
  • 20 at least one deuterium is placed on an atom that has a bond which is broken during metabolism of the compound in vivo, or is one, two or three atoms remote form the metabolized bond (e.g., which may be referred to as an ⁇ , ⁇ or ⁇ , or primary, secondary or tertiary isotope effect).
  • the compounds of the present invention may form a solvate with a solvent (including water). Therefore, in certain embodiments, the invention includes a solvated form of the 25 compounds described herein.
  • the term “solvate” refers to a molecular complex of a compound of the present invention (including a salt thereof) with one or more solvent molecules.
  • Non-limiting examples of solvents are water, ethanol, isopropanol, dimethyl sulfoxide, acetone, and other common organic solvents.
  • hydrate refers to a molecular complex comprising a compound of the invention and water.
  • the invention include those wherein the solvent may be isotopically substituted, e.g. D 2 O, acetone- d6, DMSO-d6.
  • a solvate can be in a liquid or solid form.
  • “Alkyl” is a branched or straight chain saturated aliphatic hydrocarbon group. In certain embodiments, the alkyl group contains from 1 to about 12 carbon atoms, more generally from 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms.
  • the alkyl contains from 1 to about 8 carbon atoms. In certain embodiments, the alkyl is C1-C2, C1-C3, C1-C4, C1-C5, 10 or C 1 -C 6.
  • the specified ranges as used herein indicate an alkyl group having each member of the range described as an independent species.
  • the term C 1 -C 6 alkyl as used herein indicates a straight or branched alkyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species.
  • C 1 -C 4 alkyl indicates a straight or branched alkyl group having from 1, 2, 3, or 4 15 carbon atoms and is intended to mean that each of these is described as an independent species.
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane.
  • Alkenyl is a straight chain aliphatic hydrocarbon group having one or more carbon- 20 carbon double bonds each of which is independently either cis or trans that may occur at a stable point along the chain.
  • the double bond in a long chain similar to a fatty acid has the stereochemistry as commonly found in nature.
  • a non-limiting example includes C2- C4alkenyl (i.e., having 2, 3, or 4 carbons).
  • the specified ranges as used herein indicate an alkenyl group having each member of the range described as an independent species, as described above25 for the alkyl moiety.
  • alkenyl examples include, but are not limited to, ethenyl, 1-propenyl, 2- propenyl, 1-butenyl, 2-butenyl, and 3-butenyl.
  • Alkenyls can be further substituted with alkyl to make branched alkenyls.
  • alkenyl is a C 2 -C 4 alkenyl.
  • alkenyl has two carbons.
  • alkenyl has three carbons.
  • alkenyl has four carbons.
  • Non-limiting examples of “alkenyl” include:30 ethenyl, propenyl, and butenyl. Additional non-limiting examples of “alkenyl” include: 1- 20
  • alkenyl examples include: 1-butenyl, 2- butenyl, and 3-butenyl.
  • Alkynyl is a straight chain aliphatic hydrocarbon group having one or more carbon- carbon triple bonds that may occur at any stable point along the chain, for example, C 2 -C 4 alkynyl 5 (i.e., having 2, 3, or 4 carbons).
  • the specified ranges as used herein indicate an alkynyl group having each member of the range described as an independent species, as described above for the alkyl moiety.
  • Alkynyls can be further substituted with alkyl to make branched alkynyls.
  • alkynyl examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl.
  • alkynyl is a C2-C4alkynyl.
  • 10 “alkynyl” has two carbons.
  • alkynyl has three carbons.
  • alkynyl has four carbons.
  • Non-limiting examples of “alkynyl” include: ethynyl, propynyl, and butynyl.
  • alkynyl examples include: 1-propynyl, and 2- propynyl. Additional non-limiting examples of “alkynyl” include: 1-butynyl, 2-butynyl, and 3- butynyl. 15 “Halo” and “Halogen” is independently fluorine, chlorine, bromine, or iodine. In principal embodiments the term halogen as used herein refers to fluorine or chlorine. “Haloalkyl” is a branched or straight-chain alkyl groups substituted with 1 or more halo atoms described above, up to the maximum allowable number of halogen atoms.
  • haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 20 chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • Perhaloalkyl means an alkyl group having all hydrogen atoms replaced with halogen atoms. Examples include, but are not limited to, trifluoromethyl and pentafluoroethyl.
  • aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or 25 tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6–14 aryl”).
  • an aryl group has 6 ring carbon atoms (“C 6 aryl”; e.g., phenyl).
  • an aryl group has 10 ring carbon atoms (“C 10 aryl”; e.g., naphthyl such as 1- naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C14 30 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, 21
  • the one or more fused cycloalkyl or heterocyclyl groups can be a 4- to 7-membered saturated or partially unsaturated cycloalkyl or 5 heterocyclyl groups.
  • heterocyclyl denotes saturated and partially saturated heteroatom-containing ring radicals, wherein there are 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, boron, silicone, and oxygen.
  • Heterocyclic rings may comprise monocyclic 3-10 membered rings, as well as 5-16 membered bicyclic ring systems (which can include bridged, fused, and 10 spiro-fused bicyclic ring systems). It does not include rings containing -O-O-, -O-S- or -S-S- portions.
  • saturated heterocyclyl groups include saturated 3- to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms (e.g.
  • pyrrolidinyl imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl
  • saturated 3- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms e.g. morpholinyl
  • saturated 3- to 6- 15 membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms e.g., thiazolidinyl
  • partially saturated heterocyclyl radicals include but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl.
  • Examples of partially saturated and saturated heterocyclyl groups include but are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, 20 tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2- dihydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl, 2,3,4,4a,9,9a- hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinoly
  • Heterocyclyl also includes groups wherein the heterocyclic radical is fused/condensed with an aryl or carbocycle radical, wherein the point of attachment is the heterocyclyl ring. “Heterocyclyl” also includes groups wherein the heterocyclic radical is substituted with an oxo group (i.e. For example, a partially unsaturated condensed heterocyclic group containing 30 1 to 5 nitro ms, for example, indoline or isoindoline; a partially unsaturated condensed 22
  • heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms; a partially unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms; and a saturated condensed heterocyclic group containing 1 to 2 oxygen or sulfur atoms.
  • heterocyclyl also includes “bicyclic heterocyclyl”.
  • bicyclic 5 heterocyclyl denotes a heterocyclyl as defined herein wherein there is one bridged, fused, or spirocyclic portion of the heterocyclyl.
  • heterocyclyl includes bicyclic heterocyclyls.
  • Bicyclic heterocyclyl includes groups wherein the fused heterocyclyl is substituted with an oxo group.
  • Non- 10 limiting examples of bicyclic heterocyclyls include: d term “heteroaryl” denotes stable aromatic ring systems that contain 1, 2, 3, or 4 heteroatoms independently selected from O, N, and S, wherein the ring nitrogen and sulfur atom(s) are optionally oxidized, and nitrogen atom(s) are optionally quarternized.
  • Examples include but 15 are not limited to, unsaturated 5- to 6-membered heteromonocyclyl groups containing 1 to 4 nitrogen atoms, such as pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl); unsaturated 5- to 6-membered heteromonocyclic groups containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5- to 6-membered heteromonocyclic groups containing 20 a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms
  • cycloalkyl includes a saturated or partially unsaturated (i.e., not aromatic) group containing all carbon ring atoms and from 3 to 5 14 ring carbon atoms (“C3–14 cycloalkyl”) and zero heteroatoms in the non-aromatic ring system.
  • a cycloalkyl group has 3 to 10 ring carbon atoms (“C3–10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 9 ring carbon atoms (“C 3–9 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3–8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 7 ring carbon atoms (“C3–7 cycloalkyl”). In some 10 embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C 3–6 cycloalkyl”).
  • a cycloalkyl group has 4 to 6 ring carbon atoms (“C 4–6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5–6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5–10 cycloalkyl”).
  • Exemplary C 3–6 cycloalkyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), 15 cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like.
  • Exemplary C3–8 cycloalkyl groups include, without limitation, the aforementioned C 3–6 cycloalkyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C8), and the like.
  • Exemplary C3–10 cycloalkyl groups include, without limitation, the 20 aforementioned C 3–8 cycloalkyl groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), and the like.
  • the cycloalkyl group can be saturated or can contain one or more carbon–carbon double bonds.
  • cycloalkyl also includes ring systems wherein the cycloalkyl ring, as defined above, is fused with one heterocyclyl, aryl or heteroaryl ring wherein the point of 25 attachment is on the cycloalkyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
  • cycloalkyl also includes ring systems wherein the cycloalkyl ring, as defined above, has a spirocyclic heterocyclyl, aryl or heteroaryl ring wherein the point of attachment is on the cycloalkyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic 30 ring system.
  • cycloalkyl also includes bicyclic or polycyclic fused, bridged, or spiro 24
  • ring systems that contain from 5 to 14 carbon atoms and zero heteroatoms in the non-aromatic ring system.
  • Representative examples of “cycloalkyl” include, but are not limited to , , , and . cle” refers to a ring system wherein two rings are fused together, and each 5 ring is independently selected from carbocycle, heterocyclyl, aryl, and heteroaryl.
  • Non-limiting examples of bicycle groups include: d ts 10 can be on separate rings or on the same ring. In certain embodiments both attachment points are on the same ring. In certain embodiments both attachment points are on different rings.
  • Non- limiting examples of bivalent bicycle groups include: .
  • s of dosage 15 forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, particles, spheres, creams, ointments, suppositories, inhalable forms, transdermal forms, buccal, sublingual, topical, gel, mucosal, and the like.
  • a “dosage form” can also include an implant, for example an optical implant.
  • Parental” administration of a compound includes, e.g., subcutaneous (s.c.), intravenous 20 (i.v.), intramuscular (i.m.), or intrasternal injection, or infusion techniques.
  • compositions is a composition comprising at least one active agent such as a selected active compound as described herein, and at least one other substance, such as a carrier.
  • active agent such as a selected active compound as described herein
  • other substance such as a carrier
  • a “pharmaceutically acceptable salt” is a derivative of the disclosed 5 compound in which the parent compound is modified by making inorganic and organic, acid or base addition salts thereof with a biologically acceptable lack of toxicity.
  • the salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods.
  • salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or 10 K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid.
  • a stoichiometric amount of the appropriate base such as Na, Ca, Mg, or 10 K hydroxide, carbonate, bicarbonate, or the like
  • Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
  • non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical, where practicable.
  • Salts of the present compounds further include solvates of the compounds and of the compound 15 salts.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, 20 from non-toxic inorganic or organic acids.
  • conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic,25 fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH2)q- COOH where q is 0-4, and the like, or using a different acid that produces the same counterion.
  • inorganic acids such as hydrochloric, hydrobromic, sulfur
  • carrier means a diluent, excipient, or vehicle that an active agent is used or 30 delivered in. 26
  • salubrinal offers neuroprotection through suppressing endoplasmic 15 reticulum stress, autophagy and apoptosis in a mouse TBI model (Zu-Feng Wang et al. Neurobiol. Learn. Mem. 2019, vol. 161, pp. 12-25).
  • salubrinal has reduced neuroinflammation, impulsive-like behavior, and memory deficits (Logsdon, A. et al. Brain Res. 2016, 1643, 140-151; and Rubovitch, V. et al. Neuromolecular Med. 2015 17(1), 58-70).
  • Salubrinal has been proposed as a treatment for CTE (see e.g. U.S. Patent Application No.
  • the disclosed invention provides new compounds for the treatment 5 of TBI, rTBI, CTE and other manifestations of traumatic brain injury.
  • the present invention provides a compound or the present invention, pharmaceutically acceptable salts and pharmaceutical compositions thereof, to treat, prevent or ameliorate the symptoms of a disease characterized by endoplasmic reticulum stress, for example a tauopathy.
  • the present invention provides a compound, or a pharmaceutically acceptable salt or pharmaceutical compositions thereof, to treat ameliorate the symptoms of TBI 15 (including mild traumatic brain injury, chronic traumatic brain injury, or recurring traumatic brain injury).
  • the present invention uses a compound of the present invention, pharmaceutically acceptable salts and pharmaceutical compositions thereof, to treat, prevent, or ameliorate the symptoms of chronic traumatic encephalopathy.
  • the invention provides a compound of Formula (I): (I); or a pharmaceutic y , wherein: is selected from the group consisting of aryl and heteroaryl each of which is 25 substituted wt 1, 2, or 3 R 1 substituents; 28
  • each R 1 is independently selected from the group consisting of F, Cl, Br, -C 1 -C 4 alkyl, -S-C1-C4alkyl, -S(O)-C1-C4alkyl, -S(O)2-C1-C4alkyl, -S(O)2NH2, -C1-C4haloalkyl, -O-C1-C4alkyl, -C1-C4alkyl-OH, -O-C1-C4haloalkyl, -S-C1-C4haloalkyl, -COOC1-C4al
  • the compound of Formula (I) is selected from the group consisting of 10 30
  • the compound of Formula (I) is selected from the group consisting of 5 , , ; o In certain embodiments, the compound of Formula (I) is selected from the group consisting 10 of , , , 31
  • the compound of Formula (I) is selected from the group consisting of , 10 ; 32
  • the compound of Formula (I) is selected from the group consisting of , 5 , ; or in certain embodiments, the compound of Formula (I) is selected from the group consisting of 10 , , 33
  • the compound of Formula (I) is selected from the group consisting of , , 10 , 34
  • the compound of Formula (I) is selected from the group consisting 5 of , , ; 10 or a 35
  • the compound of Formula (I) is selected from the group consisting of , , 5 ; o In certain embodiments, the compound of Formula (I) is selected from the group consisting of 10 , , 36
  • the compound of Formula (I) is selected from the group consisting of 5 , , , , 10 , 37
  • the compound of Formula (I) is selected from the group consisting of 10 38
  • the compound of Formula (I) is selected from the group consisting 5 of , , , 10 or . 39
  • the compound of Formula (I) is selected from the group consisting of , 5 , , , 40
  • the compound of Formula (I) is selected from the group consisting 5 of , 10 , 41
  • the compound of Formula (I) is selected from the group consisting of , 10 42
  • the compound of Formula (I) is selected from the group consisting of , 10 , 43
  • the compound of Formula (I) is selected from the group consisting of 5 10 or a In certain embodiments, the invention provides a compound of Formula (II): ; or a pharmaceutica , 44
  • compound of Formula (II) is selected from the group consisting 5 of 10 , , 46
  • the compound of Formula (II) is selected from the group consisting of 10 o In certain embodiments, compound of Formula (II) is selected from the group consisting of , 47
  • compound of Formula (II) is selected from the group consisting of , 10 , 51
  • the compound of Formula (II) is pharmaceutically acceptable salt thereof.
  • 5 ound of Formula II is selected from , pharmaceutically acceptable salt thereof.
  • 10 nd of Formula II is selected from , 54
  • tion provides a compound of Formula (III): 5 ; or a pharmaceutica wherein: is aryl or heteroaryl each of which is optionally substituted with 1, 2, or 3 R 5 substituents; 10 is naphthyl, 8-, 9-, or 10-membered heteroaryl each of which is substituted with 1, 2, or 3 tituents; o is indanyl optionally substituted with 1, 2, or 3 R 6 substituents; e ndependently selected from the group consisting of F, Cl, Br, -C 1 -C 4 alkyl, -S-C1-C4alkyl, -S(O)-C1-C4alkyl, -S(O)2-C1-C4alkyl, -S(O)2NH2, -C1-C4haloalkyl, -O-C1-C4alkyl, 15 -C1-C4alkyl-OH, -O-C1-
  • each R 6 is independently selected from the group consisting of F, Cl, Br, -C1-C4alkyl, -S-C1-C4alkyl, -S(O)-C1-C4alkyl, -S(O)2-C1-C4alkyl, -S(O)2NH2, -C1-C4haloalkyl, -O-C1-C4alkyl, -C 1 -C 4 alkyl-OH, -O-C 1 -C 4 haloalkyl, -S-C
  • the compound of Formula (III) is pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (III) is selected from the group 5 consisting of 10 , 59
  • the compound of Formula (III) is selected from the group 5 consisting of o 10 is or a pharmaceutically acceptable salt thereof. 60
  • the compound of Formula (III) is selected from the group consisting of 5 or
  • the invention provides a compound of Formula (IV): ; or a pharmaceutica 10 wherein: is aryl or heteroaryl each of which is optionally substituted with 1, 2, or 3 R 7 substitue is 3-, 4-, 5-, 8-, 9-, or 10-membered cycloalkyl optionally substituted with 1, 2, or 3 R 8 s u s uents; 15 or is cyclohexyl or cycloheptyl each of which is substituted with 1, 2, or 3 R 8 substituents; 61
  • each R 7 is independently selected from the group consisting of F, Cl, Br, -C 1 -C 4 alkyl, -S-C1-C4alkyl, -S(O)-C1-C4alkyl, -S(O)2-C1-C4alkyl, -S(O)2NH2, -C1-C4haloalkyl, -O-C1-C4alkyl, -C1-C4alkyl-OH, -O-C1-C4haloalkyl, -S-C1-C4haloalkyl, -COOC1-C4alkyl, -COC1-C4alkyl, -NHC(O)C 1 -C 4 alkyl, -NHC(O)-O-C 1 -C 4 alkyl, -C(O)NH(C 1 -C 4 alkyl), -C(O)NH(C 1 -C 4 alkyl-OH), 5
  • the compound of Formula (IV) is selected from the group consisting of 10 63
  • the compound of Formula (IV) is selected from the group consisting of ; 5 or a phar
  • the invention provides a compound of Formula (V): ; or a pharmaceutical 10 wherein: is heteroaryl optionally substituted with 1, 2, or 3 R 9 substituents; or is naphthyl or indanyl each of which is optionally substituted with 1, 2, or 3 R 10 substitue 15 each R 9 is independently selected from the group consisting of F, Cl, Br, -C 1 -C 4 alkyl, -S-C1-C4alkyl, -S(O)-C1-C4alkyl, -S(O)2-C1-C4alkyl, -S(O)2NH2, -C1-C4haloalkyl, -O-C1-C4alkyl, -C1-C4alkyl-OH, -O-C1-C4haloalkyl, -S
  • each R 10 is independently selected from the group consisting of F, Cl, Br, -C 1 -C 4 alkyl, -S-C1-C4alkyl, -S(O)-C1-C4alkyl, -S(O)2-C1-C4alkyl, -S(O)2NH2, -C1-C4haloalkyl, -O-C1-C4alkyl, -C1-C4alkyl-OH, -O-C1-C4haloalkyl, -S-C1-C4haloalkyl, -COOC1-C4alkyl, -COC1-C4alkyl, -NHC(O)C 1 -C 4 alkyl, -NHC(O)-O-C 1 -C 4 alkyl, -C(O)NH(C 1 -C 4 alkyl), -C(O)NH(C 1 -C 4 alkyl-OH), 5
  • the compound of Formula (V) is selected from the group 5 consisting of ; or 10 In certain embodiments, the compound of Formula (V) is selected from the group consisting of or a phar 66
  • the invention provides a compound of Formula (VI): ; or a pharmaceutica wherein: 5 is cycloalkyl optionally substituted with 1, 2, or 3 R 11 substituents; or is phenyl; is furyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, or cycloalkyl each of which is optionally substituted with 1, 2, or 3 R 12 substituents; 10 or is pyridyl, 8-, 9-, or 10-membered heteroaryl each of which is substituted with 1, 2, or 3 R 12 substituents; each R 11 is independently selected from the group consisting of F, Cl, Br, -C 1 -C 4 alkyl, -S-C1-C4alkyl, -S(O)-
  • the compound of Formula (VI) is selected from the group consisting of 10 , 68
  • the compound of Formula (VI) is selected from the group consisting of 5 or a In certain embodiments, the compound of Formula (VI) is selected from the group consisting of 10 o 71
  • the invention provides a compound of Formula (VII): ; or a pharmaceutica wherein: 5 is phenyl; naphthyl; or indanyl; is 4-, 6-, 7-, 8-, 9-, 10-, or 11-membered heterocyclyl optionally substituted with 1, 2, or 3 R 14 substituents; each R 14 is independently selected from the group consisting of F, Cl, Br, -C 1 -C 4 alkyl, -S-C1-C4alkyl, -S(O)-C1-C4alkyl, -S(O)2-C1-C4alkyl, -S(O)2NH2, -C1-C4haloalkyl, -O-C1-C4alkyl, 10 -C1-C4alkyl-OH, -O-C1-C4haloalkyl, -S-C1-C4haloalkyl, -COOC1-C4alky
  • the compound of Formula (VII) is selected from the group 5 consisting of ; or a p In certain embodiments, the compound of Formula (VII) is selected from the group 10 consisting of ; or In certain embodiments, the compound of Formula (VII) is 15 pharmaceutically acceptable salt thereof.
  • the invention provides a compound of Formula (VIII): (VIII); or a pharmaceu 5 wherein: is phenyl substituted with 1, 2, or 3 R 15 substituents; or is naphthyl, heteroaryl, cycloalkyl or heterocyclyl each of which is optionally substituted with 1, 2, or 3 R 15 substituents; is aryl, heteroaryl, cycloalkyl, or heterocyclyl each of which is optionally 10 substituted with 1, 2, or 3 R 16 substituents; each R 15 is independently selected from the group consisting of F, Cl, Br, -C 1 -C 4 alkyl, -S-C1-C4alkyl, -S(O)-C1-C4alkyl, -S(O)2-C1-C4alkyl, -S(O)2NH2, -C1-C4haloalkyl, -O-C1-C4alkyl, -C1-C4alkyl-
  • the compound of Formula (VIII) is selected from the group consisting of , 10 ; o In certain embodiments, the compound of Formula (VIII) is selected from the group consisting of , 15 , 75
  • the compound of Formula (VIII) is selected from the group consisting of 5 , , , 10 ; or 76
  • the compound of Formula (VIII) is selected from the group consisting of 5 ; o up consisting of 10 , , 77
  • the compound of Formula (VIII) is selected from the group consisting of 5 , , 10 , 78
  • the compound of Formula (VIII) is selected from the group consisting of 5 ; 10 or In certain embodiments, the compound of Formula (VIII) is selected from the group consisting of , 80
  • the compound of Formula (VIII) is selected from the group consisting of , 10 , 81
  • the compound of Formula (VIII) is selected from the group 5 consisting of , , 10 , 82
  • the compound of Formula (VIII) is selected from the group consisting of , 10 , 83
  • the compound of Formula (VIII) is pharmaceutically acceptable salt thereof.
  • ompound of Formula (VIII) is selected from the group consisting of , 10 , , 84
  • the compound of Formula (VIII) is selected from the group consisting of , , 10 , 85
  • the compound of Formula (VIII) is selected from the group consisting of 10 , 86
  • the compound of Formula (VIII) is selected from the group consisting of , 5 , d or a p y p . In certain embodiments, the compound of Formula (VIII) is selected from the group 10 consisting of , 88
  • the compound of Formula (VIII) is selected from the group consisting of , d 89
  • the compound of Formula (VIII) is selected from the group consisting of , , 5 a p In additional embodiments, the compound of Formula (VIII) is selected from the group consisting of 10 90
  • the compound of Formula (VIII) is selected from the group 5 consisting of 10 or a 92
  • the compound of Formula (VIII) is selected from the group consisting of 5 o In additional embodiments, the compound of Formula (VIII) is selected from the group 10 c , 93
  • d . 5 pharmaceutically acceptable salt thereof. endently selected from the group consisting 10 of F, Cl, Br, -C1-C4alkyl, -S-C1-C4alkyl, aryl, heteroaryl, -S(O)-C1-C4alkyl, -S(O)2-C1-C4alkyl, -S(O) 2 NH 2 , -C 1 -C 4 haloalkyl, -O-C 1 -C 4 alkyl, -C 1 -C 4 alkyl-OH, -O-C 1 -C 4 haloalkyl, -S-C 1 - C4haloalkyl, -COOC1-C4alkyl, -COC1-C4alkyl, -NHC(O)C1-C4alkyl, -NHC(O)-O-C1-C4alkyl, 94
  • R 116 is independently selected at each instance from F, Cl, Br, OH, C1-C6alkoxy, O(C1-C6alkyl), S(C1-C6alkyl), O(C1-C3haloalkyl), S(C1-C3haloalkyl), -NH2, -NH(C1-C4alkyl), and -N(C 1 -C 4 alkyl) 2 .
