WO2023196614A1 - Methods and compounds for treating neurological disorders - Google Patents

Methods and compounds for treating neurological disorders Download PDF

Info

Publication number
WO2023196614A1
WO2023196614A1 PCT/US2023/017917 US2023017917W WO2023196614A1 WO 2023196614 A1 WO2023196614 A1 WO 2023196614A1 US 2023017917 W US2023017917 W US 2023017917W WO 2023196614 A1 WO2023196614 A1 WO 2023196614A1
Authority
WO
WIPO (PCT)
Prior art keywords
optionally substituted
compound
alkyl
nhc
aromatic
Prior art date
Application number
PCT/US2023/017917
Other languages
French (fr)
Inventor
Joanna STANICKA
Amanda Zimmerman
Matthew Alexander James Duncton
Michael Rowley
Original Assignee
Axonis Therapeutics, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Axonis Therapeutics, Inc. filed Critical Axonis Therapeutics, Inc.
Publication of WO2023196614A1 publication Critical patent/WO2023196614A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

Definitions

  • Neurological disorders are detrimental to individuals due to the impact on a number of neurological functions such as sensory, motor, cognitive, and/or developmental functions in the affected individual. These disorders often result in profound and irreversible neurological effects that pose severe challenges to an afflicted patient’s everyday life. Few therapeutics have been studied or utilized to treat these neurological disorders, which causes severe challenges and suffering for these patients. Additionally, the few that have been studied or utilized are not adequately sufficient to reduce the individual’s suffering or improve recovery from these neurological disorders.
  • the present disclosure provides compounds, compositions, and methods for treating or preventing neurological disorders in a patient.
  • the disclosed methods include administration to a subject suffering from a neurological disorder of a compound disclosed herein in an amount effective.
  • the disclosure further provides pharmaceutical compositions containing one of the compounds described herein.
  • the disclosure provides a compound of formula (1-2):
  • V is O, S, NH, NZ, N-terminal linked amino acid, which R a is -CH2NH- or -C(Rd)2Q-, in which each Rd is independently -H, -Ci-Cs alkyl, -Ci-Cs cycloalkyl, -Ci-Cs aryl, or -Ci-Cs heteroaryl; Rb is -H, -OH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -Ci-Cs alkoxy, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-C aryl, or -N(R e )2, and each R e is independently -H or -Ci-Cs alkyl;
  • R2 and R3 are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-Cu aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OZ, -N(Z)2, -C(NH)N(Z)2, -OCH2OZ, -O(CH 2 ) 2 OZ, -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z) 2I -C(O)N(Z) 2I -C(O)OZ,
  • R4, Rs, Re, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted - C1-C5 alkyl, optionally substituted -Cs-Ce cycloalkyl, optionally substituted phenyl, optionally substituted - C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, - N(Z) 2 , -C(NH)N(Z) 2I -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z) 2I -C(O)N(Z) 2I -C(O)OZ, -SZ, -S(O)Z, -S(O) 2 Z, -NHC(O)Z, -NHS(O) 2 Z, -NHC(NH)N(Z)
  • the compound is a compound of formula (I-3): or a pharmaceutically acceptable salt thereof, in which
  • R4, Rs, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-C aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OZ, -N(Z)2, -C(NH)N(Z) 2 , -O(CH 2 )nOZ, -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z) 2 , -C(O)N(Z) 2I -C(O)OZ, -
  • R4 is -halo, e.g., -Cl.
  • Rs is -halo, e.g., -Cl.
  • Rs is Ci-Cs alkyl, e.g., methyl.
  • R7 is -H.