  • the compound of Formula (VIII) is pharmaceutically acceptable salt thereof.
  • the invention provides a compound of Formula (IX): (IX); or a pharmaceuti wherein: 15 is pyrimidinyl, pyrazinyl, pyridazinyl, 5-, 8-, 9- or 10-membered heteroaryl each of which i tionally substituted with 1, 2, or 3 R 17 substituents; or is pyridyl substituted with 1, 2, or 3 R 17 substituents; each s independently selected from the group consisting of F, Cl, Br, -C1-C4alkyl, -S-C 1 -C 4 alkyl, -S(O)-C 1 -C 4 alkyl, -S(O) 2 -C 1 -C 4 alkyl, -S(O) 2 NH 2 , -C 1 -C 4 haloalkyl, -O-C 1 -C 4 alkyl, 20 -C1-C4alkyl-OH, -O-C
  • the compound of Formula (IX) is selected from the group consisting of 5 , 10 96
  • the compound of Formula (IX) is selected from the group consisting of 5 d o In certain embodiments, the compound of Formula (IX) is selected from the group 10 consisting of d 97
  • the invention provides a compound of Formula (X): (X); or a pharmaceutically acceptable salt thereof, 5 wherein: is a single or double bond; Z 3 is O, NH, or S; is aryl, heteroaryl, cycloalkyl, or heterocyclyl each of which is optionally substituted with 1, 2, or 3 R 18 substituents; 10 is aryl, heteroaryl, cycloalkyl, or heterocyclyl each of which is optionally substituted with 1, 2, or 3 R 19 substituents; each R 18 is independently selected from the group consisting of F, Cl, Br, -C1-C4alkyl, -S-C 1 -C 4 alkyl, -S(O)-C 1 -C 4 alkyl, -S(O) 2 -C 1 -C 4 alkyl, -S(O) 2 NH 2 , -C 1 -C 4 haloalkyl, -O-C 1
  • the compound of Formula (X) is selected from the group consisting of , 10 99
  • the compound of Formula (X) is selected from the group consisting of 5 , ; or the group consisting of 10 , , , 100
  • the compound of Formula (X) is selected from the group consisting of 102
  • the invention provides a compound selected from the group 5 consisting of a compound of Formula (XIa), (XIb), (XIc), (XId), (XIe), (XIf) and (XIg): ), ), d 10 or wherein: is a single or double bond; m is 1 or 2; or m is 1, 2, 3, or 4; 15 Z 3 is O, NH, or S; 103
  • Z 4 is O, NH, or S; is aryl, heteroaryl, cycloalkyl, or heterocyclyl each of which is optionally substituted with 1, 2, or 3 R 18 substituents; is aryl, heteroaryl, cycloalkyl, or heterocyclyl each of which is optionally 5 substituted with 1, 2, or 3 R 19 substituents; each R 18 is independently selected from the group consisting of F, Cl, Br, -C 1 -C 4 alkyl, -S-C1-C4alkyl, -S(O)-C1-C4alkyl, -S(O)2-C1-C4alkyl, -S(O)2NH2, -C1-C4haloalkyl, -O-C1-C4alkyl, -C1-C4alkyl-OH, -O-C1-C4haloalkyl, -S-C1-C4haloalkyl, -COOC1-C4al
  • a (XIa) is selected from the group consisting of , 10 , , 106
  • m is 2. In certain embodiments, m is 1. I n certain embodiments, 2, 10 or 3 R 19 substituents. In certain embodiments, 2, or 3 R 19 substituents. 107
  • t (XIa) is selected from the group consisting of pharmaceutically acceptable salt thereof.
  • d of Formula (XIa) is: 10 pharmaceutically acceptable salt thereof.
  • d of Formula (XIa) is selected from the group consisting of pharmaceutically acceptable salt thereof.
  • the compound of Formula (XIa) is: pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (XIa) is selected from 5 a 10 p wherein mm is selected from 0, 1, 2, and 3. 110
  • the compound of Formula (XIa) is selected from 5 a p
  • mm is 0.
  • mm is 1.
  • mm is 2.
  • mm is 3.
  • the compound of Formula (XIa) is selected from the group consisting of ; or a pharmaceutically acceptable salt thereof, w 5 In certain embodiments, nn is 0. In certain embodiments, nn is 1. In certain embodiments, nn is 2. In certain embodiments, nn is 3. In certain embodiments, the compound of Formula (XIa) is selected from the group 10 consisting of ; or a pharmaceutically acceptable salt thereof, w In certain embodiments, the compound of Formula (XIa) is selected from the group consisting of 15 112
  • the compound of Formula (XIa) is selected from the group consisting of 114
  • the compound of Formula (XIa) is selected from the group consisting of 115
  • the compound of Formula (XIa) is selected from the group consisting of 5 a pharmaceutically a In certain embodiments, the compound of Formula (XIa) is selected from the group consisting of 10 r a pharmaceutically a . 116
  • the compound of Formula (XIa) is selected from the group consisting of 5 r a p In certain embodiments, the compound of Formula (XIa) is selected from the group 10 consisting of 117
  • the compound of Formula (XIa) is selected from the group 5 consisting of y 10 a In certain embodiments, the compound of Formula (XIa) is selected from the group consisting of 118
  • the compound of Formula (XIa) is selected from the group 5 consisting of 10 o In certain embodiments, the compound of Formula (XIa) is selected from the group consisting of 119
  • the compound of Formula (XIa) is selected from the group 5 consisting of a 10 p 120
  • the compound of Formula (XIa) is selected from the group consisting of 5 a p In certain embodiments, the compound of Formula (XIa) is selected from the group consisting of 10 , 121
  • the compound of Formula (XIa) is selected from the group 5 consisting of , , 10 , 122
  • the compound of Formula (XIa) is selected from the group consisting of 10 123
  • the compound of Formula (XIa) is selected from the group consisting of 5 d o In certain embodiments, the compound of Formula (XIa) is selected from the group 10 consisting of d 124
  • the compound of Formula (XIa) is selected from the group consisting of 5 a f. group 10 consisting of: , 125
  • a compound of the present invention is selected from the group consisting of: , 126
  • a compound of the present invention is selected from the group consisting of: , 10 , 127
  • a compound of the present invention is selected from the group consisting of: 5 ; 10 or a pharmaceutically acceptable salt thereof. 128
  • a compound of the present invention is selected from the group consisting of: ; or 5 In certain embodiments, the compound of Formula (XIa) is selected from the group consisting of 10 129
  • the compound of Formula (XIa) is selected from the group 5 consisting of 10 131
  • the compound of Formula (XIa) is selected from the group consisting of a 5 p In certain embodiments, the compound of Formula (XIa) is selected from the group consisting of 10 132
  • the compound of Formula (XIa) is selected from the group consisting of 5 ; In certain embodiments, the compound of Formula (XIa) is selected from the group consisting of 10 ; In certain embodiments, the compound of Formula (XIa) is selected from the group consisting of , 134
  • the compound of Formula (XIa) is selected from the group consisting of r a 5 In certain embodiments, the compound of Formula (XIa) is selected from the group consisting of 10 or a p In certain embodiments, the compound of Formula (XIa) is pharmaceutically acceptable salt thereof. 136
  • the compound of Formula (XIa) is selected from the group consisting of 5 ; or a p In certain embodiments, the compound of Formula (XIa) is selected from the group consisting of 10 d or a . 137
  • the compound of Formula (XIa) is selected from the group consisting of d 5 or a In certain embodiments, the compound of Formula (XIa) is selected from the group consisting of d 10 or a p In certain embodiments, the compound of Formula (XIa) is selected from the group consisting of 138
  • the compound of Formula (XIa) is selected from the group consisting of ; 10 o 139
  • the compound of Formula (XIa) is selected from the group consisting of d 5 or a In certain embodiments, the compound of Formula (XIa) is selected from the group consisting of 10 d o r a parmaceu ca y accepa e sa ereo. 140
  • the compound of Formula (XIa) is selected from the group consisting of d 5 o In certain embodiments, the compound of Formula (XIa) is selected from the group consisting of 10 o 141
  • the compound of Formula (XIa) is selected from the group consisting of 5 ; o In certain embodiments, the compound of Formula (XIa) is selected from the group consisting of 10 d o . 142
  • the compound of Formula (XIa) is selected from the group consisting of d 5 o In certain embodiments, the compound of Formula (XIa) is selected from the group consisting of d 10 o 143
  • the compound of Formula (XIa) is selected from the group consisting of ; 5 o In certain embodiments, the compound of Formula (XIa) is selected from the group consisting of 10 d 144
  • the compound of Formula (XIa) is selected from the group consisting of 5 ; o In certain embodiments, the compound of Formula (XIa) is selected from the group consisting of 10 d or a . 145
  • the compound of Formula (XIa) is selected from the group consisting of d 5 or a In certain embodiments, the compound of Formula (XIa) is selected from the group consisting of 10 o 146
  • the compound of Formula (XIb) is selected from the group consisting of , , 5 , , 147
  • the compound of Formula (XIc) is selected from the group consisting of 5 , , , or 10 In certain embodiments, the compound of Formula (XId) is selected from the group consisting of , 148
  • the compound of Formula (XIe) is selected from the group consisting of , , 149
  • the compound of Formula (XIf) is selected from the group consisting of , 10 or a p y p . 150
  • the compound of Formula (XIg) is selected from the group consisting of , , 5 or a
  • the invention provides to a compound of Formula (XII): ; or a pharmaceutically accep 10 wherein all variables are as defined herein.
  • the compound of Formula (XII) is selected from the group consisting of , 151
  • the compound of Formula (XII) is selected from the group consisting of ; or a phar 5 In certain embodiments, the compound of Formula (XII) is selected from the group consisting of ; or a pharm In certain embodiments, the invention provides to a compound of Formula (XIII): 10 ; or a pharmaceutically acce wherein all variables are as defined herein. In certain embodiments, the compound of Formula (XIII) is selected from the group consisting of 15 , 153
  • the compound of Formula (XIII) is selected from the group consisting of ; or a phar 5 In certain embodiments, the compound of Formula (XIII) is selected from the group consisting of ; o In certain embodiments, the invention is directed to a compound of Formula (XIV): 10 ; or a pharmaceutically acce wherein n is 0, 1, or 2; X is selected from O, S, and NR B ; 15 R B is H, C 1- C 4 alkyl, C 3- C 6 cycloalkyl, OH, O C 1- C 4 alkyl, -C(O)- C 1- C 4 alkyl, or -C(O)-O C 1- C4alkyl; and all other variables are as defined herein. In certain embodiments, the compound of Formula (XIV) is selected from the group consisting of , 155
  • the compound of Formula (XIV) is selected from the group consisting of . 10 In V): ; or a pharmaceutically acce wherein all variables are as defined herein. 156
  • the compound of Formula (XV) is selected from the group consisting of ; or a phar 5 In certain embodiments, the compound of Formula (XV) is selected from the group consisting of or a 10 In certain embodiments, the invention provides a compound of Formula (XVI): ; or a pharmaceutically accep wherein Ring T and Ring U are as defined herein. In certain embodiments, the compound of Formula (XVI) is 15 pharmaceutically acceptable salt thereof. 157
  • the invention provides a compound of Formula (XVII): ; or a pharmaceutically acc wherein Ring T an d Ring U are as defined herein. 5
  • the invention provides a compound of Formula (XVIII): ; or a pharmaceutically acce wherein Ring G, Z 1 , Z 2 , and X are as defined herein.
  • the compound of Formula (XVIII) is selected from 10 d pharmaceutically acceptable salt thereof.
  • invention provides a compound of Formula (XIX): 15 ; 158
  • the compound of Formula (XIX) is selected from 5 a p
  • the invention provides a compound of Formula (XX): (XX), or a pharmaceutically acceptable salt thereof; 10 wherein R C is C1-C6alkyl optionally substituted by 1, 2, or 3 groups independently selected at each instance from F, Cl, Br, -OH, -S-C 1 -C 4 alkyl, -S(O) 2 NH 2 , -C 1 -C 4 haloalkyl, -O-C 1 -C 4 alkyl, -C 1 - C 4 alkyl-OH, -O-C 1 -C 4 haloalkyl, -S-C 1 -C 4 haloalkyl, -NH 2 , -NH(C 1 -C 4 alkyl), -NH(C 1 -C 4 haloalkyl, -NH 2 , -NH(C 1 -C 4 alkyl), -NH(C 1 -C
  • the invention provides a compound of Formula (XXI): 5 ; or a pharmaceutically acce wherein Ring T and Ring U are as defined herein.
  • the compound of Formula (XXI) is pharmaceutically acceptable salt thereof.
  • 10 I of the invention is a compound of Formula (XXII): , or a pharmaceutically acc wherein W is S, O, or NR 32 ; 15 is aryl, heteroaryl, cycloalkyl, or heterocyclyl each of which is optionally substitute wt 1, 2, or 3 R 18 substituents; and all other variables and substituents are as defined herein. 160
  • W is S. In certain embodiments, W is O. In certain embodiments, W is NR 32 . In certain embodiments, W is NH. 5 In certain embodiments, W is N(C1-C4alkyl). In certain embodiments, W is N(C1-C4haloalkyl). In certain embodiments, the compound of Formula (XXII) is selected from the group consisting of 10 161
  • the compound of Formula (XXII) is selected from the group 5 consisting of f. 162
  • the compound of Formula (XXII) is selected from the group consisting of 5 o
  • the invention provides a compound selected from the group consisting of a compound of Formula (XXIII): 10 d 163
  • R 33 , R 34 , R 35 , and R 36 are independently selected at each instance from the group consisting of hydrogen, F, Cl, Br, -R 40 -R 41 , -C1-C4alkyl-R 40 -R 41 , -C2-C4alkenyl-R 40 -R 41 , -C 2 -C 4 alkynyl- R 40 -R 41 , -C 1 -C 4 haloalkyl- R 40 -R 41 , -R 40 -C 1 -C 4 alkyl-OR 41 , 5 -R 40 -C1-C4alkyl-N(R 41 )2, -CN, and -NO2;
  • R 40 is independently selected from bond, -O-, -S-, -S(O)-, -S(O)2-, -NR 42 -, -C(O)O-, -C(O)NR 42 -, and -C(O)-; and
  • the compound of Formula (XXIII) is selected from the group consisting of ; 5 o In certain embodiments, the compound of Formula (XXIII) is selected from the group consisting of ; 10 o In certain embodiments, the compound of Formula (XXIII) is selected from the group consisting of 165
  • the compound of Formula (XXIII) is selected from the group consisting of ; o 10 In certain embodiments, the compound of Formula (XXIII) is selected from the group consisting of 166
  • the compound of Formula (XXIII) is selected from the group consisting of 5 ; 167
  • the compound of Formula (XXIII) is selected from the group consisting of ; 5 o In certain embodiments, the compound of Formula (XXIII) is selected from the group consisting of ; 10 or 168
  • the compound of Formula (XXIII) is selected from the group consisting of 5 ; In certain embodiments, the compound of Formula (XXIII) is selected from the group consisting of 10 ; 169
  • the compound of Formula (XXIII) is selected from the group consisting of 5 ; o up consisting of 10 170
  • the compound of Formula (XXIII) is selected from the group consisting of 5 In certain embodiments, the compound of Formula (XXIII) is selected from the group consisting of 10 ; or a phar . 171
  • the compound of Formula (XXIII) is selected from the group consisting of 5 ; In certain embodiments, the compound of Formula (XXIII) is selected from the group consisting of 10 r a p 172
  • the compound of the present invention is of Formula ; o 5
  • the compound of Formula (XXIII) is selected from the group consisting of r a p
  • the compound of Formula (XXIII) is selected from the group 10 consisting of 173
  • alkyl is a C1-C6alkyl, C1-C5alkyl, C1-C4alkyl, C1-C3alkyl, or C1- C2alkyl. In certain embodiments “alkyl” has one carbon. 10 In certain embodiments “alkyl” has two carbons. In certain embodiments “alkyl” has three carbons. In certain embodiments “alkyl” has four carbons. In certain embodiments “alkyl” has five carbons. In certain embodiments “alkyl” has six carbons.
  • Non-limiting examples of “alkyl” include methyl, ethyl, propyl, butyl, pentyl, and hexyl. Additional non-limiting examples of “alkyl” include isopropyl, isobutyl, isopentyl, and isohexyl. Additional non-limiting examples of “alkyl” include sec-butyl, sec-pentyl, and sec-hexyl. 20 Additional non-limiting examples of “alkyl” include tert-butyl, tert-pentyl, and tert-hexyl. Additional non-limiting examples of “alkyl” include: neopentyl, 3-pentyl, and active pentyl. 174
  • haloalkyl In principal embodiments the term haloalkyl as used herein refers to a fluorinated, chlorinated, or fluorinated/chlorinated alkyl moiety.
  • haloalkyl is a C 1 -C 6 haloalkyl, C 1 -C 5 haloalkyl, C 1 -C 4 haloalkyl, 5 C1-C3haloalkyl, and C1-C2haloalkyl.
  • haloalkyl has one carbon.
  • haloalkyl has one carbon and one halogen.
  • haloalkyl has one carbon and two halogens.
  • haloalkyl has one carbon and three halogens. 10 In certain embodiments “haloalkyl” has two carbons. In certain embodiments “haloalkyl” has three carbons. In certain embodiments “haloalkyl” has four carbons. In certain embodiments “haloalkyl” has five carbons. In certain embodiments “haloalkyl” has six carbons. 15 Non-limiting examples of “haloalkyl” include: , , and . “ ” , 20 Embodiments of “aryl” In certain embodiments “aryl” is a 6-carbon aromatic group (phenyl). In certain embodiments “aryl” is a 10-carbon aromatic group (naphthyl). 175
  • aryl is a 6-carbon aromatic group fused to a heterocyclyl wherein the point of attachment is the aryl ring.
  • aryl include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran wherein the point of attachment for each group is on the aromatic ring.
  • 5 For exam le is an “ar l” rou . H p. I aromatic group fused to a cycloalkyl wherein the point of attachment is the aryl ring.
  • Non-limiting examples of “aryl” include dihydro-indene and tetrahydronaphthalene wherein the point of attachment for each group is on the aromatic ring.
  • heteroaryl is a 5-membered aromatic group containing 1, 2, 3, 15 or 4 nitrogen atoms.
  • Non-limiting examples of 5-membered “heteroaryl” groups include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, isoxazole, oxazole, oxadiazole, oxatriazole, isothiazole, thiazole, thiadiazole, and thiatriazole. Additional non-limiting examples of 5-membered “heteroaryl” groups include: 20 , , 176
  • ni trogen atoms i.e. pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl.
  • 6-membered “heteroaryl” groups with 1 or 2 nitrogen atoms 5 include: nd g 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.
  • Non-limiting examples of “heteroaryl” groups that are bicyclic include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzoisoxazole, benzoisothiazole, benzooxazole, and benzothiazole.
  • Additional non-limiting examples of “heteroaryl” groups that are bicyclic include: . 15 e: . ic include: . c group containing 20 1 or 2 atoms selected from nitrogen, oxygen, and sulfur. 177
  • heteroaryl groups that are bicyclic include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine. Additional non-limiting examples of “heteroaryl” groups that are bicyclic include: .
  • cycloalkyl is a C3-C8cycloalkyl, C3-C7cycloalkyl, C3- C6cycloalkyl, C3-C5cycloalkyl, C3-C4cycloalkyl, C4-C8cycloalkyl, C5-C8cycloalkyl, or C6- C 8 cycloalkyl.
  • cycloalkyl has three carbons. In certain embodiments “cycloalkyl” has four carbons. In certain embodiments “cycloalkyl” has five carbons. In certain embodiments “cycloalkyl” has six carbons.
  • cycloalkyl has seven carbons. 15 In certain embodiments “cycloalkyl” has eight carbons. In certain embodiments “cycloalkyl” has nine carbons. In certain embodiments “cycloalkyl” has ten carbons.
  • Non-limiting examples of “cycloalkyl” include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl. 20 Additional non-limiting examples of “cycloalkyl” include dihydro-indene and tetrahydronaphthalene wherein the point of attachment for each group is on the cycloalkyl ring. For example, group. However, group. 178
  • cycloalkyl groups include d Embodiments of “heterocyclyl” 5
  • heterocyclyl refers to a cyclic ring with one nitrogen atom and 3, 4, 5, 6, 7, or 8 carbon atoms.
  • heterocyclyl refers to a cyclic ring with one nitrogen atom and one oxygen atom and 3, 4, 5, 6, 7, or 8 carbon atoms.
  • heterocyclyl refers to a cyclic ring with two nitrogen atoms and 10 3, 4, 5, 6, 7, or 8 carbon atoms.
  • heterocyclyl refers to a cyclic ring with one oxygen atom and 3, 4, 5, 6, 7, or 8 carbon atoms. In certain embodiments “heterocyclyl” refers to a cyclic ring with one sulfur atom and 3, 4, 5, 6, 7, or 8 carbon atoms. 15 Non-limiting examples of “heterocyclyl” include aziridine, oxirane, thiirane, azetidine, 1,3-diazetidine, oxetane, and thietane. Additional non-limiting examples of “heterocyclyl” include pyrrolidine, 3-pyrroline, 2- pyrroline, pyrazolidine, and imidazolidine.
  • heterocyclyl examples include tetrahydrofuran, 1,3- 20 dioxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3-oxathiolane. Additional non-limiting examples of “heterocyclyl” include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiane, 1,3-dithiane, 1,4-dithiane, morpholine, and thiomorpholine.
  • heterocyclyl examples include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran wherein the point of attachment for each group is 25 on the heterocyclic ring.
  • group. Non-limitin cyclyl also include: . 5 . . 10
  • mples of “heterocyclyl” also include: . nclude: . 180
  • heterocyclyl examples include: . E mbodiments of Ring A 5 In certain embodiments, is selected from the group consisting of: 10 , 181
  • , , 5 In certain embodiments, is selected from the group consisting of: , , 185
  • Embodiments of Ring C is selected from the group consisting of: 5 , 187
  • Embodiments of Ring D In certain embodiments, is selected from the group consisting of: , 5 Embodiments of Ring E 10 In certain embodiments, is selected from the group consisting of: , 190
  • Embodiments of Ring F 5 , Embodiments of Ring G 10 is selected from the group consisting of: , 193
  • Embodiments of Ring H , 5 Embodiments of Ring I is selected from the group consisting of: 10 , , 196
  • Embodiments of Ring K is selected from the group consisting of: , 197
  • Ring L is selected from the group consisting of: , 10 198
  • Embodiments of Ring N is selected from the group consisting of: , 5 Embodiments of Ring O In certain embodiments, is selected from the group consisting of: 10 , , , 199
  • , 5 is selected from the group consisting of: , 10 , , 201
  • Embodiments of Ring Q is selected from the group consisting of: 10 , , 207
  • . 5 E is selected from the group consisting of: , 10 , 210
  • Embodiments of Ring U is selected from the group consisting of: , , 10 , , 213
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 19 are independently selected at each occurrence from the group consisting of F, Cl, Br, -R 30 -R 31 , -C1-C4alkyl-R 30 -R 31 , -C2-C4alkenyl-R 30 -R 31 , -C2-C4alkynyl-R 30 -R 31 , 10 -C 1 -C 4 haloalkyl-R 30 -R 31 , -R 30 -C 1 -C 4 alkyl-OR 31 , -R 30 -C 1 -C 4 alkyl-OR 31 , -R 30 -C 1 -C 4 alkyl-OR 31 , -R 30 -C 1
  • -R 30 -R 31 is selected from -OR 31 , -N(R 31 )(R 32 ), -C(O)OR 31 , -R 30 -C 1 -C 4 alkyl, and -R 30 -C 1 -C 4 haloalkyl.
  • -R 30 -R 31 is selected from aryl, heteroaryl, cycloalkyl, heterocycle, -O-aryl, -O-heteroaryl, -O-cycloalkyl, -O-heterocycle, -NH-aryl, -NH-heteroaryl, -NH-cycloalkyl, 20 and -NH-heterocycle.
  • -R 30 -C1-C4alkyl-OR 31 is selected from -O-CH2CH2-OH, -O-CH2CH2-O(C1-C4alkyl), -NH-CH2CH2-OH, -NH-CH2CH2-O(C1-C4alkyl), 216
  • -R 30 -C1-C4alkyl-N(R 31 )2 is selected from -O-CH2CH2-NH2, -O-CH 2 CH 2 -N(C 1- C 4 alkyl) 2 , and -O-CH 2 CH 2 -NH(C 1- C 4 alkyl).
  • R 31 is hydrogen. In certain embodiments R 31 is C1-C4alkyl.
  • R 31 is C 2 -C 4 alkenyl. In certain embodiments R 31 is C 2 -C 4 alkynyl. In certain embodiments R 31 is C1-C4haloalkyl. 10 In certain embodiments R 31 is aryl. In certain embodiments R 31 is heteroaryl. In certain embodiments R 31 is cycloalkyl. In certain embodiments R 31 is heterocycle. In certain embodiments R 31 is an amino acid moiety. 15 In certain embodiments R 32 is hydrogen. In certain embodiments R 32 is C1-C4alkyl. In certain embodiments R 32 is C 2 -C 4 alkenyl. In certain embodiments R 32 is C 2 -C 4 alkynyl.
  • R 32 is C1-C4haloalkyl. 20 In certain embodiments R 32 is aryl. In certain embodiments R 32 is heteroaryl. In certain embodiments R 32 is cycloalkyl. In certain embodiments R 32 is heterocycle. In certain embodiments R 32 is an amino acid moiety. 25 Embodiments of R 1 In certain embodiments, R 1 is C 1 -C 4 alkyl. In certain embodiments, R 1 is methyl. In certain embodiments, R 1 is ethyl. 217
  • R 1 is propyl. In certain embodiments, R 1 is isopropyl. In certain embodiments, R 1 is -SMe. In certain embodiments, R 1 is -SEt. 5 In certain embodiments, R 1 is -S(O)Me. In certain embodiments, R 1 is -S(O)Et. In certain embodiments, R 1 is -S(O) 2 Me. In certain embodiments, R 1 is -S(O)2Et. In certain embodiments, R 1 is -CF3. 10 In certain embodiments, R 1 is -OMe. In certain embodiments, R 1 is -OEt. In certain embodiments, R 1 is -CH2OH. In certain embodiments, R 1 is -CH2CH2OH.
  • R 1 is -C(O)OMe. 15 In certain embodiments, R 1 is -C(O)OEt. In certain embodiments, R 1 is -C(O)Me. In certain embodiments, R 1 is -C(O)Et. In certain embodiments, R 1 is -NHC(O)Et. In certain embodiments, R 1 is -NHC(O)Me. 20 In certain embodiments, R 1 is -NHC(O)OEt. In certain embodiments, R 1 is -NHC(O)OMe. In certain embodiments, R 1 is -C(O)NHMe. In certain embodiments, R 1 is -C(O)NHEt. In certain embodiments, R 1 is -NH 2 .
  • R 1 is -NHMe. In certain embodiments, R 1 is -NHEt. In certain embodiments, R 1 is -NHCH 2 CH 2 NH 2 . In certain embodiments, R 1 is -NMe 2 . In certain embodiments, R 1 is -NEt2. 30 In certain embodiments, R 1 is -OCF3. 218
  • R 2 In certain embodiments, R 2 is C1-C4alkyl. 10 In certain embodiments, R 2 is methyl. In certain embodiments, R 2 is ethyl. In certain embodiments, R 2 is propyl. In certain embodiments, R 2 is is isopropyl. In certain embodiments, R 2 is -SMe.
  • R 2 is -SEt. In certain embodiments, R 2 is -S(O)Me. In certain embodiments, R 2 is -S(O)Et. In certain embodiments, R 2 is -S(O) 2 Me. In certain embodiments, R 2 is -S(O)2Et. 20 In certain embodiments, R 2 is -CF 3 . In certain embodiments, R 2 is -OMe. In certain embodiments, R 2 is -OEt. In certain embodiments, R 2 is -CH2OH. In certain embodiments, R 2 is -CH 2 CH 2 OH. 25 In certain embodiments, R 2 is -C(O)OMe. In certain embodiments, R 2 is -C(O)OEt.
  • R 2 is -C(O)Me. In certain embodiments, R 2 is -C(O)Et. In certain embodiments, R 2 is -NHC(O)Et. 30 In certain embodiments, R 2 is -NHC(O)Me. 219
  • R 2 is -NHC(O)OEt. In certain embodiments, R 2 is -NHC(O)OMe. In certain embodiments, R 2 is -C(O)NHMe. In certain embodiments, R 2 is -C(O)NHEt. 5 In certain embodiments, R 2 is -NH2. In certain embodiments, R 2 is -NHMe. In certain embodiments, R 2 is -NHEt. In certain embodiments, R 2 is -NHCH2CH2NH2. In certain embodiments, R 2 is -NMe2. 10 In certain embodiments, R 2 is -NEt 2 . In certain embodiments, R 2 is -OCF 3 . In certain embodiments, R 2 is -SCF3.
  • R 3 20 In certain embodiments, R 3 is C 1 -C 4 alkyl. In certain embodiments, R 3 is methyl. In certain embodiments, R 3 is ethyl. In certain embodiments, R 3 is propyl. In certain embodiments, R 3 is isopropyl. 25 In certain embodiments, R 3 is -SMe. In certain embodiments, R 3 is -SEt.
  • R 3 is -S(O)Me. In certain embodiments, R 3 is -S(O)Et. In certain embodiments, R 3 is -S(O)2Me. 30 In certain embodiments, R 3 is -S(O)2Et. 220
  • R 3 is -CF 3 . In certain embodiments, R 3 is -OMe. In certain embodiments, R 3 is -OEt. In certain embodiments, R 3 is -CH 2 OH. 5 In certain embodiments, R 3 is -CH2CH2OH. In certain embodiments, R 3 is -C(O)OMe. In certain embodiments, R 3 is -C(O)OEt. In certain embodiments, R 3 is -C(O)Me. In certain embodiments, R 3 is -C(O)Et. 10 In certain embodiments, R 3 is -NHC(O)Et. In certain embodiments, R 3 is -NHC(O)Me.
  • R 3 is -NHC(O)OEt. In certain embodiments, R 3 is -NHC(O)OMe. In certain embodiments, R 3 is -C(O)NHMe. 15 In certain embodiments, R 3 is -C(O)NHEt. In certain embodiments, R 3 is -NH2. In certain embodiments, R 3 is -NHMe. In certain embodiments, R 3 is -NHEt. In certain embodiments, R 3 is -NHCH2CH2NH2. 20 In certain embodiments, R 3 is -NMe 2 . In certain embodiments, R 3 is -NEt 2 . In certain embodiments, R 3 is -OCF3. In certain embodiments, R 3 is -SCF3.
  • R 4 is C1-C4alkyl. In certain embodiments, R 4 is methyl. In certain embodiments, R 4 is ethyl. 5 In certain embodiments, R 4 is propyl. In certain embodiments, R 4 is isopropyl. In certain embodiments, R 4 is -SMe. In certain embodiments, R 4 is -SEt. In certain embodiments, R 4 is -S(O)Me. 10 In certain embodiments, R 4 is -S(O)Et. In certain embodiments, R 4 is -S(O) 2 Me. In certain embodiments, R 4 is -S(O)2Et. In certain embodiments, R 4 is -CF3.
  • R 4 is -OMe. 15 In certain embodiments, R 4 is -OEt. In certain embodiments, R 4 is -CH2OH. In certain embodiments, R 4 is -CH 2 CH 2 OH. In certain embodiments, R 4 is -C(O)OMe. In certain embodiments, R 4 is -C(O)OEt. 20 In certain embodiments, R 4 is -C(O)Me. In certain embodiments, R 4 is -C(O)Et. In certain embodiments, R 4 is -NHC(O)Et. In certain embodiments, R 4 is -NHC(O)Me. In certain embodiments, R 4 is -NHC(O)OEt.
  • R 4 is -NHC(O)OMe. In certain embodiments, R 4 is -C(O)NHMe. In certain embodiments, R 4 is -C(O)NHEt. In certain embodiments, R 4 is -NH 2 . In certain embodiments, R 4 is -NHMe. 30 In certain embodiments, R 4 is -NHEt. 222
  • R 5 is ethyl. In certain embodiments, R 5 is propyl. In certain embodiments, R 5 is isopropyl. In certain embodiments, R 5 is -SMe. In certain embodiments, R 5 is -SEt. 20 In certain embodiments, R 5 is -S(O)Me. In certain embodiments, R 5 is -S(O)Et. In certain embodiments, R 5 is -S(O)2Me. In certain embodiments, R 5 is -S(O)2Et. In certain embodiments, R 5 is -CF 3 . 25 In certain embodiments, R 5 is -OMe. In certain embodiments, R 5 is -OEt.
  • R 5 is -CH 2 OH. In certain embodiments, R 5 is -CH 2 CH 2 OH. In certain embodiments, R 5 is -C(O)OMe. 30 In certain embodiments, R 5 is -C(O)OEt. 223
  • R 5 is -C(O)Me. In certain embodiments, R 5 is -C(O)Et. In certain embodiments, R 5 is -NHC(O)Et. In certain embodiments, R 5 is -NHC(O)Me. 5 In certain embodiments, R 5 is -NHC(O)OEt. In certain embodiments, R 5 is -NHC(O)OMe. In certain embodiments, R 5 is -C(O)NHMe. In certain embodiments, R 5 is -C(O)NHEt. In certain embodiments, R 5 is -NH2. 10 In certain embodiments, R 5 is -NHMe. In certain embodiments, R 5 is -NHEt.
  • R 6 is ethyl. In certain embodiments, R 6 is propyl. In certain embodiments, R 6 is isopropyl. In certain embodiments, R 6 is -SMe. 30 In certain embodiments, R 6 is -SEt. 224
  • R 6 is -S(O)Me. In certain embodiments, R 6 is -S(O)Et. In certain embodiments, R 6 is -S(O)2Me. In certain embodiments, R 6 is -S(O) 2 Et. 5 In certain embodiments, R 6 is -CF3. In certain embodiments, R 6 is -OMe. In certain embodiments, R 6 is -OEt. In certain embodiments, R 6 is -CH2OH. In certain embodiments, R 6 is -CH2CH2OH. 10 In certain embodiments, R 6 is -C(O)OMe. In certain embodiments, R 6 is -C(O)OEt. In certain embodiments, R 6 is -C(O)Me.
  • R 6 is -C(O)Et. In certain embodiments, R 6 is -NHC(O)Et. 15 In certain embodiments, R 6 is -NHC(O)Me. In certain embodiments, R 6 is -NHC(O)OEt. In certain embodiments, R 6 is -NHC(O)OMe. In certain embodiments, R 6 is -C(O)NHMe. In certain embodiments, R 6 is -C(O)NHEt. 20 In certain embodiments, R 6 is -NH 2 . In certain embodiments, R 6 is -NHMe. In certain embodiments, R 6 is -NHEt. In certain embodiments, R 6 is -NHCH2CH2NH2.
  • R 6 is -NMe 2 . 25 In certain embodiments, R 6 is -NEt2. In certain embodiments, R 6 is -OCF3. In certain embodiments, R 6 is -SCF 3 . In certain embodiments, R 6 is -OCH 2 CF 3 . In certain embodiments, R 6 is -OCF2CF3. 30 In certain embodiments, R 6 is -OCH(CF3)2. 225
  • R 7 is C1-C4alkyl. In certain embodiments, R 7 is methyl. 5 In certain embodiments, R 7 is ethyl. In certain embodiments, R 7 is propyl. In certain embodiments, R 7 is isopropyl. In certain embodiments, R 7 is -SMe. In certain embodiments, R 7 is -SEt. 10 In certain embodiments, R 7 is -S(O)Me. In certain embodiments, R 7 is -S(O)Et. In certain embodiments, R 7 is -S(O)2Me. In certain embodiments, R 7 is -S(O)2Et. In certain embodiments, R 7 is -CF 3 .
  • R 7 is -OMe. In certain embodiments, R 7 is -OEt. In certain embodiments, R 7 is -CH 2 OH. In certain embodiments, R 7 is -CH 2 CH 2 OH. In certain embodiments, R 7 is -C(O)OMe. 20 In certain embodiments, R 7 is -C(O)OEt. In certain embodiments, R 7 is -C(O)Me. In certain embodiments, R 7 is -C(O)Et. In certain embodiments, R 7 is -NHC(O)Et. In certain embodiments, R 7 is -NHC(O)Me. 25 In certain embodiments, R 7 is -NHC(O)OEt.
  • R 7 is -NHC(O)OMe. In certain embodiments, R 7 is -C(O)NHMe. In certain embodiments, R 7 is -C(O)NHEt. In certain embodiments, R 7 is -NH2. 30 In certain embodiments, R 7 is -NHMe. 226
  • R 8 is methyl. In certain embodiments, R 8 is ethyl. In certain embodiments, R 8 is propyl. In certain embodiments, R 8 is isopropyl. In certain embodiments, R 8 is -SMe. 20 In certain embodiments, R 8 is -SEt. In certain embodiments, R 8 is -S(O)Me. In certain embodiments, R 8 is -S(O)Et. In certain embodiments, R 8 is -S(O)2Me. In certain embodiments, R 8 is -S(O) 2 Et. 25 In certain embodiments, R 8 is -CF3. In certain embodiments, R 8 is -OMe. In certain embodiments, R 8 is -OEt. In certain embodiments, R 8 is -CH 2 OH. In certain embodiments, R 8 is -CH2CH2OH. 30 In certain embodiments, R 8 is -C(O)OMe. 227
  • R 8 is -C(O)OEt. In certain embodiments, R 8 is -C(O)Me. In certain embodiments, R 8 is -C(O)Et. In certain embodiments, R 8 is -NHC(O)Et. 5 In certain embodiments, R 8 is -NHC(O)Me. In certain embodiments, R 8 is -NHC(O)OEt. In certain embodiments, R 8 is -NHC(O)OMe. In certain embodiments, R 8 is -C(O)NHMe. In certain embodiments, R 8 is -C(O)NHEt. 10 In certain embodiments, R 8 is -NH 2 . In certain embodiments, R 8 is -NHMe.
  • R 9 is C1-C4alkyl. In certain embodiments, R 9 is methyl. In certain embodiments, R 9 is ethyl. In certain embodiments, R 9 is propyl. In certain embodiments, R 9 is isopropyl. 30 In certain embodiments, R 9 is -SMe. 228
  • R 9 is -SEt. In certain embodiments, R 9 is -S(O)Me. In certain embodiments, R 9 is -S(O)Et. In certain embodiments, R 9 is -S(O) 2 Me. 5 In certain embodiments, R 9 is -S(O)2Et. In certain embodiments, R 9 is -CF3. In certain embodiments, R 9 is -OMe. In certain embodiments, R 9 is -OEt. In certain embodiments, R 9 is -CH2OH. 10 In certain embodiments, R 9 is -CH 2 CH 2 OH. In certain embodiments, R 9 is -C(O)OMe. In certain embodiments, R 9 is -C(O)OEt.
  • R 9 is -C(O)Me. In certain embodiments, R 9 is -C(O)Et. 15 In certain embodiments, R 9 is -NHC(O)Et. In certain embodiments, R 9 is -NHC(O)Me. In certain embodiments, R 9 is -NHC(O)OEt. In certain embodiments, R 9 is -NHC(O)OMe. In certain embodiments, R 9 is -C(O)NHMe. 20 In certain embodiments, R 9 is -C(O)NHEt. In certain embodiments, R 9 is -NH 2 . In certain embodiments, R 9 is -NHMe. In certain embodiments, R 9 is -NHEt.
  • R 9 is -NHCH 2 CH 2 NH 2 . 25 In certain embodiments, R 9 is -NMe2. In certain embodiments, R 9 is -NEt2. In certain embodiments, R 9 is -OCF 3 . In certain embodiments, R 9 is -SCF 3 . In certain embodiments, R 9 is -OCH2CF3. 30 In certain embodiments, R 9 is -OCF2CF3. 229
  • R 9 is -OCH(CF 3 ) 2 .
  • R 10 is C 1 -C 4 alkyl. 5 In certain embodiments, R 10 is methyl. In certain embodiments, R 10 is ethyl. In certain embodiments, R 10 is propyl. In certain embodiments, R 10 is isopropyl. In certain embodiments, R 10 is -SMe. 10 In certain embodiments, R 10 is -SEt. In certain embodiments, R 10 is -S(O)Me. In certain embodiments, R 10 is -S(O)Et. In certain embodiments, R 10 is -S(O)2Me.
  • R 10 is -S(O) 2 Et. 15 In certain embodiments, R 10 is -CF3. In certain embodiments, R 10 is -OMe. In certain embodiments, R 10 is -OEt. In certain embodiments, R 10 is -CH 2 OH. In certain embodiments, R 10 is -CH2CH2OH. 20 In certain embodiments, R 10 is -C(O)OMe. In certain embodiments, R 10 is -C(O)OEt. In certain embodiments, R 10 is -C(O)Me. In certain embodiments, R 10 is -C(O)Et. In certain embodiments, R 10 is -NHC(O)Et.
  • R 10 is -NHC(O)Me. In certain embodiments, R 10 is -NHC(O)OEt. In certain embodiments, R 10 is -NHC(O)OMe. In certain embodiments, R 10 is -C(O)NHMe. In certain embodiments, R 10 is -C(O)NHEt. 30 In certain embodiments, R 10 is -NH2. 230
  • R 10 is -NHMe. In certain embodiments, R 10 is -NHEt. In certain embodiments, R 10 is -NHCH2CH2NH2. In certain embodiments, R 10 is -NMe 2 . 5 In certain embodiments, R 10 is -NEt2. In certain embodiments, R 10 is -OCF3. In certain embodiments, R 10 is -SCF 3 . In certain embodiments, R 10 is -OCH2CF3. In certain embodiments, R 10 is -OCF2CF3. 10 In certain embodiments, R 10 is -OCH(CF 3 ) 2 . Embodiments of R 11 In certain embodiments, R 11 is C1-C4alkyl. In certain embodiments, R 11 is methyl.
  • R 11 is ethyl. In certain embodiments, R 11 is propyl. In certain embodiments, R 11 is isopropyl. In certain embodiments, R 11 is -SMe. In certain embodiments, R 11 is -SEt. 20 In certain embodiments, R 11 is -S(O)Me. In certain embodiments, R 11 is -S(O)Et. In certain embodiments, R 11 is -S(O)2Me. In certain embodiments, R 11 is -S(O)2Et. In certain embodiments, R 11 is -CF 3 . 25 In certain embodiments, R 11 is -OMe. In certain embodiments, R 11 is -OEt.
  • R 11 is -CH 2 OH. In certain embodiments, R 11 is -CH 2 CH 2 OH. In certain embodiments, R 11 is -C(O)OMe. 30 In certain embodiments, R 11 is -C(O)OEt. 231
  • R 11 is -C(O)Me. In certain embodiments, R 11 is -C(O)Et. In certain embodiments, R 11 is -NHC(O)Et. In certain embodiments, R 11 is -NHC(O)Me. 5 In certain embodiments, R 11 is -NHC(O)OEt. In certain embodiments, R 11 is -NHC(O)OMe. In certain embodiments, R 11 is -C(O)NHMe. In certain embodiments, R 11 is -C(O)NHEt. In certain embodiments, R 11 is -NH2. 10 In certain embodiments, R 11 is -NHMe. In certain embodiments, R 11 is -NHEt.
  • R 12 is ethyl. In certain embodiments, R 12 is propyl. In certain embodiments, R 12 is isopropyl. In certain embodiments, R 12 is -SMe. 30 In certain embodiments, R 12 is -SEt. 232
  • R 12 is -S(O)Me. In certain embodiments, R 12 is -S(O)Et. In certain embodiments, R 12 is -S(O)2Me. In certain embodiments, R 12 is -S(O) 2 Et. 5 In certain embodiments, R 12 is -CF3. In certain embodiments, R 12 is -OMe. In certain embodiments, R 12 is -OEt. In certain embodiments, R 12 is -CH2OH. In certain embodiments, R 12 is -CH2CH2OH. 10 In certain embodiments, R 12 is -C(O)OMe. In certain embodiments, R 12 is -C(O)OEt. In certain embodiments, R 12 is -C(O)Me.
  • R 12 is -C(O)Et. In certain embodiments, R 12 is -NHC(O)Et. 15 In certain embodiments, R 12 is -NHC(O)Me. In certain embodiments, R 12 is -NHC(O)OEt. In certain embodiments, R 12 is -NHC(O)OMe. In certain embodiments, R 12 is -C(O)NHMe. In certain embodiments, R 12 is -C(O)NHEt. 20 In certain embodiments, R 12 is -NH 2 . In certain embodiments, R 12 is -NHMe. In certain embodiments, R 12 is -NHEt. In certain embodiments, R 12 is -NHCH2CH2NH2.
  • R 12 is -NMe 2 . 25 In certain embodiments, R 12 is -NEt2. In certain embodiments, R 12 is -OCF3. In certain embodiments, R 12 is -SCF 3 . In certain embodiments, R 12 is -OCH 2 CF 3 . In certain embodiments, R 12 is -OCF2CF3. 30 In certain embodiments, R 12 is -OCH(CF3)2. 233
  • R 14 is C1-C4alkyl. In certain embodiments, R 14 is methyl. In certain embodiments, R 14 is ethyl. In certain embodiments, R 14 is propyl. In certain embodiments, R 14 is isopropyl. 10 In certain embodiments, R 14 is -SMe. In certain embodiments, R 14 is -SEt. In certain embodiments, R 14 is -S(O)Me. In certain embodiments, R 14 is -S(O)Et. In certain embodiments, R 14 is -S(O) 2 Me.
  • R 14 is -S(O)2Et. In certain embodiments, R 14 is -CF3. In certain embodiments, R 14 is -OMe. In certain embodiments, R 14 is -OEt. In certain embodiments, R 14 is -CH2OH. 20 In certain embodiments, R 14 is -CH 2 CH 2 OH. In certain embodiments, R 14 is -C(O)OMe. In certain embodiments, R 14 is -C(O)OEt. In certain embodiments, R 14 is -C(O)Me. In certain embodiments, R 14 is -C(O)Et. 25 In certain embodiments, R 14 is -NHC(O)Et.