  • the compound is a compound of formula (I-4): or a pharmaceutically acceptable salt thereof, in which R4, Rs, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Cs-Cu aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OZ, -N(Z) 2 , -C(NH)N(Z) 2 , -O(CH 2 ) n OZ, -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)OZ,
  • the compound is a compound of formula (I-5): or a pharmaceutically acceptable salt thereof, in which R4, Rs, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-Cu aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OZ, -N(Z) 2 , -C(NH)N(Z) 2 , -O(CH 2 ) n OZ, -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)OZ,
  • Rb is optionally substituted -Ci-Cs alkyl, e.g., -(CH2)sCH3, -CH3, -C(CH3)3, or -CH(CH 3 ) 2 .
  • Rb is carboxyl substituted -Ci-Cs alkyl, e.g., -(CH2)4COOH, -CH2COOH, -(CH 2 ) 2 COOH, -(CH 2 )3COOH, -CH(CH3)(CH 2 )3COO 2 )3COOH.
  • Rb is an amino acid, alanine, phenylalanine, glycine, N,N- dimethylglycine, lysine, glutamic acid, aspartic acid, leucine, or isoleucine.
  • Rb is optionally substituted -Ci-Cs alkoxy, e.g., -OCH2CH3 or
  • Rb is -N(R e )2, e.g., -NHCH2CH3.
  • R a is -CH2NH-.
  • R a is -C(Rd)2O-, in which Rd is -CH2O- or -CH(CH3)O-.
  • R2 is selected from -H, -halo, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C5 alkenyl, optionally substituted -C2-C5 alkynyl, optionally substituted -C7-C14 arylalkyl, and -CN.
  • R3 is selected from -H, -halo, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C5 alkenyl, optionally substituted -C2-C5 alkynyl, optionally substituted -C7-C14 arylalkyl, and -CN.
  • the disclosure provides a compound of formula (11-2): or a pharmaceutically acceptable salt thereof, in which V is O, S, NH, NZ, or CH2; which
  • R a ’ is -H, -OH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, or optionally substituted -Ce-Cu aryl; and R a is -CH2NH- or -C(Rd)2O-, ‘in which each Rd is independently -H, -Ci-Cs alkyl, -Ci-Cs cycloalkyl, -Ci-Cs aryl, or -Ci-Cs heteroaryl; Rb is H, OH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -Ci-Cs alkoxy, optionally substituted -C3-
  • the compound is a compound of formula (11-3): or a pharmaceutically acceptable salt thereof, in which R4, Rs, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-Cu aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OZ, -N(Z) 2 , -C(NH)N(Z) 2 , -O(CH 2 ) n OZ, -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)OZ,
  • R4 is -halo, e.g., -Cl.
  • Rs is -halo, e.g., -Cl.
  • Rs is C1-C6 alkyl, e.g., methyl.
  • R4 is -H.
  • R7 is -H.
  • the compound is a compound of formula (II-4): or a pharmaceutically acceptable salt thereof, in which R4, Rs, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C 3 -Ci2 cycloalkyl, optionally substituted -Ce-Cu aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OZ
  • the compound is a compound of formula (II-5): or a pharmaceutically acceptable salt thereof, in which R4, Rs, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C 3 -Ci2 cycloalkyl, optionally substituted -Ce-Cu aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OZ, -N(Z) 2 , -C(NH)N(Z) 2 , -O(CH 2 ) n OZ, -C(O)Z, -OC(O)Z, -OC(O)OZ, -OZ,
  • R1’ is -C(O)R a ’. In some embodiments, R a ’ is optionally substituted -Ci-Cs o
  • R1’ is .
  • Rb is optionally substituted -Ci-Cs alkyl, e.g., -(CH2)sCH3, -CH3, -C(CH3)3, or -CH(CH3)2.
  • Rb is carboxyl substituted -Ci-C 8 alkyl, e.g, -(CH2)4COOH, -CH2COOH, -(CH 2 ) 2 COOH, -(CH 2 )3COOH, -CH(CH3)(CH 2 )3COOH, -C(CH3)2(CH 2 )3COOH.
  • Rb is an amino acid, e.g., NH 2 , alanine, phenylalanine, glycine, N,N- dimethylglycine, lysine, glutamic acid, aspartic acid, leucine, or isoleucine.