  • R 14 is -NHC(O)Me. In certain embodiments, R 14 is -NHC(O)OEt. In certain embodiments, R 14 is -NHC(O)OMe. In certain embodiments, R 14 is -C(O)NHMe. 30 In certain embodiments, R 14 is -C(O)NHEt. 234
  • R 14 is -NH 2 . In certain embodiments, R 14 is -NHMe. In certain embodiments, R 14 is -NHEt. In certain embodiments, R 14 is -NHCH 2 CH 2 NH 2 . 5 In certain embodiments, R 14 is -NMe2. In certain embodiments, R 14 is -NEt2. In certain embodiments, R 14 is -OCF 3 . In certain embodiments, R 14 is -SCF3. In certain embodiments, R 14 is -OCH2CF3. 10 In certain embodiments, R 14 is -OCF 2 CF 3 . In certain embodiments, R 14 is -OCH(CF 3 ) 2 .
  • R 15 is C1-C4alkyl. In certain embodiments, R 15 is methyl. In certain embodiments, R 15 is ethyl. In certain embodiments, R 15 is propyl. 20 In certain embodiments, R 15 is isopropyl. In certain embodiments, R 15 is -SMe. In certain embodiments, R 15 is -SEt. In certain embodiments, R 15 is -S(O)Me. In certain embodiments, R 15 is -S(O)Et. 25 In certain embodiments, R 15 is -S(O)2Me.
  • R 15 is -S(O)2Et. In certain embodiments, R 15 is -CF 3 . In certain embodiments, R 15 is -OMe. In certain embodiments, R 15 is -OEt. 30 In certain embodiments, R 15 is -CH2OH. 235
  • R 15 is -CH 2 CH 2 OH. In certain embodiments, R 15 is -C(O)OMe. In certain embodiments, R 15 is -C(O)OEt. In certain embodiments, R 15 is -C(O)Me. 5 In certain embodiments, R 15 is -C(O)Et. In certain embodiments, R 15 is -NHC(O)Et. In certain embodiments, R 15 is -NHC(O)Me. In certain embodiments, R 15 is -NHC(O)OEt. In certain embodiments, R 15 is -NHC(O)OMe. 10 In certain embodiments, R 15 is -C(O)NHMe.
  • R 15 is -C(O)NHEt. In certain embodiments, R 15 is -NH2. In certain embodiments, R 15 is -NHMe. In certain embodiments, R 15 is -NHEt. 15 In certain embodiments, R 15 is -NHCH2CH2NH2. In certain embodiments, R 15 is -NMe2. In certain embodiments, R 15 is -NEt 2 . In certain embodiments, R 15 is -OCF 3 . In certain embodiments, R 15 is -SCF3. 20 In certain embodiments, R 15 is -OCH 2 CF 3 . In certain embodiments, R 15 is -OCF 2 CF 3 . In certain embodiments, R 15 is -OCH(CF3)2.
  • R 16 is C 1 -C 4 alkyl. In certain embodiments, R 16 is methyl. In certain embodiments, R 16 is ethyl. 30 In certain embodiments, R 16 is propyl. 236
  • R 16 is isopropyl. In certain embodiments, R 16 is -SMe. In certain embodiments, R 16 is -SEt. In certain embodiments, R 16 is -S(O)Me. 5 In certain embodiments, R 16 is -S(O)Et. In certain embodiments, R 16 is -S(O)2Me. In certain embodiments, R 16 is -S(O) 2 Et. In certain embodiments, R 16 is -CF3. In certain embodiments, R 16 is -OMe. 10 In certain embodiments, R 16 is -OEt. In certain embodiments, R 16 is -CH 2 OH. In certain embodiments, R 16 is -CH2CH2OH.
  • R 16 is -C(O)OMe. In certain embodiments, R 16 is -C(O)OEt. 15 In certain embodiments, R 16 is -C(O)Me. In certain embodiments, R 16 is -C(O)Et. In certain embodiments, R 16 is -NHC(O)Et. In certain embodiments, R 16 is -NHC(O)Me. In certain embodiments, R 16 is -NHC(O)OEt. 20 In certain embodiments, R 16 is -NHC(O)OMe. In certain embodiments, R 16 is -C(O)NHMe. In certain embodiments, R 16 is -C(O)NHEt. In certain embodiments, R 16 is -NH2.
  • R 16 is -NHMe. 25 In certain embodiments, R 16 is -NHEt. In certain embodiments, R 16 is -NHCH2CH2NH2. In certain embodiments, R 16 is -NMe 2 . In certain embodiments, R 16 is -NEt 2 . In certain embodiments, R 16 is -OCF3. 30 In certain embodiments, R 16 is -SCF3. 237
  • R 17 In certain embodiments, R 17 is C1-C4alkyl. In certain embodiments, R 17 is methyl. 10 In certain embodiments, R 17 is ethyl. In certain embodiments, R 17 is propyl. In certain embodiments, R 17 is isopropyl. In certain embodiments, R 17 is -SMe. In certain embodiments, R 17 is -SEt.
  • R 17 is -S(O)Me. In certain embodiments, R 17 is -S(O)Et. In certain embodiments, R 17 is -S(O) 2 Me. In certain embodiments, R 17 is -S(O) 2 Et. In certain embodiments, R 17 is -CF3. 20 In certain embodiments, R 17 is -OMe. In certain embodiments, R 17 is -OEt. In certain embodiments, R 17 is -CH2OH. In certain embodiments, R 17 is -CH2CH2OH. In certain embodiments, R 17 is -C(O)OMe. 25 In certain embodiments, R 17 is -C(O)OEt. In certain embodiments, R 17 is -C(O)Me.
  • R 17 is -C(O)Et. In certain embodiments, R 17 is -NHC(O)Et. In certain embodiments, R 17 is -NHC(O)Me. 30 In certain embodiments, R 17 is -NHC(O)OEt. 238
  • R 17 is -NHC(O)OMe. In certain embodiments, R 17 is -C(O)NHMe. In certain embodiments, R 17 is -C(O)NHEt. In certain embodiments, R 17 is -NH 2 . 5 In certain embodiments, R 17 is -NHMe. In certain embodiments, R 17 is -NHEt. In certain embodiments, R 17 is -NHCH 2 CH 2 NH 2 . In certain embodiments, R 17 is -NMe2. In certain embodiments, R 17 is -NEt2. 10 In certain embodiments, R 17 is -OCF 3 . In certain embodiments, R 17 is -SCF 3 . In certain embodiments, R 17 is -OCH2CF3.
  • R 17 is -OCF2CF3. In certain embodiments, R 17 is -OCH(CF 3 ) 2 . 15 Embodiments of R 18 In certain embodiments, R 18 is C 1 -C 4 alkyl. In certain embodiments, R 18 is methyl. In certain embodiments, R 18 is ethyl. 20 In certain embodiments, R 18 is propyl. In certain embodiments, R 18 is isopropyl. In certain embodiments, R 18 is -SMe. In certain embodiments, R 18 is -SEt. In certain embodiments, R 18 is -S(O)Me. 25 In certain embodiments, R 18 is -S(O)Et. In certain embodiments, R 18 is -S(O)2Me. In certain embodiments, R 18 is -S(O) 2 Et. In certain embodiments, R 18 is -CF 3 . In certain embodiments, R 18 is -OMe. 30 In certain embodiments, R 18 is -OEt. 239
  • R 18 is -CH 2 OH. In certain embodiments, R 18 is -CH2CH2OH. In certain embodiments, R 18 is -C(O)OMe. In certain embodiments, R 18 is -C(O)OEt. 5 In certain embodiments, R 18 is -C(O)Me. In certain embodiments, R 18 is -C(O)Et. In certain embodiments, R 18 is -NHC(O)Et. In certain embodiments, R 18 is -NHC(O)Me. In certain embodiments, R 18 is -NHC(O)OEt. 10 In certain embodiments, R 18 is -NHC(O)OMe. In certain embodiments, R 18 is -C(O)NHMe.
  • R 18 is -C(O)NHEt. In certain embodiments, R 18 is -NH2. In certain embodiments, R 18 is -NHMe. 15 In certain embodiments, R 18 is -NHEt. In certain embodiments, R 18 is -NHCH2CH2NH2. In certain embodiments, R 18 is -NMe 2 . In certain embodiments, R 18 is -NEt 2 . In certain embodiments, R 18 is -OCF3. 20 In certain embodiments, R 18 is -SCF 3 . In certain embodiments, R 18 is -OCH 2 CF 3 . In certain embodiments, R 18 is -OCF2CF3. In certain embodiments, R 18 is -OCH(CF3)2.
  • R 19 is C 1 -C 4 alkyl. In certain embodiments, R 19 is methyl. 30 In certain embodiments, R 19 is ethyl. 240
  • R 19 is propyl. In certain embodiments, R 19 is isopropyl. In certain embodiments, R 19 is -SMe. In certain embodiments, R 19 is -SEt. 5 In certain embodiments, R 19 is -S(O)Me. In certain embodiments, R 19 is -S(O)Et. In certain embodiments, R 19 is -S(O) 2 Me. In certain embodiments, R 19 is -S(O)2Et. In certain embodiments, R 19 is -CF3. 10 In certain embodiments, R 19 is -OMe. In certain embodiments, R 19 is -OEt. In certain embodiments, R 19 is -CH2OH. In certain embodiments, R 19 is -CH2CH2OH.
  • R 19 is -C(O)OMe. 15 In certain embodiments, R 19 is -C(O)OEt. In certain embodiments, R 19 is -C(O)Me. In certain embodiments, R 19 is -C(O)Et. In certain embodiments, R 19 is -NHC(O)Et. In certain embodiments, R 19 is -NHC(O)Me. 20 In certain embodiments, R 19 is -NHC(O)OEt. In certain embodiments, R 19 is -NHC(O)OMe. In certain embodiments, R 19 is -C(O)NHMe. In certain embodiments, R 19 is -C(O)NHEt. In certain embodiments, R 19 is -NH 2 .
  • R 19 is -NHMe. In certain embodiments, R 19 is -NHEt. In certain embodiments, R 19 is -NHCH 2 CH 2 NH 2 . In certain embodiments, R 19 is -NMe 2 . In certain embodiments, R 19 is -NEt2. 30 In certain embodiments, R 19 is -OCF3. 241
  • R 20 is H. 10 In certain embodiments, R 20 is methyl. In certain embodiments, R 20 is ethyl. In certain embodiments, R 20 is propyl. In certain embodiments, R 20 is is isopropyl. 15 Embodiments of R 21 In certain embodiments, R 21 is H.
  • R 21 is methyl. In certain embodiments, R 21 is ethyl. In certain embodiments, R 21 is propyl. 20 In certain embodiments, R 21 is isopropyl.
  • X is -O-. In certain embodiments, X is -S-. 25 In certain embodiments, X is -NR B -. In certain embodiments, X is -NH-. In certain embodiments, X is -N(Me)-. In certain embodiments, X is -N(Et)-. In certain embodiments, X is -N(cyclopropyl)-. 30 In certain embodiments, X is -N(OH)-. 242
  • X is -N(OMe)-. In certain embodiments, X is -N(OEt)-. In certain embodiments, X is -N(-C(O)Me)-. In certain embodiments, X is -N(-C(O)Et)-. 5 In certain embodiments, X is -N(-C(O)OMe)-. In certain embodiments, X is -N(-C(O)OEt)-.
  • a compound of the invention comprises an amino acid moiety.
  • the amino acid moiety is formed from one amino acid residue.
  • the amino acid moiety is formed from two amino acid residues, which may be the same or different, connected by an amide (peptide) bond.
  • the amino acid moiety is formed from three amino acids, which may be the same or different, connected by 10 amide (peptide) bond.
  • the amino acid moiety is attached to the rest of the compound of the invention through an ester bond, which is formed by the carboxylic group of the amino acid and a hydroxyl group present in the compound.
  • the amino acid moiety is attached to the rest of the compound of the invention through an amide bond, which is formed by the carboxylic group of the amino acid and an amino group present in the compound, 15 or, alternatively, by the alpha-amino group of the amino acid and a carboxylic group present in the compound.
  • the amino acid moiety is derived from alanine .
  • the amino acid moiety is derived rginine, 20 e, , y p d, . 244
  • the amino acid moiety is derived from cysteine . In certain embodiments, the amino acid moiety is derived ine, . mbodiments, the amino acid moiety is derived from glutamic acid, 5 . In certain embodiments, the amino acid moiety is derived from glycine . In certain embodiments, the amino acid moiety is derived tidine, . ve embodiments, the amino acid moiety is derived from isoleucine, 10 . In certain embodiments, the amino acid moiety is derived from leucine . In certain embodiments, the amino acid moiety is deriv y ne, . 245
  • R 1 is an amino acid moiety.
  • R 2 is an amino acid moiety.
  • R 3 is an amino acid moiety.
  • R 4 is an amino acid moiety.
  • R 5 is an amino acid moiety. 15
  • R 6 is an amino acid moiety.
  • R 7 is an amino acid moiety.
  • R 8 is an amino acid moiety.
  • R 9 is an amino acid moiety.
  • R 10 is an amino acid moiety. 20
  • R 11 is an amino acid moiety.
  • R 12 is an amino acid moiety.
  • R 14 is an amino acid moiety.
  • R 15 is an amino acid moiety.
  • R 16 is an amino acid moiety.
  • 25 In certain embodiments, R 17 is an amino acid moiety.
  • R 18 is an amino acid moiety.
  • R 19 is an amino acid moiety.
  • a compound of the invention is 247
  • each R 18 and each R 19 is independently selected from the group consisting of cycloalkyl, aryl, heteroaryl, C(O)NHOH, OC(O)NH2, -S(O)NH2, F, Cl, Br, -C1-C4alkyl, -S-C1-C4alkyl, -S(O)-C1-C4alkyl, -S(O)2-C1-C4alkyl, -S(O)2NH2, -C1-C4haloalkyl, -O-C1-C4alkyl, -C 1 -C 4 alkyl-OH, -O-C 1 -C 4 haloalkyl, -S-C 1 -C 4 haloalkyl, -COOC 1 -C 4 alkyl, -COC 1 -C 4 alkyl, 5 -NHC(O)C1-C4alkyl, -NHC(O)-O-C1-
  • each R 18 and each R 19 is independently selected from the group consisting of F, Cl, Br, -C1-C4alkyl, -S-C1-C4alkyl, -S(O)-C1-C4alkyl, -S(O)2-C1-C4alkyl, -S(O)2NH2, -C1-C4haloalkyl, -O-C1-C4alkyl, -C1-C4alkyl-OH, -O-C1-C4haloalkyl, -S-C1-C4haloalkyl, -COOC1-C4alkyl, -COC 1 -C 4 alkyl, -NHC(O)C 1 -C 4 alkyl, -NHC(O)-O-C 1 -C 4 alkyl, -C(O)NH(C 1 -C 4 alkyl), 5 -C(O)NH(C1-C4alkyl-
  • Ring A is selected from the group consisting of aryl and heteroaryl each of which is substituted with 1, 2, or 3 R 1 substituents; 15 or Ring A is cycloalkyl or heterocyclyl each of which is optionally substituted with 1, 2, or 3 R 1 substituents;
  • Ring Q is aryl, heteroaryl, cycloalkyl, or heterocyclyl each of which is optionally substituted with 1, 2, or 3 R 18 substituents
  • Ring S is aryl, heteroaryl, cycloalkyl, or heterocyclyl each of which is optionally substituted with 1, 2, or 3 R 19 substituents
  • Ring T is aryl, heteroaryl, cycloalkyl, or heterocyclyl each of which is optionally substituted with 1, 2, or 3 R 18 substituents
  • Ring U is aryl, heteroaryl, cycloalkyl, or heterocyclyl each of which is optionally substituted with 1, 2, or 3 R 19 substituents
  • each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 19 is 10 independently selected from the group
  • R 1 is selected from the group consisting of -C1-C4alkyl, -S(O)-C1-C4alkyl, -S(O)2-C1-C4alkyl, -O-C1-C4alkyl, -O-C1-C4haloalkyl, -S-C1-C4haloalkyl, -C1-C4alkyl-OH, -COOC 1 -C 4 alkyl, -COC 1 -C 4 alkyl, -NHC(O)C 1 -C 4 alkyl, -NHC(O)-O-C 1 -C 4 alkyl, 15 -C(O)NH(C1-C4alkyl), -C(O)NH(C1-C4alkyl-OH), -C(O)N(C1-C4alkyl)2, -NH2, -
  • R 4 is selected from the group consisting of -C 1 -C 4 alkyl, -S(O)-C 1 -C 4 alkyl, -S(O) 2 -C 1 -C 4 alkyl, -O-C1-C4alkyl, -O-C1-C4haloalkyl, -S-C1-C4haloalkyl, -C1-C4alkyl-OH, -COOC1-C4alkyl, -COC1-C4alkyl, -NHC(O)C1-C4alkyl, -NHC(O)-O-C1-C4alkyl, 10 -C(O)NH(C 1 -C 4 alkyl), -C(O)NH(C 1 -C 4 alkyl-OH), -C(O)N(C 1 -C 4 alkyl) 2
  • R 5 is selected from the group consisting of -C 1 -C 4 alkyl, -S(O)-C 1 -C 4 alkyl, -S(O) 2 -C 1 -C 4 alkyl, 15 -O-C1-C4alkyl, -O-C1-C4haloalkyl, -S-C1-C4haloalkyl, -C1-C4alkyl-OH, -COOC1-C4alkyl, -COC1-C4alkyl, -NHC(O)C1-C4alkyl, -NHC(O)-O-C1-C4alkyl, -C(O)NH(C 1 -C 4 alkyl), -C(O)NH(C 1 -C 4 alkyl-OH), -C(O)N(C 1 -C 4 alkyl) 2
  • R 6 is selected from the group consisting of -C 1 -C 4 alkyl, -S(O)-C 1 -C 4 alkyl, -S(O) 2 -C 1 -C 4 alkyl, -O-C1-C4alkyl, -O-C1-C4haloalkyl, -S-C1-C4haloalkyl, -C1-C4alkyl-OH, -COOC1-C4alkyl, -COC1-C4alkyl, -NHC(O)C1-C4alkyl, -NHC(O)-O-C1-C4alkyl, -C(O)NH(C 1 -C 4 alkyl), -C(O)NH(C 1 -C 4 alkyl-OH), -C(O)N(C 1 -C 4 alkyl) 2
  • R 7 is selected from the group consisting of -C 1 -C 4 alkyl, -S(O)-C 1 -C 4 alkyl, -S(O) 2 -C 1 -C 4 alkyl, -O-C1-C4alkyl, -O-C1-C4haloalkyl, -S-C1-C4haloalkyl, -C1-C4alkyl-OH, 30 -COOC1-C4alkyl, -COC1-C4alkyl, -NHC(O)C1-C4alkyl, -NHC(O)-O-C1-C4alkyl, 266
  • R 8 is selected 5 from the group consisting of -C1-C4alkyl, -S(O)-C1-C4alkyl, -S(O)2-C1-C4alkyl, -O-C1-C4alkyl, -O-C1-C4haloalkyl, -S-C1-C4haloalkyl, -C1-C4alkyl-OH, -COOC 1 -C 4 alkyl, -COC 1 -C 4 alkyl, -NHC(O)C 1 -C 4 alkyl, -NHC(O)-O-C 1 -C 4 alkyl, -C(O)NH(C1-C4alkyl), -C(O)NH(C1-C4alkyl-OH), -C(O)N(C1-C4alkyl)2, -NH2, -NH(
  • R 10 is selected from the group consisting of -C1-C4alkyl, -S(O)-C1-C4alkyl, -S(O)2-C1-C4alkyl, 20 -O-C 1 -C 4 alkyl, -O-C 1 -C 4 haloalkyl, -S-C 1 -C 4 haloalkyl, -C 1 -C 4 alkyl-OH, -COOC 1 -C 4 alkyl, -COC 1 -C 4 alkyl, -NHC(O)C 1 -C 4 alkyl, -NHC(O)-O-C 1 -C 4 alkyl, -C(O)NH(C1-C4alkyl), -C(O)NH(C1-C4alkyl-OH), -C(O)N(C1-C4alkyl)
  • R 11 is selected from the group consisting of -C1-C4alkyl, -S(O)-C1-C4alkyl, -S(O)2-C1-C4alkyl, -O-C 1 -C 4 alkyl, -O-C 1 -C 4 haloalkyl, -S-C 1 -C 4 haloalkyl, -C 1 -C 4 alkyl-OH, -COOC 1 -C 4 alkyl, -COC 1 -C 4 alkyl, -NHC(O)C 1 -C 4 alkyl, -NHC(O)-O-C 1 -C 4 alkyl, -C(O)NH(C1-C4alkyl), -C(O)NH(C1-C4alkyl-OH), -C(O)N(C1-C4alky
  • R 12 is selected from the group consisting of -C1-C4alkyl, -S(O)-C1-C4alkyl, -S(O)2-C1-C4alkyl, -O-C 1 -C 4 alkyl, -O-C 1 -C 4 haloalkyl, -S-C 1 -C 4 haloalkyl, -C 1 -C 4 alkyl-OH, 5 -COOC1-C4alkyl, -COC1-C4alkyl, -NHC(O)C1-C4alkyl, -NHC(O)-O-C1-C4alkyl, -C(O)NH(C1-C4alkyl), -C(O)NH(C1-C4alkyl-OH), -C(O)N(C1-C4alkyl)2, -
  • R 14 is 10 selected from the group consisting of -C 1 -C 4 alkyl, -S(O)-C 1 -C 4 alkyl, -S(O) 2 -C 1 -C 4 alkyl, -O-C 1 -C 4 alkyl, -O-C 1 -C 4 haloalkyl, -S-C 1 -C 4 haloalkyl, -C 1 -C 4 alkyl-OH, -COOC1-C4alkyl, -COC1-C4alkyl, -NHC(O)C1-C4alkyl, -NHC(O)-O-C1-C4alkyl, -C(O)NH(C1-C4alkyl), -C(O)NH(C1-C4alkyl-OH), -C(O)N(C1-C4alky
  • R 15 is selected from the group consisting of -C 1 -C 4 alkyl, -S(O)-C 1 -C 4 alkyl, -S(O) 2 -C 1 -C 4 alkyl, -O-C 1 -C 4 alkyl, -O-C 1 -C 4 haloalkyl, -S-C 1 -C 4 haloalkyl, -C 1 -C 4 alkyl-OH, -COOC1-C4alkyl, -COC1-C4alkyl, -NHC(O)C1-C4alkyl, -NHC(O)-O-C1-C4alkyl, 20 -C(O)NH(C 1 -C 4 alkyl), -C(O)NH(C 1 -C 4 alkyl-OH), -C(O)N(C 1 -C 4 alkyl
  • R 16 is selected from the group consisting of -C 1 -C 4 alkyl, -S(O)-C 1 -C 4 alkyl, -S(O) 2 -C 1 -C 4 alkyl, 25 -O-C1-C4alkyl, -O-C1-C4haloalkyl, -S-C1-C4haloalkyl, -C1-C4alkyl-OH, -COOC1-C4alkyl, -COC1-C4alkyl, -NHC(O)C1-C4alkyl, -NHC(O)-O-C1-C4alkyl, -C(O)NH(C 1 -C 4 alkyl), -C(O)NH(C 1 -C 4 alkyl-OH), -C(O)N(C 1 -C 4 alkyl)
  • R 18 is selected from the group consisting of -C1-C4alkyl, -S(O)-C1-C4alkyl, -S(O)2-C1-C4alkyl, 10 -O-C 1 -C 4 alkyl, -O-C 1 -C 4 haloalkyl, -S-C 1 -C 4 haloalkyl, -C 1 -C 4 alkyl-OH, -COOC 1 -C 4 alkyl, -COC 1 -C 4 alkyl, -NHC(O)C 1 -C 4 alkyl, -NHC(O)-O-C 1 -C 4 alkyl, -C(O)NH(C1-C4alkyl), -C(O)NH(C1-C4alkyl-OH), -C(O)N(C1-C4alkyl)
  • a pharmaceutical composition for treating or preventing a tauopathy or traumatic brain injury in a human patient comprising an effective amount of a compound of any one of embodiments 1-90 or a pharmaceutically acceptable salt thereof.
  • 96. A method for the treatment or prevention of a tauopathy or a traumatic brain injury in a 20 human patient comprising administering an effective amount of a compound of any one of embodiments 1-90 or a pharmaceutically acceptable salt thereof, to the human patient in need thereof.
  • 97. The method of embodiment 96, for the treatment of a traumatic brain injury. 25 98.
  • the method of embodiment 97, wherein the traumatic brain injury is a repetitive traumatic brain injury (rTBI). 99.
  • the method of embodiment 99, wherein the tauopathy is chronic traumatic encephalopathy (CTE). 5 101. The method of embodiment 99, wherein the tauopathy is Alzheimer’s disease. 102. The method of embodiment 99, wherein the tauopathy is Parkinson’s disease. 103. The method of embodiment 99, wherein the tauopathy is prion disease. 10 104. The method of embodiment 99, wherein the tauopathy is amyotrophic lateral sclerosis (ALS). 105. The method of embodiment 99, wherein the tauopathy is motor neuron disease 15 (MND). 106. The method of embodiment 99, wherein the tauopathy is frontotemporal dementia. 107. The method of embodiment 99, wherein the tauopathy is progressive supranuclear 20 palsy. 108.
  • CTE chronic traumatic encephalopathy
  • compositions 25 A compound of the present invention or its pharmaceutically acceptable salt can be administered as the neat chemical, but is more typically administered as a pharmaceutical composition, that includes an effective amount of the compound for a patient, typically a human, 276
  • the pharmaceutical composition may contain a compound or salt thereof as the only active agent, or, in an alternative embodiment, the compound or its salt and at least one additional active agent to treat, prevent or 5 ameliorate the symptoms of the disease.
  • the pharmaceutical compositions of the invention may be administered in a therapeutically effective amount by any desired mode of administration.
  • the compound or its pharmaceutically acceptable salt is delivered in an effective amount with a pharmaceutically acceptable carrier for oral delivery.
  • the oral delivery for example in a liquid or a solid dosage 10 form can be given prior to potential concussive or percussive assault.
  • the liquid or solid oral form can be given for a period of time as prescribed by the healthcare practitioner, or indefinitely, to a human diagnosed with, or at risk of developing, a disease characterized by endoplasmic reticulum stress.
  • the compound as described herein can be administered 15 by intravenous infusion after a brain injury for immediate treatment.
  • the compound described herein can be administered by injection, including by bolus or intra-arterial injection.
  • a pharmaceutical composition can be used that is suitable for oral (including liquid, solid form or buccal and sub-lingual), rectal, nasal, topical, 20 transdermal, pulmonary, vaginal or parenteral (including intramuscular, intra-arterial, intrathecal, subcutaneous and intravenous), injections, inhalation or spray, intra-aortal, intracranial, subdermal, intraperitoneal, subcutaneous, or by other means of administration containing conventional pharmaceutically acceptable carriers.
  • a typical manner of administration is oral, topical or intravenous, using a convenient daily dosage regimen which can be adjusted according to the 25 degree of affliction.
  • Suitable dosage ranges depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and the preferences and experience of the medical practitioner involved.
  • One of ordinary skill in the art will be able, without undue experimentation and in 277
  • the pharmaceutical composition is in a dosage form that contains from about 1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 50 mg to 5 about 800 mg, or from about 20 mg to about 600 mg of the active compound.
  • dosage forms with at least about 1, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 mg of active compound, or its salt and at most about 1 gram of active compound or its salt.
  • the pharmaceutical composition is in a dosage form that contains from about 1 mg to about 1000 mg, from about 10 mg to about 750 mg, from about 50 mg to about 10 500 mg, or from about 5, 10, 15, or 20 mg to about 250 mg of the active compound or its pharmaceutically acceptable salt.
  • dosage forms are those delivering at least 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 mg of active compound, or its salt.
  • the weight can refer to either the compound alone or the compound in combination with its pharmaceutically acceptable salt.
  • compounds disclosed herein are administered once a day (QD), twice a day (BID), three times a day (TID), or four times a day.
  • the compound of the present invention is administered orally once a day. In certain embodiments the compound of the present invention is administered orally twice a day. In certain embodiments the compound of the present invention is administered orally three 20 times a day. In certain embodiments the compound of the present invention is administered orally four times a day. In certain embodiments the compound or its salt of the present invention is administered intravenously, using a schedule as directed by the healthcare provider. In certain embodiments, the compound is administered at least once a day, once a week, once every two weeks, three weeks, 25 one month or less frequently. In certain embodiments the compound of the present invention is administered intravenously twice a day.
  • the pharmaceutical composition may also include an effective amount of the active compound described herein and an additional active agent, wherein the additional active agent is administered according to its own treatment regimen, or as determined by the healthcare provider, 30 or alternatively synchronized with the compound of the present invention. 278
  • a therapeutic amount may for example be in the range of about 0.0001 mg/kg to about 25 mg/kg body weight.
  • the subject can be administered as many doses as is required to reduce and/or alleviate the signs, symptoms, or causes of the disease, or bring about any other desired alteration of a biological system.
  • the therapeutic amount of number of doses 5 required to reduce and/or alleviate the signs, symptoms, or causes of the disease may vary according to the specific endoplasmic reticulum stress-related disease.
  • formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient.
  • An effective amount of the disclosed compound or its salt may be administered based on 10 the weight, size, or age of the patient.
  • a therapeutic amount may for example be in the range of about 10 mg/kg to about 250 mg/kg body weight, or about 10 mg/kg to about 10 mg/kg, in at least one dose.
  • the patient can be administered as many doses as are required to reduce and/or alleviate and/or cure the disease.
  • formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient.
  • the pharmaceutical preparations are often in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packed tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number 20 of any of these in packaged form.
  • the compound is administered as a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salts include: acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, 25 fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, mal
  • ammonium, potassium, calcium, and magnesium as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.
  • the pharmaceutical compositions can be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, syrup, suspensions, creams, ointments, lotions, paste, gel, spray, aerosol, foam, or oil, injection or infusion solution, a transdermal patch, a subcutaneous patch, an inhalation formulation, in a medical device, suppository, buccal, or 10 sublingual formulation, parenteral formulation, or an ophthalmic solution, or the like, preferably in unit dosage form suitable for single administration of a precise dosage.
  • solid, semi-solid or liquid dosage forms such as, for example, tablets, suppositories, pills, capsules, powders, liquids, syrup, suspensions, creams, ointments, lotions, paste, gel, spray, aerosol, foam, or oil, injection or infusion solution, a transdermal patch, a subcutaneous patch, an inhalation formulation, in a medical device,
  • Carriers include excipients and diluents and should be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated.
  • the carrier can be inert, or it can possess pharmaceutical benefits of its own.
  • the amount of carrier 15 employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound.
  • Classes of carriers include, but are not limited to adjuvants, binders, buffering agents, coloring agents, diluents, disintegrants, excipients, emulsifiers, flavorants, gels, glidents, lubricants, preservatives, stabilizers, surfactants, solubilizer, tableting agents, wetting agents, or 20 solidifying material.
  • Some carriers may be listed in more than one class, for example vegetable oil may be used as a lubricant in some formulations and a diluent in others.
  • Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin, talc, petroleum jelly, lanoline, polyethylene glycols, alcohols, 25 transdermal enhancers and vegetable oils.
  • Optional active agents may be included in a pharmaceutical composition, which do not substantially interfere with the activity of the compound of the present invention.
  • Some excipients include, but are not limited, to liquids such as water, saline, glycerol, polyethylene glycol, hyaluronic acid, ethanol, and the like.
  • the compound can be provided, for 30 example, in the form of a solid, a liquid, spray dried material, a microparticle, nanoparticle, 280
  • Suitable excipients for non-liquid formulations are also known to those of skill in the art. A thorough discussion of pharmaceutically acceptable excipients and salts is available in Remington’s Pharmaceutical Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990). 5 Additionally, auxiliary substances, such as wetting or emulsifying agents, biological buffering substances, surfactants, and the like, can be present in such vehicles.
  • a biological buffer can be any solution which is pharmacologically acceptable, and which provides the formulation with the desired pH, i.e., a pH in the physiologically acceptable range.
  • buffer solutions include saline, phosphate buffered saline, Tris buffered saline, Hank’s buffered saline, and the like.
  • conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like.
  • Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, and the like, an active compound as described herein and optional pharmaceutical adjuvants in an excipient, 15 such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension.
  • an excipient such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like
  • the pharmaceutical composition to be administered can also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and the like.
  • permeation enhancer excipients including polymers such as: polycations (chitosan and its quaternary ammonium derivatives, poly-L- arginine, aminated gelatin); polyanions (N-carboxymethyl chitosan, poly-acrylic acid); and25 thiolated polymers (carboxymethyl cellulose-cysteine, polycarbophil-cysteine, chitosan- thiobutylamidine, chitosan-thioglycolic acid, chitosan-glutathione conjugates).
  • polycations chitosan and its quaternary ammonium derivatives, poly-L- arginine, aminated gelatin
  • polyanions N-carboxymethyl chitosan, poly-acrylic acid
  • 25 thiolated polymers carbboxymethyl cellulose-cysteine, polycarbophil-cysteine, chitosan- thiobutylamidine, chitosan
  • the excipient is selected from butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl 30 cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, 281
  • compositions/combinations can be formulated for oral administration.
  • the composition may take the form of a tablet, capsule, a softgel capsule or can be an aqueous or nonaqueous solution, suspension, or syrup.
  • Tablets and capsules are typical oral administration forms. Tablets and capsules for oral use can include one or more commonly 10 used carriers such as lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added.
  • the compositions of the disclosure can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like.
  • suitable binders, lubricants, disintegrating 15 agents, and coloring agents can also be incorporated into the mixture.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, 20 and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • the active agent can be combined with any oral, non- toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like and with emulsifying and suspending agents. If desired, flavoring, coloring and/or sweetening agents 25 can be added as well.
  • Other optional components for incorporation into an oral formulation herein include, but are not limited to, preservatives, suspending agents, thickening agents, and the like.
  • Parenteral formulations can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solubilization or suspension in liquid prior to injection, or as emulsions. Typically, sterile injectable suspensions are formulated according to techniques 30 known in the art using suitable carriers, dispersing, or wetting agents and suspending agents.
  • sterile injectable formulation can also be a sterile injectable solution or a suspension in a acceptably nontoxic parenterally acceptable diluent or solvent.
  • acceptable vehicles and solvents that can be employed are water, Ringer’s solution and isotonic sodium chloride solution.
  • sterile, fixed oils, fatty esters, or polyols are conventionally employed as solvents or 5 suspending media.
  • parenteral administration can involve the use of a slow release or sustained release system such that a constant level of dosage is maintained.
  • Parenteral administration includes intraarticular, intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, and include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render 10 the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • aqueous and non-aqueous, isotonic sterile injection solutions which can contain antioxidants, buffers, bacteriostats, and solutes that render 10 the formulation isotonic with the blood of the intended recipient
  • aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • Administration via certain parenteral routes can involve introducing the formulations of the disclosure into the body of a patient through a needle or a catheter, propelled by a sterile syringe or some other mechanical device such as a continuous infusion system.
  • a 15 formulation provided by the disclosure can be administered using a syringe, injector, pump, or any other device recognized in the art for parenteral administration.
  • Preparations according to the disclosure for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions.
  • non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, 20 gelatin, and injectable organic esters such as ethyl oleate.
  • Such dosage forms can also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They can be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured using sterile water, or some other sterile injectable medium, immediately 25 before use. Sterile injectable solutions are prepared by incorporating one or more of the compounds of the disclosure in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile 30 vehicle which contains the basic dispersion medium and the required other ingredients from those 283
  • sterile powders for the preparation of sterile injectable solutions typical methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile- filtered solution thereof.
  • a parenteral composition suitable for administration 5 by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized.
  • the pharmaceutical compositions of the disclosure can be administered in the form of suppositories for rectal administration.
  • compositions of the disclosure can also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl 15 alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, propellants such as fluorocarbons or nitrogen, and/or other conventional solubilizing or dispersing agents.
  • Formulations for buccal administration include tablets, lozenges, gels and the like.
  • buccal administration can be effected using a transmucosal delivery system as 20 known to those skilled in the art.
  • the compounds of the disclosure can also be delivered through the skin or mucosal tissue using conventional transdermal drug delivery systems, i.e., transdermal “patches” wherein the agent is typically contained within a laminated structure that serves as a drug delivery device to be affixed to the body surface.
  • the drug composition is typically contained in a layer, or “reservoir,” underlying an upper backing layer.
  • the laminated 25 device can contain a single reservoir, or it can contain multiple reservoirs.
  • the reservoir comprises a polymeric matrix of a pharmaceutically acceptable contact adhesive material that serves to affix the system to the skin during drug delivery.
  • suitable skin contact adhesive materials include, but are not limited to, polyethylenes, polysiloxanes, polyisobutylenes, polyacrylates, polyurethanes, and the like.
  • the drug-containing reservoir and skin contact adhesive are present as separate and distinct layers, with the adhesive underlying the reservoir which, in this case, can be either a polymeric matrix as described above, or it can be a liquid or gel reservoir, or can take some other form.
  • the backing layer in these laminates, which serves as the upper surface of the device, 5 functions as the primary structural element of the laminated structure and provides the device with much of its flexibility.
  • the material selected for the backing layer should be substantially impermeable to the active agent and any other materials that are present.
  • the compositions of the disclosure can be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration.
  • the compound may, 10 for example generally have a small particle size for example of the order of 5 microns or less.
  • Such a particle size can be obtained by means known in the art, for example by micronization.
  • the active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • CFC chlorofluorocarbon
  • the aerosol can conveniently also 15 contain a surfactant such as lecithin.
  • the dose of drug can be controlled by a metered valve.
  • the active ingredients can be provided in a form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP).
  • the powder carrier will form a gel in the nasal cavity.
  • the powder composition can be presented in unit dose form for 20 example in capsules or cartridges of e.g., gelatin or blister packs from which the powder can be administered by means of an inhaler.
  • Formulations suitable for rectal administration are typically presented as unit dose suppositories. These may be prepared by admixing the active compound with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.
  • Formulations suitable for administration to the lungs can be delivered by a wide range of passive breath driven and active power driven single/-multiple dose dry powder inhalers (DPI).
  • DPI dry powder inhalers
  • the devices most commonly used for respiratory delivery include nebulizers, metered-dose inhalers, and dry powder inhalers.
  • nebulizers include jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. Selection of a suitable lung 285
  • Intranasal Formulations 5 the compounds described herein may be delivered intranasally. Intranasal delivery can provide a non-invasive method of delivering the compounds while bypassing the blood-brain barrier (Hanson, L. et al. BMC Neuroscience 2008, 9(suppl.3):55). Intranasal delivery can also more rapidly deliver the active compound than oral administration, which may be advantageous for treatment of certain diseases.
  • an intranasal formulation of a compound described herein may also include one or more of the following: solubilizing agents, polar solvents, dry acidulant, sequestrants, alkaline agents, counter-irritant agents, local anesthetic, and preservatives.
  • an intranasal formulation of a compound described herein are aqueous based intranasal preparations where water makes up from about 80%w/v to about 96%w/v 15 of the total preparation and has a pH of from about 2-7 such as a pH range of about 3-6.
  • an intranasal formulation of a compound described herein additionally includes an amount of humectant such as hyaluronic acid, polyethylene glycol or glycerol (glycerine) from about 1 to about 10%w/v of the total preparation.
  • an intranasal formulation of a compound described herein 20 additionally includes an amount of a polar solvent, such as ethanol, from about 0.2 to about 2%w/v of the total preparation.
  • an intranasal formulation of a compound described herein additionally includes an amount of a counter-irritant or local anesthetic, such as menthol.
  • an intranasal formulation of a compound described herein 25 additionally includes an amount of a preservative, such as a quaternary ammonium salt preservative.
  • an intranasal formulation of a compound described herein additionally includes an amount of buffer such as sodium phosphate, citrate or acetate.
  • the intranasal formulation may further comprise at least one pharmaceutically acceptable 30 diluent, excipient, or carrier.
  • the diluent, excipient, or carrier may be a flavor agent, sweetener, 286
  • the intranasal formulation further comprises a co-solvent and/or 5 solubilizer (including ethanol, benzyl alcohol, phospholipids, cyclodextrins, surfactants, and polyethylene glycols).
  • a co-solvent and/or 5 solubilizer including ethanol, benzyl alcohol, phospholipids, cyclodextrins, surfactants, and polyethylene glycols.
  • any of the compounds described herein, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, can be used to treat, prevent or ameliorate a disease characterized by endoplasmic reticulum stress, for example a traumatic brain injury 15 tauopathy.
  • Neurons are particularly sensitive to the accumulation of misfolded proteins.
  • the ER stress is involved in TBI and complications of TBI such as chronic TBI (also referred to as rTBI), CTE, as well as neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, prion disease, amyotrophic lateral sclerosis (ALS), motor neuron disease (MND), frontotemporal dementia, progressive supranuclear palsy, and corticobasal degeneration.
  • a compound described herein, or a pharmaceutically acceptable salt thereof is used to treat, prevent or ameliorate a disease characterized by 287
  • endoplasmic reticulum stress selected from the group consisting of TBI (including mild traumatic brain injury, chronic traumatic brain injury, or recurring traumatic brain injury), CTE, Alzheimer’s disease, Parkinson’s disease, prion disease, amyotrophic lateral sclerosis (ALS), motor neuron disease (MND), frontotemporal dementia, progressive supranuclear palsy, and corticobasal 5 degeneration.
  • TBI including mild traumatic brain injury, chronic traumatic brain injury, or recurring traumatic brain injury
  • CTE including mild traumatic brain injury, chronic traumatic brain injury, or recurring traumatic brain injury
  • Alzheimer’s disease Parkinson’s disease
  • prion disease amyotrophic lateral sclerosis (ALS), motor neuron disease (MND)
  • frontotemporal dementia progressive supranuclear palsy
  • corticobasal 5 degeneration corticobasal 5 degeneration.
  • the disease is characterized as a tauopathy.
  • a compound described herein, or a pharmaceutically acceptable 10 salt thereof is used to treat, prevent, or ameliorate a secondary condition arising from traumatic brain injury, including but not limited to post-concussion syndrome, second-impact syndrome, post-traumatic seizures, post-traumatic epilepsy, movement disorders, ataxia, spasticity, myoclonus, loss of movement control, loss of hearing, loss of vision, loss of smell, hypopituitarism, obsessive compulsive disorder, dysthymia, depression, bipolar disorder, anxiety 15 disorder, and psychosis.
  • a compound described herein, or a pharmaceutically acceptable salt thereof is used to treat, prevent, or ameliorate chronic traumatic encephalopathy.
  • a compound described herein, or a pharmaceutically acceptable salt thereof is used to treat, prevent, or ameliorate a disease characterized by the aggregation of 20 tau protein (tauopathy).
  • Tauopathies include but are not limited to CTE, Alzheimer’s disease, frontotemporal dementia, progressive supranuclear palsy, and corticobasal degeneration.
  • the method comprises administering an effective amount of the compound of the invention or its salt as described herein, optionally including a pharmaceutically acceptable excipient, carrier, or adjuvant (i.e., a pharmaceutically acceptable composition), 25 optionally in combination or alternation with an additional therapeutically active agent or combination of agents.
  • the additional therapeutically active agent binds Protein Kinase R-like ER Kinase (PERK).
  • the additional therapeutically active agent is GSK2606414. 288
  • a compound of the present invention, or a pharmaceutically acceptable salt thereof is used to treat a disease characterized by endoplasmic reticulum stress, including but not limited to TBI, rTBI and CTE.
  • a compound of Formula (A), or a pharmaceutically acceptable salt 5 thereof is used to treat a disease characterized by endoplasmic reticulum stress, including but not limited to TBI, rTBI and CTE.
  • a compound of Formula (B), or a pharmaceutically acceptable salt thereof is used to treat a disease characterized by endoplasmic reticulum stress, including but not limited to TBI, rTBI and CTE.
  • a compound of Formula (I) or its pharmaceutically acceptable salt is used to treat a disease characterized by endoplasmic reticulum stress, including but not limited to TBI, rTBI and CTE.
  • a compound of Formula (II) or its pharmaceutically acceptable salt is used to treat a disease characterized by endoplasmic reticulum stress, including but not 15 limited to TBI, rTBI and/or CTE.
  • a compound of Formula (III) or its pharmaceutically acceptable salt is used to treat a disease characterized by endoplasmic reticulum stress, including but not limited to TBI, rTBI and/or CTE.
  • a compound of Formula (IV) or its pharmaceutically acceptable 20 salt is used to treat a disease characterized by endoplasmic reticulum stress, , including but not limited to TBI, rTBI and/or CTE.
  • a compound of Formula (V) or its pharmaceutically acceptable salt is used to treat a disease characterized by endoplasmic reticulum stress, including but not limited to TBI, rTBI and/or CTE.
  • a compound of Formula (VI) or its pharmaceutically acceptable salt is used to treat a disease characterized by endoplasmic reticulum stress, including but not limited to TBI, rTBI and/or CTE.
  • a compound of Formula (VII) or its pharmaceutically acceptable salt is used to treat a disease characterized by endoplasmic reticulum stress, including but not 30 limited to TBI, rTBI and/or CTE. 289
  • a compound of Formula (VIII) or its pharmaceutically acceptable salt is used to treat a disease characterized by endoplasmic reticulum stress, including but not limited to TBI, rTBI and/or CTE.
  • a compound of Formula (IX) or its pharmaceutically acceptable 5 salt is used to treat a disease characterized by endoplasmic reticulum stress, including but not limited to TBI, rTBI and/or CTE.
  • a compound of Formula (X) or its pharmaceutically acceptable salt is used to treat a disease characterized by endoplasmic reticulum stress, including but not limited to TBI, rTBI and/or CTE.
  • a compound of Formula (XIa) or its pharmaceutically acceptable salt is used to treat a disease characterized by endoplasmic reticulum stress, including but not limited to TBI, rTBI and/or CTE.
  • a compound of Formula (XIb) or its pharmaceutically acceptable salt is used to treat a disease characterized by endoplasmic reticulum stress, including but not 15 limited to TBI, rTBI and/or CTE.
  • a compound of Formula (XIc) or its pharmaceutically acceptable salt is used to treat a disease characterized by endoplasmic reticulum stress, including but not limited to TBI, rTBI and/or CTE.
  • a compound of Formula (XId) or its pharmaceutically acceptable 20 salt is used to treat a disease characterized by endoplasmic reticulum stress, including but not limited to TBI, rTBI and/or CTE.
  • a compound of Formula (XIe) or its pharmaceutically acceptable salt is used to treat a disease characterized by endoplasmic reticulum stress, including but not limited to TBI, rTBI and/or CTE.
  • a compound or its pharmaceutically acceptable salt of Formula (XIf) is used to treat a disease characterized by endoplasmic reticulum stress, including but not limited to TBI, rTBI and/or CTE.
  • a compound of Formula (XIg) or its pharmaceutically acceptable salt is used to treat a disease characterized by endoplasmic reticulum stress, including but not 30 limited to TBI, rTBI and/or CTE.
  • a compound of Formula (XII) or its pharmaceutically acceptable salt is used to treat a disease characterized by endoplasmic reticulum stress, including but not limited to TBI, rTBI and/or CTE.