  • Rb is optionally substituted -Ci-Cs alkoxy, e.g., -OCH2CH3 or
  • each R c is independently
  • R2’ and R3’ together with the atoms to which each is attached, form optionally substituted cyclopentyl or optionally substituted cyclohexyl. In some embodiments, R2’ and R3’, together with the atom to which each is attached, join to form cyclopentyl.
  • V is O, S, or NH.
  • the disclosure provides a compound of formula (I) or formula (II), as is described herein.
  • the present disclosure provides compounds of Table 1 .
  • the disclosure provides a pharmaceutically composition including a compound described herein (e.g., any one of the compounds of Formulas (I), (I-2), (I-3), (I-4), (I-5), (II), (II-2), (II-3), (I I-4) , (I I-5) and Table 1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • a compound described herein e.g., any one of the compounds of Formulas (I), (I-2), (I-3), (I-4), (I-5), (II), (II-2), (II-3), (I I-4) , (I I-5) and Table 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • the disclosure provides a method for treating a neurological disorder, which includes administering to a subject in need thereof a therapeutically effective amount of a compound described herein (e.g., any one of the compounds of Formulas (I), (I-2), (I-3), (I-4), (I-5), (II), (II-2), (II-3), (I I-4) , (I I-5) and Table 1) or a pharmaceutically acceptable salt thereof.
  • a compound described herein e.g., any one of the compounds of Formulas (I), (I-2), (I-3), (I-4), (I-5), (II), (II-2), (II-3), (I I-4) , (I I-5) and Table 1 or a pharmaceutically acceptable salt thereof.
  • the neurological disorder is a neurotraumatic disorder, a neurodevelopmental disorder, or an affective disorder.
  • the neurological disorder is a neurotraumatic disorder, e.g., spinal cord injury, traumatic brain injury, stroke, peripheral nerve injury, multiple sclerosis, ischemia, amyotrophic lateral sclerosis, Parkinson’s disease, Alzheimer’s disease, myelopathy, hypoxic-ischemic encephalopathy, tumor-associated epilepsy, spasticity, or peripheral neuropathy.
  • a neurotraumatic disorder e.g., spinal cord injury, traumatic brain injury, stroke, peripheral nerve injury, multiple sclerosis, ischemia, amyotrophic lateral sclerosis, Parkinson’s disease, Alzheimer’s disease, myelopathy, hypoxic-ischemic encephalopathy, tumor-associated epilepsy, spasticity, or peripheral neuropathy.
  • the neurological disorder is a neurodevelopmental disorder, e.g., an autism spectrum disorder, Rett syndrome, Fragile X syndrome, Angelman syndrome, Tuberous Sclerosis Complex (TSC), cerebral palsy, Down syndrome, pain (e.g., neuropathic pain, chronic pain, or inflammatory pain), Dravet syndrome, epilepsy (e.g., temporal lobe epilepsy), or sudden unexpected death in epilepsy.
  • a neurodevelopmental disorder e.g., an autism spectrum disorder, Rett syndrome, Fragile X syndrome, Angelman syndrome, Tuberous Sclerosis Complex (TSC), cerebral palsy, Down syndrome, pain (e.g., neuropathic pain, chronic pain, or inflammatory pain), Dravet syndrome, epilepsy (e.g., temporal lobe epilepsy), or sudden unexpected death in epilepsy.
  • the pain is neuropathic pain, inflammation, inflammatory pain, arthritic pain, diabetic pain, or neuralgia.
  • the epilepsy is temporal lobe epilepsy, refractory epilepsy, neurotrauma associated epilepsy, status epilepticus, tumor associated epilepsy, hypoxic-ischemic encephalopathy and sudden unexpected death in epilepsy.
  • the neurological disorder is an affective disorder, e.g., schizophrenia, bipolar disorder, anxiety disorder, or major depressive disorder.
  • the term “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11 %, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1 %, or less in either direction (greater than or less than) of a stated value, unless otherwise stated or otherwise evident from the context (e.g., where such number would exceed 100% of a possible value).
  • Compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.
  • one or more compounds depicted herein may exist in different tautomeric forms.
  • references to such compounds encompass all such tautomeric forms.
  • tautomeric forms result from the swapping of a single bond with an adjacent double bond and the concomitant migration of a proton.
  • a tautomeric form may be a prototropic tautomer, which is an isomeric protonation states having the same empirical formula and total charge as a reference form.
  • moieties with prototropic tautomeric forms are ketone — enol pairs, amide — imidic acid pairs, lactam — lactim pairs, amide — imidic acid pairs, enamine — imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, such as, 1 H- and 3H-imidazole, 1 H-, 2H- and 4H-1 ,2,4-triazole, 1 H- and 2H-isoindole, and 1 H- and 2H-pyrazole.
  • tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • tautomeric forms result from acetal interconversion.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopica lly enriched atoms.
  • Exemplary isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 0, 32 P, 33 P, 35 S, 18 F, 36 CI, 123 l and 125 l.
  • Isotopically-labeled compounds e.g., those labeled with 3 H and 14 C
  • Tritiated (i.e., ,sup.3H) and carbon-14 (i.e., 14 C)) isotopes can be useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H or D) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements).
  • one or more hydrogen atoms are replaced by 2 H, D, or 3 H, or one or more carbon atoms are replaced by 13 C- or 14 C-enriched carbon.
  • Positron emitting isotopes such as 15 O, 13 N, 11 C, and 18 F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy.
  • PET positron emission tomography
  • isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed for compounds of the present invention described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • substituents of compounds of the present disclosure are disclosed in groups or in ranges. It is specifically intended that the present disclosure include each and every individual subcombination of the members of such groups and ranges.
  • the term “Ci-Ce alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and Ce alkyl.
  • the present disclosure is intended to cover individual compounds and groups of compounds (e.g., genera and subgenera) containing each and every individual subcombination of members at each position.
  • optionally substituted X is intended to be equivalent to “X, wherein X is optionally substituted” (e.g., “alkyl, wherein said alkyl is optionally substituted”). It is not intended to mean that the feature “X” (e.g., alkyl) per se is optional.
  • certain compounds of interest may contain one or more “optionally substituted” moieties.
  • substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent, e.g., any of the substituents or groups described herein.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • substituents envisioned by the present disclosure are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • optionally substituted refers to having 0, 1 , or more substituents (e.g., 0-25, 0-20, 0-10, or 0-5 substituents).
  • any values provided in a range of values include both the upper and lower bounds, and any values contained within the upper and lower bounds.
  • the terms “administer” and “administering” are used to indicate the process of providing a therapeutic, pharmaceutical, housing compartment, medication, or the like thereof to a subject.
  • a pharmaceutical is provided via oral administration.
  • the terms “improve” and “improving,” in reference to recovery from a disease or condition, e.g., a neurological disorder refer to an enhancement of recovery in one or more parameters measuring or quantifying the severity of the neurological disorder relative to the recovery in these parameters in or prior to treatment with the compounds or compositions described herein. Alternatively, improvement may be measured with respect to a reference subject having the same diagnosis as the subject but that did not receive treatment with a compound or composition of the disclosure.
  • such parameters may include motor and sensory function in a subject. Methods for assessing motor and sensory function in a subject suffering from a neurological disorder are known in the art and are further described herein.
  • compositions refers to an active compound, formulated together with one or more pharmaceutically acceptable excipients.
  • a compound of the disclosure is present in unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population.
  • pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions) or tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, or pastes for application to the tongue.
  • pharmaceutically acceptable excipient refers to any inactive ingredient (for example, a vehicle capable of suspending or dissolving the active compound) having the properties of being nontoxic and non-inflammatory in a subject.
  • Typical excipients include, for example: antiadherents, antioxidants, binders, coatings, compression aids, dis integrants, dyes, emollients, emulsifiers, diluents, film formers or coatings, flavors, fragrances, glidants, lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, or waters of hydration.