  • a compound of Formula (XIII) or its pharmaceutically acceptable 5 salt is used to treat a disease characterized by endoplasmic reticulum stress, including but not limited to TBI, rTBI and/or CTE.
  • a compound of Formula (XIV) or its pharmaceutically acceptable salt is used to treat a disease characterized by endoplasmic reticulum stress, including but not limited to TBI, rTBI and/or CTE.
  • a compound of Formula (XV) or its pharmaceutically acceptable salt is used to treat a disease characterized by endoplasmic reticulum stress, including but not limited to TBI, rTBI and/or CTE.
  • a compound of Formula (XVI) or its pharmaceutically acceptable salt is used to treat a disease characterized by endoplasmic reticulum stress, including but not 15 limited to TBI, rTBI and/or CTE.
  • a compound of Formula (XVII) or its pharmaceutically acceptable salt is used to treat a disease characterized by endoplasmic reticulum stress, including but not limited to TBI, rTBI and/or CTE.
  • the disease characterized by endoplasmic reticulum stress is 20 traumatic brain injury, including mild traumatic brain injury, chronic traumatic brain injury, or recurring traumatic brain injury. In certain embodiments, the disease characterized by endoplasmic reticulum stress is chronic traumatic encephalopathy. In certain embodiments, the disease characterized by endoplasmic reticulum stress is a neurodegenerative disease. In certain embodiments, the disease characterized by endoplasmic reticulum stress is Alzheimer’s disease. 25 In certain embodiments, the disease characterized by endoplasmic reticulum stress is Parkinson’s disease. In certain embodiments, the disease characterized by endoplasmic reticulum stress is a prion disease.
  • the disease characterized by endoplasmic reticulum stress is amyotrophic lateral sclerosis (ALS). In certain embodiments, the disease characterized by endoplasmic reticulum stress is motor neuron disease (MND). In certain embodiments, the disease 30 characterized by endoplasmic reticulum stress is frontotemporal dementia. In certain 291
  • the disease characterized by endoplasmic reticulum stress is progressive supranuclear palsy. In certain embodiments, the disease characterized by endoplasmic reticulum stress is corticobasal degeneration.
  • a compound of the present invention, or a pharmaceutically 5 acceptable salt thereof is used to treat TBI (including mild traumatic brain injury, chronic traumatic brain injury, or recurring traumatic brain injury).
  • a compound of Formula (A), or a pharmaceutically acceptable salt thereof is used to treat TBI (including mild traumatic brain injury, chronic traumatic brain injury, or recurring traumatic brain injury).
  • a compound of Formula (B), or a pharmaceutically acceptable salt thereof is used to treat TBI (including mild traumatic brain injury, chronic traumatic brain injury, or recurring traumatic brain injury).
  • a compound of Formula (I) or its pharmaceutically acceptable salt is used to treat TBI (including mild traumatic brain injury, chronic traumatic brain injury, or 15 recurring traumatic brain injury).
  • a compound of Formula (II) or its pharmaceutically acceptable salt is used to treat TBI (including mild traumatic brain injury, chronic traumatic brain injury, or recurring traumatic brain injury).
  • a compound of Formula (III) or its pharmaceutically acceptable 20 salt is used to treat TBI (including mild traumatic brain injury, chronic traumatic brain injury, or recurring traumatic brain injury).
  • a compound of Formula (IV) or its pharmaceutically acceptable salt is used to treat TBI (including mild traumatic brain injury, chronic traumatic brain injury, or recurring traumatic brain injury).
  • a compound of Formula (V) or its pharmaceutically acceptable salt is used to treat TBI (including mild traumatic brain injury, chronic traumatic brain injury, or recurring traumatic brain injury).
  • a compound of Formula (VI) or its pharmaceutically acceptable salt is used to treat TBI (including mild traumatic brain injury, chronic traumatic brain injury, or 30 recurring traumatic brain injury).
  • a compound of Formula (VII) or its pharmaceutically acceptable salt is used to treat TBI (including mild traumatic brain injury, chronic traumatic brain injury, or recurring traumatic brain injury).
  • a compound of Formula (VIII) or its pharmaceutically acceptable 5 salt is used to treat TBI (including mild traumatic brain injury, chronic traumatic brain injury, or recurring traumatic brain injury).
  • a compound of Formula (IX) or its pharmaceutically acceptable salt is used to treat TBI (including mild traumatic brain injury, chronic traumatic brain injury, or recurring traumatic brain injury).
  • a compound of Formula (X) or its pharmaceutically acceptable salt is used to treat TBI (including mild traumatic brain injury, chronic traumatic brain injury, or recurring traumatic brain injury).
  • a compound of Formula (XIa) or its pharmaceutically acceptable salt is used to treat TBI (including mild traumatic brain injury, chronic traumatic brain injury, or 15 recurring traumatic brain injury).
  • a compound of Formula (XIb) or its pharmaceutically acceptable salt is used to treat TBI (including mild traumatic brain injury, chronic traumatic brain injury, or recurring traumatic brain injury).
  • a compound of Formula (XIc) or its pharmaceutically acceptable 20 salt is used to treat TBI (including mild traumatic brain injury, chronic traumatic brain injury, or recurring traumatic brain injury).
  • a compound of Formula (XId) or its pharmaceutically acceptable salt is used to treat TBI (including mild traumatic brain injury, chronic traumatic brain injury, or recurring traumatic brain injury).
  • a compound of Formula (XIe) or its pharmaceutically acceptable salt is used to treat TBI (including mild traumatic brain injury, chronic traumatic brain injury, or recurring traumatic brain injury).
  • a compound or its pharmaceutically acceptable salt of Formula (XIf) is used to treat TBI (including mild traumatic brain injury, chronic traumatic brain injury, or 30 recurring traumatic brain injury).
  • a compound of Formula (XIg) or its pharmaceutically acceptable salt is used to treat TBI (including mild traumatic brain injury, chronic traumatic brain injury, or recurring traumatic brain injury).
  • a compound of Formula (XII) or its pharmaceutically acceptable 5 salt is used to treat TBI (including mild traumatic brain injury, chronic traumatic brain injury, or recurring traumatic brain injury).
  • a compound of Formula (XIII) or its pharmaceutically acceptable salt is used to treat TBI (including mild traumatic brain injury, chronic traumatic brain injury, or recurring traumatic brain injury).
  • a compound of Formula (XIV) or its pharmaceutically acceptable salt is used to treat TBI (including mild traumatic brain injury, chronic traumatic brain injury, or recurring traumatic brain injury).
  • a compound of Formula (XV) or its pharmaceutically acceptable salt is used to treat TBI (including mild traumatic brain injury, chronic traumatic brain injury, or 15 recurring traumatic brain injury).
  • a compound of Formula (XVI) or its pharmaceutically acceptable salt is used to treat TBI (including mild traumatic brain injury, chronic traumatic brain injury, or recurring traumatic brain injury).
  • a compound of Formula (XVII) or its pharmaceutically acceptable 20 salt is used to treat TBI (including mild traumatic brain injury, chronic traumatic brain injury, or recurring traumatic brain injury).
  • a compound of the present invention, or a pharmaceutically acceptable salt thereof is used to treat CTE.
  • a compound of Formula (A), or a pharmaceutically acceptable salt 25 thereof is used to treat CTE.
  • a compound of Formula (B), or a pharmaceutically acceptable salt thereof is used to treat CTE.
  • a compound of Formula (I) or its pharmaceutically acceptable salt is used to treat CTE.
  • a compound of Formula (II) or its pharmaceutically acceptable salt is used to treat CTE.
  • a compound of Formula (III) or its pharmaceutically acceptable salt is used to treat CTE. 5
  • a compound of Formula (IV) or its pharmaceutically acceptable salt is used to treat CTE.
  • a compound of Formula (V) or its pharmaceutically acceptable salt is used to treat CTE.
  • a compound of Formula (VI) or its pharmaceutically acceptable 10 salt is used to treat CTE.
  • a compound of Formula (VII) or its pharmaceutically acceptable salt is used to treat CTE.
  • a compound of Formula (VIII) or its pharmaceutically acceptable salt is used to treat CTE.
  • a compound of Formula (IX) or its pharmaceutically acceptable salt is used to treat CTE.
  • a compound of Formula (X) or its pharmaceutically acceptable salt is used to treat CTE.
  • a compound of Formula (XIa) or its pharmaceutically acceptable 20 salt is used to treat CTE.
  • a compound of Formula (XIb) or its pharmaceutically acceptable salt is used to treat CTE.
  • a compound of Formula (XIc) or its pharmaceutically acceptable salt is used to treat CTE.
  • a compound of Formula (XId) or its pharmaceutically acceptable salt is used to treat CTE.
  • a compound of Formula (XIe) or its pharmaceutically acceptable salt is used to treat CTE.
  • a compound or its pharmaceutically acceptable salt of Formula 30 (XIf) is used to treat CTE. 295
  • a compound of Formula (XIg) or its pharmaceutically acceptable salt is used to treat CTE. In certain embodiments, a compound of Formula (XII) or its pharmaceutically acceptable salt is used to treat CTE. 5 In certain embodiments, a compound of Formula (XIII) or its pharmaceutically acceptable salt is used to treat CTE. In certain embodiments, a compound of Formula (XIV) or its pharmaceutically acceptable salt is used to treat CTE. In certain embodiments, a compound of Formula (XV) or its pharmaceutically acceptable 10 salt is used to treat CTE. In certain embodiments, a compound of Formula (XVI) or its pharmaceutically acceptable salt is used to treat CTE.
  • a compound of Formula (XVII) or its pharmaceutically acceptable salt is used to treat CTE.
  • the disease characterized by endoplasmic reticulum stress is a tauopathy such as a neurodegenerative disease.
  • Endoplasmic reticulum stress caused in certain cases by TBI, can lead to the unfolded protein response (ER-UPR), which is involved in human 20 tauopathies.
  • the UPR is activated in response to an accumulation of unfolded or misfolded proteins in the endoplasmic reticulum.
  • the UPR performs several functions to restore homeostasis following ER stress: slowing or stopping protein translation, degrading misfolded proteins, and inducing production of molecular chaperones involved in protein folding. If ER stress is brief, the UPR pathways work in parallel to organize a series of pro-adaptive cascades to restore proteostasis25 and the cell survives. However, in case of severe prolonged ER stress, the UPR activates the pro- apoptotic pathway.
  • Alzheimer’s Disease In certain embodiments, the disease characterized by endoplasmic reticulum stress is Alzheimer’s disease. Studies have shown that activation of the ER-UPR can precede accumulation 30 of aggregated tau in Alzheimer’s disease, potentially protecting neurons from toxic build up of tau. 296
  • Parkinson’s Disease the disease characterized by endoplasmic reticulum stress is Parkinson’s disease.
  • Tau levels in the cerebrospinal fluid are closely correlated with cognitive 10 impairment, and CSF tau levels have been shown to be predictive of the disease course.
  • a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat or prevent Parkinson’s disease.
  • Amyotrophic Lateral Sclerosis the disease characterized by endoplasmic reticulum stress is 15 amyotrophic lateral sclerosis (ALS).
  • ALS is a neurodegenerative disease characterized by degeneration of the motor system. ER stress is known to play an important role in the pathogenesis of ALS through the dysregulation of proteostasis. The involvement of the UPR pathway in ALS has been shown in ALS patients’ post-mortem spinal cord as well as in ALS mice.
  • a compound of the present invention or a pharmaceutically acceptable salt thereof is 20 used to treat or prevent ALS.
  • step 1 compound 1-1 is treated with 5 chloral (or chloral hydrate) to give chloralamide compound 1-2.
  • the reaction is typically carried out in a suitable organic solvent, such as toluene, dioxane, or DCM.
  • the reaction is optionally carried at an increased temperature (for example, under reflux at 80-110°C when performed in toluene).
  • step 2 compound 1-2 is converted to compound 1-3 in the reaction with a chlorinating agent, such as thionyl chloride (SOCl 2 ), phosphorus oxychloride (POCl 3 ), PCl 5 , or oxalyl chloride.
  • a chlorinating agent such as thionyl chloride (SOCl 2 ), phosphorus oxychloride (POCl 3 ), PCl 5 , or oxalyl chloride.
  • Step 2 is carried out in a suitable organic solvent, such as DCM, THF, dioxane, or diethyl ether, in the presence of catalytic amount of DMF to promote the reaction.
  • the reaction is optionally carried out at an increased temperature (under reflux at 50-60°C when THF is used as a solvent).
  • step 3 the chloroamide compound 1-3 is treated with potassium isocyanate (Z 2 is O in KZ 2 CN) or potassium thiocyanate (Z 2 is S in KZ 2 CN) to provide isocyanate 1-4a (Z 2 is O) or isothiocyanate 15 1-4b (Z 2 is S), respectively.
  • Step 3 is carried out in a suitable organic solvent, such as anhydrous acetone. In certain embodiments, the reaction is carried out at an increased temperature (about 40°C).
  • step 4 isocyanate or isothiocyanate 1-4 is treated with amine 1-5 in a suitable organic solvent, such as THF. The reaction is optionally performed at an increased temperature (about 50- 60°C).
  • Reaction of step 4 provides urea 1-6a or thiourea compound 1-6b.
  • the reaction is carried out in the presence of a base, such as diisopropylethylamine, when needed.
  • a base such as diisopropylethylamine
  • the final product is purified by silica gel or alumina column chromatography or by crystallization, recrystallization and/or precipitation from an organic solvent or mixture of organic solvents.
  • Suitable solvents for crystallization, recrystallization, and/or precipitation include, but are not limited to, THF, Et2O, acetone, acetonitrile, dichloromethane, 25 ethyl acetate, methanol, ethanol, isopropanol, dioxane, pentane, hexane, heptane, petroleum ether, toluene, DMF, diglyme, dimethoxyethane (monoglyme), and methyl tert-butyl ether (MTBE).
  • THF THF
  • Et2O acetone
  • acetonitrile dichloromethane
  • dichloromethane 25 ethyl acetate
  • methanol ethanol
  • isopropanol dioxane
  • pentane pentane
  • hexane hexane
  • heptane petroleum ether
  • DMF diglyme
  • a mixture of water-miscible organic solvent and water is used for crystallization, recrystallization, and/or precipitation of the final product.
  • the reaction sequence of Scheme 1 is modified so that compound 1-3 is first converted to aminoamide 2-1 in the reaction with ammonia in a suitable organic solvent, 5 for example diethyl ether, THF, DCM, or dioxane, as illustrated in Scheme 2 (step 1).
  • compound 2-1 is brought into the reaction with isocyanate (Z 2 is O) or isothiocyanate (Z 2 is s) 2-2 to give final product 1-6.
  • step 2 The reaction of step 2 is carried out in a suitable organic solvent, such as THF, optionally at an increased temperature (under reflux at 50-60°C).
  • a suitable organic solvent such as THF
  • Scheme 2 10 eaction sequence shown in Scheme 3.
  • Scheme 3 15 p , p y o give chloralamide compound 3-2.
  • the reaction is carried out in a suitable organic solvent, such as toluene, optionally at an increased temperature (under reflux at 80-110°C).
  • step 2 compound 3- 20 2 is converted to compound 3-3 in the reaction with a chlorinating agent, such as thionyl chloride 299
  • Step 2 is carried out in a suitable organic solvent, such as THF, dioxane, DCM, or diethyl ether, in the presence of catalytic amount of DMF.
  • the reaction is optionally carried out at an increased temperature (under reflux at 50- 60°C when THF is used as a solvent).
  • the compound 3-3 is brought into the reaction with 5 amine 3-4 to provide final compound 3-5 of Formula (X).
  • Step 3 is typically carried out in a suitable organic solvent, such as THF, Et2O or toluene, optionally at an increased temperature when needed.
  • reaction is carried out in the presence of a suitable base, such as tertiary amine, for example, diisopropylethylamine or triethylamine.
  • a suitable base such as tertiary amine, for example, diisopropylethylamine or triethylamine.
  • Final compound 3-5 is optionally purified by silica gel or alumina column chromatography or by crystallization, recrystallization and/or 10 precipitation from an organic solvent or mixture of organic solvents.
  • Suitable solvents for crystallization, recrystallization, and/or precipitation include, but are not limited to, THF, Et 2 O, acetone, acetonitrile, dichloromethane, ethyl acetate, methanol, ethanol, isopropanol, dioxane, pentane, hexane, heptane, petroleum ether, toluene, DMF, diglyme, dimethoxyethane (monoglyme), and methyl tert-butyl ether (MTBE).
  • a mixture of water- 15 miscible organic solvent and water is used for crystallization, recrystallization, and/or precipitation of the final product.
  • a compound of Formula (XIa) can be synthesized according to one of the following schemes: 5 Exemplary synthesis of N-(2,2,2-trichloro-1-(3-(quinolin-8-yl)-2-thioxotetrahydropyrimidin- 1(2H)-yl)ethyl)cinnamamide E - t 10 Exemplary synthesis of 3-cyclohexyl-N-(2,2,2-trichloro-1-(3-(quinolin-8-yl)-2- thioxotetrahydropyrimidin-1(2H)-yl)ethyl)propenamide 303
  • one amino functionality of diamine 5-1 is first protected with an amino protecting group (PG 1 ), such as tert-butyloxycarbonyl (BOC) protecting group or benzyloxycarbonyl (Cbz) protecting group, to provide compound 5-2.
  • Boc protecting group is 5 removable under acidic conditions.
  • Cbz protecting group is removable under catalytic hydrogenolysis (H 2 in the presence of Pd/C).
  • step 2 of Scheme 5 compound 5-2 is brought into reaction with isocyanate (Z 2 is O) or isothiocyanates (Z 2 is S) 5-3 to provide compound 5-4.
  • the reaction is carried out in a suitable organic solvent, for example, THF, toluene, acetonitrile, dioxane, DCM, or EtOAc.
  • the reaction is optionally carried out in the presence of a base, such as tertiary amine (Et 3 N or i-Pr 2 NEt)
  • step 3 N or i-Pr 2 NEt amino-protecting group PG 1 is removed from compound 5-4 to release free amino group and 15 provide compound 5-5.
  • compound 5-5 is brought into reaction with compound 5-6 in the presence of an amide coupling reagent to provide compound 5-7.
  • Amide coupling reagents are known to those skilled in the art and described, for example, in Dunetz, J. R., et al. “Large-scale applications of amide coupling reagents for the synthesis of pharmaceuticals”. Org. Process Res. Dev.2026, 20, 20 140-177 (DOI: 10.1021/op500305s).
  • Amide coupling reagents for use in the synthesis of compounds of this invention include, but are not limited to, 2-ethoxy-1-ethoxycarbonyl-1,2- dihydroquinoline (EEDQ); n-propanephosphonic acid anhydride (T3P); ethylmethylphosphonic anhydride (EMPA); 1,1′-carbonyldiimidazole (CDI); dicyclohexylcarbodiimide (DCC); N,N′- diisopropylcarbodiimide (DIC), ethyl-(N′,N′-dimethylamino)propylcarbodiimide hydrochloride25 (known as EDC, EDAC, EDCl, or WSC), (benzotriazol-1- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1- yloxy)tripyrrolidinophosphonium hexafluoro
  • HATU N,N,N',N'-tetramethyluronium hexafluorophosphate
  • HBTU O-(7-benzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate
  • TBTU O-(7-benzotriazol-1-yl)-N,N,N',N'- tetramethyluronium tetrafluoroborate
  • the solvent used in step 4 is any suitable organic solvent including but not limited to DMAc, DCM, THF, DMF, ACN, dioxane, diethyl ether, 5 diglyme, DME, DMSO, EtOAc, heptane, MTBE, or toluene.
  • the amide coupling reaction is performed in the presence of tertiary amine, such as diisopropylethylamine (iso-Pr 2 NRt)
  • compound 5-6 is first converted into an acid chloride (in a reaction with SOCl2 or oxalyl chloride) in organic solvent, such as DCM, and in the presence of DMF as an activator.
  • step 5 compound 5-7 is reacted with chloral to give final compound 5-8 of Formula (XIb).
  • Compounds of Formula (XIc) of this invention are synthesized according to Scheme 6. 15 Scheme 6 , titution of chlorine substituent in compound 6-2 with amine substituent in compound 6-1. The reaction is carried out in a suitable polar organic solvent in the presence of a suitable base, optionally at an 20 increased temperature.
  • the polar organic solvent examples include, but are not limited to, THF, dioxane, DMF, and acetonitrile.
  • the base examples include, but are not limited to, tertiary amine, such as triethylamine and diisopropylethylamine.
  • the reaction is carried out under an increased temperature to facilitate the reactivity of the reactant.
  • Final product 6-3 is optionally be purified by recrystallization, precipitation or chromatographically, when needed.
  • Suitable solvents for recrystallization and/or precipitation include, but are not limited to, THF, Et 2 O, acetone, acetonitrile, CH 2 Cl 2 , dichloroethane, EtOAc, MeOH, EtOH, isopropanol, dioxane, 309
  • step 6 compound 8- 7 is reacted with isocyanate (Z 2 is O) or isothiocyanate (Z 2 is S) 8-8 to afford the desired compound 8-9 of Formula (XII).
  • a suitable polar solvent such as THF, diethyl ether, or dioxane
  • a suitable base such as sodium bis(trimethylsilyl)amide
  • 10 compound 9-1 is directly reacted with amine 9-3 in the presence of an amide coupling reagent, such as EEDQ, T3P, EMPA, CDI, DCC, DIC, EDC, BOP, PyBOP, HATU, HBTU, or TBTU.
  • an amide coupling reagent such as EEDQ, T3P, EMPA, CDI, DCC, DIC, EDC, BOP, PyBOP, HATU, HBTU, or TBTU.
  • an optional base such as tertiary amine.
  • compound 9-1 (Z 2 is O) used in Scheme 9 to prepare compound 15 9-4 of Formula (XIII) is prepared as described in Scheme 10.
  • Scheme 10 312 is prepared as described in Scheme 10.
  • step 1 of Scheme 10 is performed by reacting compound 10-1 with ammonium acetate under conditions of copper-catalyzed aerobic oxidation as described in Wu et al. “Tandem synthesis of 2-aryl-1,2,3-triazoles from ⁇ -arylhydrazonoketones with NH 4 OAc via 5 copper-catalyzed aerobic oxidation”. Tetrahedron Lett. 2015, 56(17), 2145-2148 (DOI: 10.1016/j.tetlet.2015.03.019). Illustrative examples of the synthesis of substituted 1,2,3-triazoles are also described in WO2022/081573; A. C. Tome, Product Class 13: 1,2,3-Triazoles, pp.
  • Step 2 of Scheme 10 includes saponification of ethyl ester 10-2 formed in step 1 to prepare corresponding carboxylic acid 9-1.
  • the reaction in step 2 is typically performed in the presence of a base, such diluted aqueous solution of alkali metal hydroxide (NaOH, KOH) or diluted aqueous solution of alkaline earth hydroxide optionally at decreased temperature (0-15 o C).
  • a base such as diluted aqueous solution of alkali metal hydroxide (NaOH, KOH) or diluted aqueous solution of alkaline earth hydroxide optionally at decreased temperature (0-15 o C).
  • the hydrolysis of ester 10-2 to free acid 9-1 is carried out in diluted acid, such as aqueous HCl.
  • a suitable solvent in the reaction of step 2 includes, but is not limited to, water, water/THF, water/dioxane, water/EtOAc mixture, or water/DCM mixture. Additional examples of the suitable solvent include acetone, acetonitrile, DMF, ethanol, methanol and their mixture with water.
  • intermediate 11-3 is obtained staring from isothiocyanate 11-1, which is first reacted with ammonia to give corresponding thiourea compound 11-2, followed by reaction of 11- 2 with chloral with subsequent reaction with a chlorinating agent, such as PCl 5 or SOCl 2 .
  • a chlorinating agent such as PCl 5 or SOCl 2 .
  • compound 11-4 is reacted with intermediate 11-3 to give final compound 11-5 of Formula (XIV).
  • compound 11-4 3- phenyloxetan-3-amine
  • Scheme 12 10 In certain embodiments, when Ring T is phenyl, X is O and n is 1, compound 11-4 (3- benzyloxetan-3-amine) is prepared as shown in Scheme 13 or Scheme 14.
  • Scheme 14 Lett. 2011, 52: 565–567 (DOI: 10.1016/j.tetlet.2010.11.118) and in WO2022/020247. 5 Compounds of Formula (XV) of this invention are synthesized according to Scheme 15.
  • Scheme 15 In certain embodiments, when X is O, compound 15-1 is prepared as described in Kang, 10 G., et al. Org. Lett.2024, 26, 14, 2729–2732 (DOI: 10.1021/acs.orglett.3c01439). In certain embodiments, when X is S, compound 15-1 is prepared as described in WO2001/014339.
  • the reaction in Scheme 16 is carried out in a suitable organic solvent.
  • the suitable organic solvent includes, but is not limited to, acetonitrile, THF, diethyl ether, dioxane, toluene, EtOAc, heptane, DMF, DCM, or mixture thereof.
  • the reaction of Scheme 16 is carried out in the presence of a suitable base, including, but not limited to, tertiary amine base, such as triethylamine or 5 diisopropylethylamine.
  • the reaction is optionally performed at an increased temperature. In certain embodiments, the reaction is carried out under reflux at boiling point of the suitable solvent, or mixture of solvents, used in the reaction.
  • Scheme 17 10 the reaction of compound 17-1 with ethyl bromoacetate in step 1 to give compound 17-2 is carried in a suitable polar organic solvent, such as THF, DMF, or dioxane, in 15 the presence of a suitable base, such potassium carbonate, sodium carbonate, or cesium carbonate.
  • a suitable polar organic solvent such as THF, DMF, or dioxane
  • a suitable base such potassium carbonate, sodium carbonate, or cesium carbonate.
  • step 2 the ethyl ester group in compound 17-2 is converted into amide group in the reaction with ammonia, for example, ammonia in methanolic solution (NH3/MeOH).
  • step 3 compound 17-3 is first brought into the reaction with chloral, followed by the treatment of the reaction product with a chlorinating agent, such PCl 5 , SOCl 2 , or oxalyl chloride, to give compound 17-4.
  • a chlorinating agent such PCl 5 , SOCl 2 , or oxalyl chloride
  • step 4 20 chlorine substituent in compound 17-4 is substituted with isothiocyanate group in the reaction with potassium isothiocyanate to provide compound 17-5.
  • Step 4 can be carried out in an organic 316
  • step 5 isothiocyanate 17-5 is treated with amine 17-6 in a suitable organic solvent, such as THF, and optionally at an increased temperature (about 50-60°C) to provide thiourea compound 17-7 of Formula (XVII).
  • a suitable organic solvent such as THF
  • the reaction is optionally carried out in the presence of a base, such as a tertiary 5 amine, for example, diisopropylethylamine, when needed.
  • the final product is purified by silica gel or alumina column chromatography or by crystallization, recrystallization and/or precipitation from an organic solvent or mixture of organic solvents.
  • Suitable solvents for crystallization, recrystallization, and/or precipitation include, but are not limited to, THF, Et2O, acetone, acetonitrile, dichloromethane, ethyl acetate, methanol, ethanol, 10 isopropanol, dioxane, pentane, hexane, heptane, petroleum ether, toluene, DMF, diglyme, dimethoxyethane (monoglyme), and methyl tert-butyl ether (MTBE).
  • a mixture of water-miscible organic solvent and water is used for crystallization, recrystallization, and/or precipitation of the final product.
  • step 3 the chloroamide compound 18-3 is treated with potassium isocyanate (Z 2 is O in KZ 2 CN) or potassium thiocyanate (Z 2 is S in KZ 2 CN) to provide isocyanate 18-4a (Z 2 is O) or isothiocyanate 18-4b (Z 2 is S), respectively.
  • Step 3 is carried out in a suitable organic solvent, such as anhydrous acetone.
  • the reaction is carried out at an increased temperature (about 40°C).
  • isocyanate or isothiocyanate 18-4 is treated with amine 18-5 in a suitable organic solvent, such as THF.
  • reaction of step 4 provides a compound of Formula (XVIII).
  • reaction is carried out in the presence of a base, such as diisopropylethylamine, when needed.
  • a base such as diisopropylethylamine
  • the final product is purified by silica gel or alumina column chromatography or by crystallization, recrystallization and/or precipitation from an organic solvent or mixture of organic solvents.
  • Suitable solvents for crystallization, recrystallization, and/or precipitation include, but are not limited to, THF, Et2O, acetone, acetonitrile, dichloromethane, ethyl acetate, methanol, ethanol, isopropanol, dioxane, pentane, hexane, heptane, petroleum ether, toluene, DMF, diglyme, 15 dimethoxyethane (monoglyme), and methyl tert-butyl ether (MTBE).
  • a mixture of water-miscible organic solvent and water is used for crystallization, recrystallization, and/or precipitation of the final product.
  • Step 2 is carried out in a suitable organic solvent, such as DCM, THF, dioxane, or diethyl ether, in the presence of catalytic amount of DMF to promote the reaction.
  • a suitable organic solvent such as DCM, THF, dioxane, or diethyl ether, in the presence of catalytic amount of DMF to promote the reaction.
  • the reaction is optionally carried out at an increased 5 temperature (under reflux at 50-60°C when THF is used as a solvent).
  • step 3 the chloroamide compound 19-3 is treated with potassium isocyanate (Z 2 is O in KZ 2 CN) or potassium thiocyanate (Z 2 is S in KZ 2 CN) to provide isocyanate 19-4a (Z 2 is O) or isothiocyanate 19-4b (Z 2 is S), respectively.
  • Step 3 is carried out in a suitable organic solvent, such as anhydrous acetone. In certain embodiments, the reaction is carried out at an increased temperature (about 40°C).
  • step 10 4 isocyanate or isothiocyanate 19-4 is treated with amine 19-5 in a suitable organic solvent, such as THF. The reaction is optionally performed at an increased temperature (about 50-60°C). Reaction of step 4 provides a compound of Formula (XVIII).
  • the reaction is carried out in the presence of a base, such as diisopropylethylamine, when needed.
  • a base such as diisopropylethylamine
  • the final product is purified by silica gel or alumina column chromatography or by 15 crystallization, recrystallization and/or precipitation from an organic solvent or mixture of organic solvents.
  • Suitable solvents for crystallization, recrystallization, and/or precipitation include, but are not limited to, THF, Et 2 O, acetone, acetonitrile, dichloromethane, ethyl acetate, methanol, ethanol, isopropanol, dioxane, pentane, hexane, heptane, petroleum ether, toluene, DMF, diglyme, dimethoxyethane (monoglyme), and methyl tert-butyl ether (MTBE).
  • a 20 mixture of water-miscible organic solvent and water is used for crystallization, recrystallization, and/or precipitation of the final product.
  • Compounds of Formula (XX) of this invention are synthesized according to Scheme 20.
  • step 20 compound 20-1 is treated with chloral (or chloral hydrate) to give chloralamide compound 20-2.
  • the reaction is typically carried out in a suitable organic solvent, such as toluene, dioxane, or DCM.
  • the reaction is optionally carried at an increased temperature (for example, under reflux at 80-110°C when performed in toluene).
  • step 2 compound 20-2 is 5 converted to compound 20-3 in the reaction with a chlorinating agent, such as thionyl chloride (SOCl2), phosphorus oxychloride (POCl3), PCl5, or oxalyl chloride.
  • SOCl2 thionyl chloride
  • POCl3 phosphorus oxychloride
  • PCl5 oxalyl chloride
  • Step 2 is carried out in a suitable organic solvent, such as DCM, THF, dioxane, or diethyl ether, in the presence of catalytic amount of DMF to promote the reaction.
  • the reaction is optionally carried out at an increased temperature (under reflux at 50-60°C when THF is used as a solvent).
  • the chloroamide 10 compound 20-3 is treated with potassium isocyanate (Z 2 is O in KZ 2 CN) or potassium thiocyanate (Z 2 is S in KZ 2 CN) to provide isocyanate 20-4a (Z 2 is O) or isothiocyanate 20-4b (Z 2 is S), respectively.
  • Step 3 is carried out in a suitable organic solvent, such as anhydrous acetone.
  • the reaction is carried out at an increased temperature (about 40°C).
  • isocyanate or isothiocyanate 20-4 is treated with amine 20-5 in a suitable organic solvent, such 15 as THF.
  • the reaction is optionally performed at an increased temperature (about 50-60°C).
  • Reaction of step 4 provides a compound of Formula (XVIII).
  • the reaction is carried out in the presence of a base, such as diisopropylethylamine, when needed.
  • the final product is purified by silica gel or alumina column chromatography or by crystallization, recrystallization and/or precipitation from an organic solvent or mixture of organic 20 solvents.
  • Suitable solvents for crystallization, recrystallization, and/or precipitation include, but are not limited to, THF, Et 2 O, acetone, acetonitrile, dichloromethane, ethyl acetate, methanol, ethanol, isopropanol, dioxane, pentane, hexane, heptane, petroleum ether, toluene, DMF, diglyme, dimethoxyethane (monoglyme), and methyl tert-butyl ether (MTBE).
  • a mixture of water-miscible organic solvent and water is used for crystallization, recrystallization, 25 and/or precipitation of the final product.
  • Scheme 21 5 palladium compound, one or more ligands, and one or more bases.
  • the reaction is typically carried out in a suitable organic solvent, such as toluene, dioxane, or DCM.
  • the reaction is optionally carried at an increased temperature (for example, under reflux at 80-110°C when performed in toluene).
  • Step 2 is carried out in an atmosphere of hydrogen and in a suitable organic solvent, such as ethanol, 10 methanol, THF, dioxane, or diethyl ether, in the presence of catalytic amount of palladium or platinum to promote the reaction.
  • Step 3 is carried out in a suitable organic solvent, such as THF or DCM, in the presence of a suitable base, such as tertiary amine, for example, triethylamine or diisopropylethylamine 321
  • Step 2 is carried out in a 10 suitable organic solvent, such as DCM, THF, dioxane, or diethyl ether, in the presence of catalytic amount of DMF to promote the reaction.
  • the reaction is optionally carried out at an increased temperature (under reflux at 50-60°C when THF is used as a solvent).
  • Compound 22-3 is used as a staring compound to prepare compound of Formula (XXII).
  • Compound 4-1 is prepared as described for in Scheme 4.
  • step 3 compound 22-3 is brought into the reaction with amide 4-1 15 in the presence of a suitable strong base capable of deprotonating amide nitrogen.
  • Examples of a strong base include, but are not limited to, sodium hydride (for example, 60% dispersion in oil) and sodium bis(trimethylsilyl)amide.
  • the reaction is carried out in a suitable organic solvent, optionally at an increased temperature.
  • compound 4-1 is first dissolved in an aprotic polar organic solvent, such as THF, and the reaction solution is cooled when needed.
  • solution 20 of sodium bis(trimethylsilyl)amide in THF or solid sodium hydride (60% dispersion in oil) is added portion-wise to the reaction solution, followed by addition of a solution of compound 22-3 in an 322
  • the target compounds of the present invention can be manufactured according to routes described in the Working Examples below or as otherwise known in the patent or scientific literature and if appropriate supported by the knowledge of the ordinary worker or common general 5 knowledge. All reagents were purchased from commercial suppliers and used without further purification unless otherwise stated. 1H NMR spectra were recorded in deuterated chloroform (CDCl 3 ) or deuterated dimethyl sulfoxide (DMSO-d 6 ) on Bruker Advance NMRS-400 at 400 MHz in 5 mm outer diameter tubes (Wilmad NMR tubes (Sigma-Aldrich), 5mm Thin Wall, 7′′ Length) at 300.0 Kelvin.
  • Example 1 Synthesis of Target Compounds Preparation of Salubrinal, (E)-N-(2,2,2-trichloro-1-(3-(quinolin-8- yl)thioureido)ethyl)cinnamamide 20 327
  • Step 1 To a stirred, room temperature solution of (2E)-3-phenylprop-2-enamide (1 g, 6.79 mmol) in toluene (15 mL) was added 2,2,2-trichloroethane-1,1-diol (1.12 g, 6.79 mmol). The mixture was heated to 120 °C and stirred at reflux for 18 hours. The mixture was concentrated under reduced pressure to give a crude product, which was purified by recrystallization in ethyl acetate to give 5 (2E)-3-phenyl-N-(2,2,2-trichloro-1-hydroxyethyl)prop-2-enamide (400 mg, 19.99% yield). LC- MS (ES-) found: 291.9 [M-H]-.
  • Step 2 To a stirred solution of (2E)-3-phenyl-N-(2,2,2-trichloro-1-hydroxyethyl)prop-2-enamide (200 mg, 0.678 mmol) in dry THF (5 mL) was added SOCl2 (187.15 mL, 2.58 mmol). The mixture 10 was stirred at 60 °C under N 2 for 3 hours.
  • Step 3 To a stirred solution of (E)-N-(1,2,2,2-tetrachloroethyl)cinnamamide (1 g, 3.19 mmol) in acetone (10 mL) was added KSCN (0.38 g, 3.83 mmol). The mixture was heated to reflux and 15 stirred at reflux for 2 hours. The mixture was then cooled to room temperature and a precipitate formed. The precipitate was filtered off and the filtrate was concentrated under reduced pressure.
  • Step 2 To a stirred, room temperature solution of N 1 -(2-fluorophenyl)propane-1,3-diamine (1 g, 20 5.94 mmol) in dioxane (10 mL) was added 1-(quinolin-8-yl)imidazolidine-2-thione (913 mg, 5.12 329
  • Step 3 To a stirred, 0 °C solution of N-(1,2,2,2-tetrachloroethyl)cinnamamide (245 mg, 0.79 mmol) in DMF (5 mL) was added triethylamine (0.27 mL, 1.99 mmol). The mixture was stirred at 10 0 °C for 15 minutes. A 0 °C THF solution of 1-(2-fluorophenyl)tetrahydropyrimidine-2(1H)-thione (140 mg, 0.66 mmol) was then added. Then mixture was warmed to room temperature and stirred for 24 hours. Water was added and the mixture was extracted with EtOAc (2 x 50 ml).
  • the reaction vessel was then equipped with a Soxhlet extraction device charged with molecular sieves (20 g).
  • the mixture 5 was heated to 110°C and stirred at reflux for 12 hours. After 12 hours at reflux, the extraction thimble of molecular sieves was replaced with a fresh portion of molecular sieves (20 g), and the mixture was heated at reflux for an additional 12 hours.
  • Step 2 To a stirred solution of 3-phenyl-N-(2,2,2-trichloro-1-hydroxyethyl)propanamide (450 mg, 1.52 mmol) in in dry THF (5 mL) was added SOCl 2 (4.5 mL, 62.04 mmol). The mixture was stirred at 60 °C under N2 for 3 hours. The mixture was concentrated under reduced pressure to give a 15 crude mixture of 3-phenyl-N-(1,2,2,2-tetrachloroethyl)propanamide (465 mg), which was sufficiently pure to be used in the next step without further purification.
  • Step 3 To a stirred, room temperature solution of 3-phenyl-N-(1,2,2,2- tetrachloroethyl)propanamide (450 mg, 1.26 mmol) in acetone (10 mL) at was added KSCN (162 mg, 2.2 mmol). The mixture was stirred at room temperature for 16 hours and a precipitate formed. 20 The precipitate was filtered off and the filtrate was concentrated under reduced pressure.
  • Step 4 To a stirred solution 3-phenyl-N-(2,2,2-trichloro-1-isothiocyanatoethyl)propanamide (0.3 g, 0.889 mmol) in THF (3 mL) was added 1-methylpiperazine (0.106 g, 1.06 mmol). The mixture was heated to 60 °C and stirred for 1 hour. After completion of the reaction step (as determined by LC-MS and TLC analysis), H 2 O (30 mL) was added, and the mixture was extracted with CH 2 Cl 2 5 (3 x 50 mL).
  • Step 2 To a stirred vessel containing methyl 3-(quinolin-8-ylamino)propanoate (2.4 g, 10.42 mmol) was added ammonium hydroxide (3.65 mL , 104.23 mmol). The mixture was stirred at 70 15 °C for 24 hours. Bicarbonate solution (50 mL) was added and the mixture was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over Na2SO4, filtered, and then concentrated under reduced pressure to give 3-(quinolin-8-ylamino)propanamide (53.49% yield). LC-MS (ES+) found: 217.2 [M+H] + .
  • Step 3 To a stirred, 0 °C solution of 3-(quinolin-8-ylamino)propanamide (1.2 g, 5.58 mmol) in 20 THF (12 mL) was added 4.0 M LiAlH4 in THF (4 mL , 8.36 mmol). The mixture was heated to 70 °C and stirred for 5 hours. THF:water (50 mL) was added and the organic layer was extracted, and concentrated under reduced pressure to give N 1 -(quinolin-8-yl)propane-1,3-diamine (80.21% yield). LC-MS (ES+) found: 202.1 [M+H] + .
  • Step 4 To a stirred solution of N 1 -(quinolin-8-yl)propane-1,3-diamine (500 mg , 2.48 mmol) in 25 dioxane (5 mL) was added di(1H-imidazol-1-yl)methanethione (619.79 mg, 3.48 mmol).
  • the 333 To a stirred solution of N 1 -(quinolin-8-yl)propane-1,3-diamine (500 mg , 2.48 mmol) in 25 dioxane (5 mL) was added di(1H-imidazol-1-yl)methanethione (619.79 mg, 3.48 mmol).
  • the 333 To a stirred solution of N 1 -(quinolin-8-yl)propane-1,3-diamine (500 mg , 2.48 mmol) in 25 dioxane (5 mL) was added di(1H-imidazol-1-yl)me
  • Step 5 To a stirred, room temperature solution of (2E)-3-phenylprop-2-enamide (1 g, 6.79 mmol) 10 in toluene (15 mL) was added 2,2,2-trichloroethane-1,1-diol (1.12 g, 6.79 mmol). The mixture was heated to 120 °C and stirred at reflux for 18 hours. The mixture was concentrated under reduced pressure to give a crude product, which was purified by recrystallization in ethyl acetate to give (2E)-3-phenyl-N-(2,2,2-trichloro-1-hydroxyethyl)prop-2-enamide (400 mg, 19.99% yield). LC- MS (ES-) found: 291.9 [M-H]-.
  • Step 7 To a stirred solution of (E)-N-(1,2,2,2-tetrachloroethyl)cinnamamide (200 mg, 0.64 mmol) in DMF (5 mL) was added 1-(quinolin-8-yl)tetrahydropyrimidine-2(1H)-thione (155.48 mg, 0.64 mmol) followed by K2CO3 (264.54 mg, 1.92 mmol). The mixture was stirred at room temperature for 24 hours.
  • Step 2 To a stirred solution of 3-cyclohexyl-N-(2,2,2-trichloro-1-hydroxyethyl)propanamide (450 mg, 1.49 mmol) in in dry THF (5 mL) was added SOCl2 (4.5 mL, 62.04 mmol). The mixture was 20 stirred at 60 °C under N2 for 3 hours. The mixture was concentrated under reduced pressure to give a crude mixture of 3-cyclohexyl-N-(1,2,2,2-tetrachloroethyl)propanamide (465 mg, 87% yield), which was sufficiently pure to be used in the next step without further purification. 335
  • Step 3 To a stirred, room temperature solution of 3-cyclohexyl-N-(1,2,2,2- tetrachloroethyl)propanamide (450 mg, 1.26 mmol) in acetone (10 mL) was added KSCN (162 mg, 2.2 mmol). The mixture was stirred at room temperature for 16 hours and a precipitate formed. The precipitate was filtered off and the filtrate was concentrated under reduced pressure.
  • Step 4 To a stirred solution of 3-cyclohexyl-N-(2,2,2-trichloro-1- isothiocyanatoethyl)propanamide (0.3 g, 0.872 mmol) in THF (3 mL) was added butan-1-amine (0.106 g, 1.45 mmol). The mixture was heated to 60 °C and stirred for 1 hour. After completion of the reaction step (as determined by LC-MS and TLC analysis), H2O (30 mL) was added, and the mixture was extracted with CH 2 Cl 2 (3 x 50 mL).
  • Step 2 To a stirred solution of (2E)-3-phenyl-N-(2,2,2-trichloro-1-hydroxyethyl)prop-2-enamide 10 (200 mg, 0.678 mmol) in dry THF (5 mL) was added SOCl 2 (187.15 mL, 2.58 mmol). The mixture was stirred at 60 °C under N 2 for 3 hours. The mixture was concentrated under reduced pressure to give a crude mixture of (E)-N-(1,2,2,2-tetrachloroethyl)cinnamamide, which was sufficiently pure to be used in the next step without further purification.
  • Step 3 To a stirred, room temperature solution of (E)-N-(1,2,2,2-tetrachloroethyl)cinnamamide 15 (200 mg, 645.96 mmol) in DMF (5 mL) was added 4-(4-chlorophenyl)thiazol-2-amine (149.9 mg, 709.6 mmol), The mixture was stirred at room temperature under N2 for 24 hours. The mixture was concentrated under reduced pressure to give a crude residue. Water was added, and the mixture was extracted with EtOAc (3 x 50 ml).
  • Step 2 To a stirred solution of (2E)-3-phenyl-N-(2,2,2-trichloro-1-hydroxyethyl)prop-2-enamide (200 mg, 0.678 mmol) in dry THF (5 mL) was added SOCl 2 (187.15 mL, 2.58 mmol). The mixture 15 was stirred at 60 °C under N 2 for 3 hours. The mixture was concentrated under reduced pressure to give a crude mixture of (E)-N-(1,2,2,2-tetrachloroethyl)cinnamamide, which was sufficiently pure to be used in the next step without further purification.
  • Step 3 To a stirred, room temperature solution of (E)-N-(1,2,2,2-tetrachloroethyl)cinnamamide (200 mg, 0.639 mmol) in DMF (5 mL) was added benzo[d]thiazol-2-amine (95.97 mg, 0.639 20 mmol). The mixture was stirred at room temperature under N2 for 24 hours. The mixture was concentrated under reduced pressure to give a crude residue. Water was added, and the mixture was extracted with EtOAc (3 x 50 ml). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude product, which was 338
  • Step 2 To a stirred solution of (E)-3-(4-cyanophenyl)acrylamide (1.0 g, 5.81 mmol) in toluene 20 (10 mL) was added 2,2,2-trichloroethane-1,1-diol (0.96 g, 5.81 mmol). The mixture was heated to 120 °C and stirred at reflux for 12 hours. The mixture was concentrated under reduced pressure to give (E)-3-(4-cyanophenyl)-N-(2,2,2-trichloro-1-hydroxyethyl)acrylamide (26.94 % yield). LC- 339
  • Step 4 To a stirred, 0 °C solution of 1-(quinolin-8-yl)tetrahydropyrimidine-2(1H)-thione (380.71 10 mg , 1.56 mmol) in DMF (15 mL) was added TEA (0.68 mL , 4.69 mmol).
  • Step 2 To a stirred vessel containing methyl 3-((2-methoxyphenyl)amino)propanoate (2.4 g, 10.42 mmol) was added ammonium hydroxide (24 mL). The mixture was stirred at 70 °C for 24 hours.
  • Step 3 To a stirred, 0 °C solution of 3-((2-methoxyphenyl)amino)propanamide (1 g, 5.15 mmol) in THF (10 mL) was added 4.0 M LiAlH4 in THF (10 mL). The mixture was heated to 70 °C and stirred 5 hours. THF: water (50 mL) was added and the organic layer was extracted, and concentrated under reduced pressure to give N 1 -(2-methoxyphenyl)propane-1,3-diamine (53.88% yield). LC-MS (ES+) found: 181.1 [M+H] + .
  • Step 4 To a stirred solution of N 1 -(2-methoxyphenyl)propane-1,3-diamine (2 g, 11.1 mmol) in dioxane (10 mL) was added di(1H-imidazol-1-yl)methanethione (1.98 g, 11.1 mmol). The mixture 341
  • Step 2 To a stirred vessel containing methyl 3-((2-methoxyphenyl)amino)propanoate (2.4 g, 10.42 mmol) was added ammonium hydroxide (24 mL). The mixture was stirred at 70 °C for 24 hours.
  • Step 3 To a stirred, 0 °C solution of 3-((2-methoxyphenyl)amino)propanamide (1 g, 5.15 mmol) in THF (10 mL) was added 4.0 M LiAlH 4 in THF (10 mL). The mixture was heated to 70 °C and stirred 5 hours. THF: water (50 mL) was added and the organic layer was extracted, and concentrated under reduced pressure to give N 1 -(2-methoxyphenyl)propane-1,3-diamine (53.88% yield). LC-MS (ES+) found: 181.1 [M+H] + . 343
  • Step 4 To a stirred solution of N 1 -(2-methoxyphenyl)propane-1,3-diamine (2 g, 11.1 mmol) in dioxane (10 mL) was added di(1H-imidazol-1-yl)methanethione (1.98 g, 11.1 mmol). The mixture was heated to reflux and stirred for 3 hours. Water (5 mL) was added and the mixture was extracted with EtOAc (2 x 50 mL).
  • Step 2 To a solution of 2-(2-(quinolin-8-ylamino)ethyl)isoindoline-1,3-dione (3 g, 9.45 mmol) in EtOH (30 mL) was added NH 2 NH 2 ⁇ H 2 O (50-60%) (1.5 mL) The mixture was heated to 80 °C and stirred under N2 for 2 hours. The mixture was concentrated under reduced pressure to give a crude 20 residue. Water was added, and the mixture was extracted with EtOAc (3 x 50 ml). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under 345
  • Step 3 To a stirred solution of N 1 -(quinolin-8-yl)ethane-1,2-diamine (1.5 g, 8.01 mmol) in dioxane (20mL) was added 1-(quinolin-8-yl)imidazolidine-2-thione (2 g, 11.21 mmol). The mixture was heated to 80 °C and stirred under N 2 for 3 hours. Water was added and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine,10 dried over Na2SO4, filtered, and then concentrated under reduced pressure to give 1-(quinolin-8- yl)imidazolidine-2-thione (1.50 g, 81.66% yield) as gammy liquid.
  • Step 4 To a solution of (E)-N-(1,2,2,2-tetrachloroethyl)cinnamamide (1.2g, 3.92 mmol) in DMF (10 mL) was added TEA (792.85mg, 7.85 mmol) and 1-(quinolin-8-yl)imidazolidine-2-thione (600 mg, 2.62 mmol). The mixture was stirred at room temperature under N2 for 24 hours. The reaction mixture was concentrated under reduced pressure. Water was added and the mixture was extracted 20 with EtOAc (3 x 50 mL).
  • Step 2 To a stirred solution of 3-cyclohexylpropanamide (500 mg, 0.64 mmol) in toluene (2 mL, 15 6.44 mmol) was added 2,2,2-trichloroethane-1,1-diol (149.15 mg, 0.9 mmol). The mixture was heated to 120 °C and stirred at reflux for 12 hours. The mixture was concentrated under reduced pressure. Water (50 mL) was added and the crude material was extracted with ethyl acetate (2 x 50 mL).
  • Step 4 To a stirred solution of 3-cyclohexyl-N-(1,2,2,2-tetrachloroethyl)propanamide (500 mg, 5 1.56 mmol) in DMF (5 mL) was added Na2CO3 (0.7 mL, 4.67 mmol) and 1-(quinolin-8- yl)tetrahydropyrimidine-2(1H)-thione (378.95 mg, 1.56 mmol).
  • Step 3 To a stirred, 0 °C solution of 3-((3-chloroquinolin-8-yl)amino)propanamide (1 g, 4 mmol) 10 in THF (2.88 mL, 40.05 mmol) was added 4.0 M LiAlH4 in THF (0.23 mL , 6.01 mmol). The mixture was heated to 70 °C and stirred for 5 hours. THF:water (50 mL) was added and the organic layer was extracted, and concentrated under reduced pressure to give N 1 -(3-chloroquinolin-8- yl)propane-1,3-diamine (1.0 g, 84.74% yield).
  • Step 4 To a stirred solution of N 1 -(3-chloroquinolin-8-yl)propane-1,3-diamine (1.0 g, 4.24 mmol) 15 in dioxane (20 mL) was added di(1H-imidazol-1-yl)methanethione (0.76 g, 4.24 mmol). The mixture was heated to reflux and stirred for 3 hours. Water (50 mL) was added and the mixture was extracted with ethyl acetate (2 x 100 mL).
  • Step 5 To a stirred solution of 1-(3-chloroquinolin-8-yl)tetrahydropyrimidine-2(1H)-thione (500 mg, 1.8 mmol) in DMF (10 mL) was added TEA (127.26 mg, 1.26 mmol) and (E)-N-(1,2,2,2- tetrachloroethyl)cinnamamide (563.42 mg , 1.8 mmol). The mixture was stirred at room temperature for 24 hours. Bicarbonate solution (50 mL) was added and the crude material was 25 extracted with CH2Cl2 (2 x 50 mL).
  • Step 2 To a solution of methyl 3-(quinolin-8-ylamino)propanoate (2 gm, 8.69 mmol) in THF (30 5 mL) was added 30% NH4OH.
  • Step 3 To a stirred, 0 °C solution of 3-(quinolin-8-ylamino)propanamide (1 g, 4.65 mmol) in THF (30 mL) was added 2.4 M LiAlH4 in THF (3.87 mL, 9.29 mmol) dropwise. The mixture was warmed to room temperature and stirred for 10 minutes. The mixture was then heated gradually to 15 70 °C and stirred for 3 hours. The mixture was then cooled to 0 °C.
  • Step 4 To a stirred, room temperature solution of N 1 -(quinolin-8-yl)propane-1,3-diamine (300 mg, 1.49 mmol) in dioxane (10 mL) was added di(1H-imidazol-1-yl)methanethione (318.75 mg, 1.79 mmol) The mixture heated to 100 °C and stirred under N2 for 2 hours. The mixture was concentrated under reduced pressure. Water was added and the mixture was extracted with EtOAc (3 x 50 mL).
  • Step 5 To a stirred, 0 °C solution of (E)-N-(1,2,2,2-tetrachloroethyl)-3-(4- (trifluoromethyl)phenyl)acrylamide (200 mg, 0.53 mmol) in THF (4 mL) was added NaH (25.19 mg, 1.05 mmol). The mixture was stirred at 0 °C for 15 minutes. A 0 °C THF solution of 1- (quinolin-8-yl)tetrahydropyrimidine-2(1H)-thione (153.28 mg, 0.63 mmol) was then added. The 5 mixture was warmed to room temperature and stirred for 16 hours.
  • Step 2 To a solution of methyl 3-(quinolin-8-ylamino)propanoate (2 gm, 8.69 mmol) in THF (30 15 mL) was added 30% NH4OH. The mixture was then purged with ammonia gas keeping the pressure at about 10 bar for 3 hours. The mixture was then heated to 70 °C and stirred under N230 hours. The reaction mixture was concentrated under reduced pressure. NaHCO 3 solution was added, and the mixture was extracted with EtOAc (2 x 100 mL).
  • Step 3 To a stirred, 0 °C solution of 3-(quinolin-8-ylamino)propanamide (1 g, 4.65 mmol) in THF (30 mL) was added 2.4 M LiAlH4 in THF (3.87 mL, 9.29 mmol) dropwise. The mixture was warmed to room temperature and stirred for 10 minutes. The mixture was then heated gradually to 70 °C and stirred for 3 hours. The mixture was then cooled to 0 °C.
  • Step 4 To a stirred, room temperature solution of N 1 -(quinolin-8-yl)propane-1,3-diamine (300 10 mg, 1.49 mmol) in dioxane (10 mL) was added di(1H-imidazol-1-yl)methanethione (318.75 mg, 1.79 mmol) The mixture heated to 100 °C and stirred under N 2 for 2 hours. The mixture was concentrated under reduced pressure. Water was added and the mixture was extracted with EtOAc (3 x 50 mL).
  • Step 5 To a stirred, 0 °C solution of (E)-3-(4-nitrophenyl)-N-(1,2,2,2-tetrachloroethyl)acrylamide (220 mg, 0.61 mmol) in THF (5 mL) was added NaH (44 mg, 1.84 mmol). The mixture was stirred20 at 0 °C for 15 minutes. A 0 °C THF solution of 1-(quinolin-8-yl)tetrahydropyrimidine-2(1H)- thione (153.28 mg, 0.63 mmol) was then added. The mixture was warmed to room temperature and stirred for 16 hours. Water was added and the mixture was extracted with EtOAc (2 x 50 mL).
  • Step 6 To a stirred, room temperature solution of (E)-3-(4-nitrophenyl)-N-(2,2,2-trichloro-1-(3- (quinolin-8-yl)-2-thioxotetrahydropyrimidin-1(2H)-yl)ethyl)acrylamide (55 mg, 0.09 mmol) in 355
  • Step 2 To a stirred, room temperature solution of N 1 -(pyridin-2-yl)propane-1,3-diamine (150 mg, 0.99 mmol) in dioxane (10 mL) was added di(1H-imidazol-1-yl)methanethione (212.14 mg, 1.19 mmol) The mixture heated to 50 °C and stirred under N2 for 1 hour. The mixture was concentrated under reduced pressure. Water was added and the mixture was extracted with EtOAc (3 x 50 mL).
  • Step 2 To a stirred, 0 °C solution of tert-butyl (3-((2-nitrophenyl)amino)propyl)carbamate (1 g, 3.39 mmol) in DCM (30 mL) was added TFA (2.58 mL, 33.86 mmol) dropwise. The mixture was gradually warmed to room temperature and stirred for 3 hours. The mixture was concentrated under reduced pressure and azeotroped with DCM three times. Water was then added and the 360
  • Step 3 To a solution of N1-(2-nitrophenyl)propane-1,3-diamine (200 mg, 1.02 mmol) in dioxane (10 mL) was added di(1H-imidazol-1-yl)methanethione (913 mg, 5.12 mmol) The mixture was heated to 70 °C and stirred under N 2 for 5 hours. The reaction mixture was concentrated under reduced pressure. Water was added and the mixture was extracted with EtOAc (3 x 50 mL).
  • Step 4 To a stirred, 0 °C solution of N-(1,2,2,2-tetrachloroethyl)cinnamamide (100 mg, 0.32 15 mmol) in THF (5 mL) was added NaH (25.19 mg, 1.05 mmol). The mixture was stirred at 0 °C for 15 minutes. A 0 °C THF solution of 1-(2-nitrophenyl)tetrahydropyrimidine-2(1H)-thione (91 mg, 0.38 mmol) was then added. The mixture was warmed to room temperature and stirred for 16 hours. Water was added and the mixture was extracted with EtOAc (2 x 50 mL).
  • Step 5 To a stirred, room temperature solution of (E)-N-(2,2,2-trichloro-1-(3-(2-nitrophenyl)-2- 25 thioxotetrahydropyrimidin-1(2H)-yl)ethyl)cinnamamide (100 mg, 0.19 mmol) in MeOH:H2O (1:1) (4 mL) was added Fe (53 mg, 0.95 mmol) and ammonium chloride (100 mg, 1.9 mmol). The mixture was heated to 60 °C and stirred for 1 hour. The mixture was cooled to room temperature and filtered through a celite pad, and the filtrate was concentrated under reduced pressure. Water was then added and the mixture was extracted with EtOAc (2 x 20 ml). The combined organic 361
  • In vitro models include but are not limited to cell assays or 5 organoids.
  • In vitro models of TBI are known to the skilled artisan and reviewed in, for example, Kumaria A, Tolias CM. “In vitro models of neurotrauma” Br J Neurosurg.2008 Apr;22(2):200-6. and Morrison B 3rd, Elkin BS, Dollé JP, Yarmush ML. “In vitro models of traumatic brain injury” Annu Rev Biomed Eng.2011 Aug 15;13:91-126.
  • the administration of a compound of the invention prior to bTBI is also evaluated in an 20 animal model to ascertain whether the use of a compound of the invention ameliorates neuropsychiatric deficits in the form of impulsive-like behavior as measured by the elevated plus maze (EPM) test, and spatial memory as measured by the Morris water maze (MWM) test.
  • Rats for the biochemical characterization studies are divided into control or blast groups based on time of euthanasia (30 min, 24 h, or 21 days). The time points ae chosen to look at 1) 25 acute ER stress activation, 2) subsequent iron toxicity, and 3) tauopathy. Sham rats are anesthetized but not exposed to blast. The rats for behavior are divided according to assay and time point (72 h, 7 days, and 1 month).
  • PET imaging PET imaging technique using 18 F radiopharmaceuticals is used for antemortem diagnosis of CTE.
  • [F-18]Flornaptitril [F-18]FDDNP) is used for the PET imaging.
  • [F-18]Flornaptitril is known as a radiopharmaceutical able to simultaneously detect both beta- 5 amyloid plaques and tau macroaggregates. The presence and distribution of these proteins in the brain is linked to the development and progression of CTE.
  • PET imaging for the CTE diagnosis is known in the art and described in Pierre, K., et al. “Chronic traumatic encephalopathy: update on current clinical diagnosis and management”.
  • Biomedicines 2021, 9(4), 415 (DOI: 10.3390/biomedicines9040415); Huang, C.-X., et al. “Positron emission tomography imaging for 10 the assessment of mild traumatic brain injury and chronic traumatic encephalopathy: recent advances in radiotracers”. Neural Regeneration Research, 2022, vol.77, No.1, pp. 74-81 (DOI: 10.4103/1673-5374.314285); Chen, S. T., et al. “FDDNP-PET tau brain protein binding patterns in military personnel with suspected chronic traumatic encephalopathy”. J. Alzheimers Dis.2018, 65(1), pp. 79-88 (DOI:10.3233/JAD-171152); Lesman-Segev, O.
  • a Sprague-Dawley rat is positioned in a protective PVC tubing to prevent injury to the peripheral organs, and an acceleration wave is generated and allowed to collide with the skull of the rat.
  • the blast is delivered to the right side of the rat’s skull with the head freely mobile.
  • the wave produced is 1 ms in duration.3-6-month-old25 male Sprague-Dawley rats are used for this study.
  • the intensity of the injury is adjusted in a step- wise manner by decreasing or increasing the thickness of the membrane that exploded with pressurized nitrogen gas.
  • An injury paradigm of 50 PSI is selected, which correlates with human concussion, that is the most common type of injury linked to CTE.
  • Blast model apparatus is described in Lucke-Wold, B. P. et al. “Endoplasmic reticulum stress modulation as a target for 30 ameliorating effects of blast induced traumatic brain injury”. J. Neurotrauma. Supplement 1, 2017; 364
  • the Sprague Dawley rats are given either one injury, or six injuries over a two-week period. Various time points of sacrifice are chosen to look at markers of ER stress and tauopathy.
  • the assay is used to ascertain whether the compound of the invention reduces C/EBP Homologous Protein (CHOP) and GADD34 that are markers of ER 5 stress.
  • a compound of the invention is dissolved in 0.9% saline and administered at a concentration of 1 mg/kg at a single time 5 minutes post-blast.0.9% saline is used for the vehicle in rats not receiving the compound of the invention.
  • a compound of the invention is administered to the rats after injury to target ER stress.
  • the 10 compound of the invention is administered by IP injection 30 minutes after injury using a dose of 1 mg/kg.
  • Western blot analysis, immuno-histochemistry, and PCR at various time points after injury are used.
  • LICOR western blot protocol, IHC world immunohistochemistry protocol, and Applied Biosystems PCR protocol are used for the assays.
  • Example 3 – Cell culture NG-108 cells are cultured in a humidified incubator (5% CO 2 at 37°C) in T75 culture flasks.
  • DMEM Modified Eagle Medium
  • FBS fetal bovine serum
  • HAT hypoxanthine-aminopterin-thymidine 20
  • DMEM differentiation media
  • TUN tunicamycin
  • TUN + a compound of the invention TUN is administered (1 ⁇ g/mL) to cells for 6 h prior to collection to activate the ER stress response, and the compound of the invention is administered (100 ⁇ M) to cells 30 min prior to collection.
  • Control and TUN cells are administered DMSO (0.5%) 30 min prior to collection.
  • Cells are collected in 1% sodium dodecyl sulfate (SDS) for measurement of protein expression.
  • SDS sodium dodecyl sulfate
  • Example 4 Western blot analysis
  • frontal cortex is collected from blast and control rats. In vitro cell collection is also conducted. Protein samples are prepared in 1% SDS, and the assay is performed as previously described in Lucke-Wold, B.P. et al. “Bryostatin-1 restores blood brain barrier 5 integrity following blast-induced traumatic brain injury”. Mol. Neurobiol.2015 Dec; 52(3): 1119- 1134. DOI: 10.1007/s12035-014-8902-7.
  • Primary antibodies are rabbit anti-phosphoPERK mAB (1:1000), anti-PERK mAB (1:1000), and anti-phosphoeiF2a (1:1000); mouse anti-NFjB p65 (1:200); mouse anti-AT8; and mouse anti-CP13.
  • a rabbit antib-actin mAB (1:10,000) is used as an endogenous control to normalize protein loading.
  • Secondary antibodies are IRDye® 800CW (goat 10 anti-rabbit) and IRDye® 680RD (goat anti-mouse). Images are collected and analyzed with an Odyssey fluorescent scanner. Images are converted to gray scale and the values calculated after background subtraction and then normalized to b-actin to measure relative intensity.
  • Example 5 Immunohistochemistry 15 Brains are rapidly removed and placed into an ice-cold protease/phosphatase inhibitor cocktail mix (HaltTM; Thermo Scientific; Pittsburgh, PA). Tissues are flash frozen in liquid nitrogen for storage at -80°C. Fixed brain tissue for the TBI and control rats are prepared as previously described in Lucke-Wold, B.P. et al. Mol. Neurobiol.2015; 52(3): 1119-1134. Briefly, rats are anesthetized with 4% isoflurane and cardiac perfused with ice-cold 0.9% saline, followed 20 by 4% paraformaldehyde for 15 min.
  • Brain slabs 25 are sectioned (10 ⁇ m), mounted onto slides, and prepared for staining. Standard protocols for Perls DAB and cresyl violet are used for the iron staining (Sigma Aldrich).
  • FST Forced Swim Test
  • EPM Elevated Plus Maze
  • the rat is placed in the middle of the EPM and tracking is performed with Any-Maze software for 5 min. The percentage time spent in the open arms and distance traveled is recorded and quantified.
  • the training paradigm consists of 6 days of acquisition with a hidden platform followed by a probe trial on day 7. During spatial acquisition, rats are placed into the maze apparatus four 20 times from four different locations. Each rat has a 2 min trial to locate the platform.
  • Example 10 – PET identification of CET 5 A PET imaging technique using a radiopharmaceutical, such as [18-F]FDDNP, is used in this invention to identify CTE and its progression in a patient. An example of this technique is described in US Patent 10,357,217.
  • the [18-F]FDDNP PET imaging is used for (i) determination of the regional brain PET activities for CTE; (ii) staging of CTE for a patient based on regional intensity and spatial patterns of brain signals measured by PET imaging; and (iii) diagnosis or 10 identification of CTE based on PET imaging profiles.
  • a magnetic resonance image (MRI) and PET images of the patient’s brain are obtained using radiopharmaceutical tracer, for example [18-F]FDDNP, which is administered to a patent.
  • PET images used in the diagnosis or identification of CTE include dynamic PET images or static PTE images.
  • MRI and PET images may be obtained using a separate PET scanner and MRI 15 scanner.
  • PET and MRI scan images are obtained using a single scanner (a combined MRI-PET scanner).
  • the PET images are mapped to a common space using MRI image as a guide.
  • DVR distribution volume ration
  • DVR distribution volume ration
  • a PET imaging to identify and/or determine the progression of CTE includes the steps of: (i) obtaining an MRI image of the patient’s brain; (ii) obtaining in vivo PET images of the patient’s brain after a radiopharmaceutical 25 tracer (for example, [18-F]FDDNP) is administered to the patient; (iii) generating distribution volume ratio (DVR) images of the patient’s brain and mapping the same images onto the common space (the DVR images comprise a plurality of different brain regions and each region defines a different region of interest (ROI)); 30 (iv) extracting DVR values for the ROIs of the patient; 368
  • Example 11 Human Brain Organoid Model Organoids are simplified in vitro versions of an organ that recapitulate its structural features. Current iterations of organoids are derived from human pluripotent stem cell sources and 10 utilize processes that occur during normal development, such as self-assembly, self-patterning, and self-driven morphogenesis, to generate organ-like architecture. The in vitro nature of brain organoids facilitates experimental manipulations and sampling that would not otherwise be possible in vivo.
  • Brain organoids can be prepared and injured, followed by administration of a compound described herein, in a suitable carrier.
  • the compound can be administered as a 20 solution in buffer or DMSO.
  • Example 12 In vitro ER Stress Assay 25 Adherent PC12 cells were maintained in Dulbecco’s Modified Eagle’s Medium (DMEM) supplemented with 15% serum, 10 mM HEPES, 1X L glutamine, and 1X Penicillin-streptomycin. For the ER stress assay adherent PC12 cells were plated in 50 ⁇ L complete cell culture medium. The cells were allowed to attach for 24 hours before the culture medium in the plates were completely replaced with 40 ⁇ L fresh DMEM. Then, the cells were pre-incubated with different 30 doses of compounds. After 48 hours, cell viability was assessed using Cell Titer-Glo. Cell viability 369
  • Test compounds (1 ⁇ M) were incubated with microsomes (0.4 ⁇ mg/mL protein) in phosphate buffer (100 ⁇ mM, pH 7.4) in the presence of an NADPH regeneration system. The final organic solvent content in the reaction mixture was maintained at ⁇ 1%. Incubations were conducted at 37 ⁇ °C and aliquots were collected at 0, 5, 10, 20, 30, and 60 minutes. The reactions were terminated at each time point by the addition of ice- 15 cold acetonitrile containing an internal standard. 373

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Abstract

La présente invention concerne des composés et des utilisations pour traiter une tauopathie et des troubles associés à des tauopathies, comprenant, entre autres, une lésion cérébrale traumatique (LCT), par exemple une LCT répétitive (LCTr), ainsi que des sels pharmaceutiquement acceptables et des compositions pharmaceutiques de ceux-ci. L'invention concerne également des procédés de prévention, de minimisation ou de traitement du stress du réticulum endoplasmique, comprenant l'encéphalopathie traumatique chronique (ETC) par administration d'une quantité efficace d'un composé de la présente invention ou d'un sel pharmaceutiquement acceptable, ou d'une composition pharmaceutique de celui-ci à un patient en ayant besoin.
PCT/US2025/039330 2024-07-26 2025-07-25 Composés et utilisations pour traiter une tauopathie Pending WO2026025073A1 (fr)

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US202563751114P 2025-01-29 2025-01-29
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