  • Excipients include, but are not limited to: butylated optionally substituted hydroxytoluene (e.g., BHT), calcium carbonate, calcium phosphate dibasic, calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, optionally substituted hydroxypropyl cellulose, optionally substituted hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch, stearic acid, stearic acid, suc
  • the term “pharmaceutically acceptable salt” represents those salts of the compounds described that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. These salts may be acid addition salts involving inorganic or organic acids.
  • the salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable acid. Methods for preparation of the appropriate salts are well-established in the art.
  • subject can be a human, non-human primate, or other mammal, such as but not limited to dog, cat, horse, cow, pig, goat, monkey, rat, mouse, and sheep. In preferred embodiments, the subject is a human.
  • a therapeutically effective amount refers to an amount sufficient to effect beneficial or desired results, such as clinical results, and, as such, a “therapeutically effective amount” depends upon the context in which it is being applied.
  • a therapeutically effective amount of a compound is, for example, an amount sufficient to reverse alleviate the neurological disorder.
  • the term “treat,” or “treating,” refers to a therapeutic treatment of a neurological disorder in a subject.
  • the effect of treatment can include reversing, alleviating, reducing severity of, inhibiting the progression of, reducing the likelihood of recurrence of the neurological disorder or one or more symptoms or manifestations of the neurological disorder, stabilizing (i.e., not worsening) the state of the neurological disorder as compared to the state and/or the condition of the disease or disorder in the absence of the therapeutic treatment.
  • alkcycloalkyl refers to monovalent radical of formula -RR’, in which R is alkylene, and R’ is cycloalkyl.
  • alkenyl refers to a branched or straight-chain monovalent unsaturated aliphatic radical containing at least one carbon-carbon double bond and no carbon-carbon triple bonds, and only C and H when unsubstituted. Monovalency of an alkenyl group does not include the optional substituents on the alkenyl group. For example, if an alkenyl group is attached to a compound, monovalency of the alkenyl group refers to its attachment to the compound and does not include any additional substituents that may be present on the alkenyl group.
  • the alkenyl group may contain, e.g., 2-20, 2-18, 2-16, 2-14, 2-12, 2-10, 2-8, 2-6, or 2-4 carbon atoms (e.g., C2-C20, C2-C18, C2-C16, C2-C14, C2-C12, C2-C10, C2-C8, C2-C6, or C2-C4).
  • Examples include, but are not limited to, ethenyl, 1 -propenyl, 2-propenyl, 1 -methylethenyl, 1 -butenyl, 2-butenyl, 3-butenyl, and the like.
  • alkheterocyclyl refers to a monovalent radical of formula -RR’, in which R is alkylene, and R’ is heterocycle.
  • alkoxy refers to a monovalent radical of formula -OR, in which R is alkyl.
  • alkyl refers to a branched or straight-chain monovalent saturated aliphatic radical containing only C and H when unsubstituted.
  • the monovalency of an alkyl group does not include the optional substituents on the alkyl group.
  • monovalency of the alkyl group refers to its attachment to the compound and does not include any additional substituents that may be present on the alkyl group.
  • the alkyl group may contain, e.g., 1-20, 1-18, 1-16, 1-14, 1-12, 1-10, 1-8, 1-6, 1-4, or 1-2 carbon atoms (e.g., C1- C20, C1-C18, C1-C16, C1-C14, C1-C12, C1-C10, Ci-Cs, C1-C6, C1-C4, or C1-C2).
  • Examples include, but are not limited to, methyl, ethyl, isobutyl, sec-butyl, and tert-butyl.
  • alkylene refers to a divalent radical obtained by removing a hydrogen atom from a carbon atom of an alkyl group.
  • the divalency of an alkylene group does not include the optional substituents on the alkylene group.
  • alkylene groups include, but are not limited to, methylene, ethylene, and n-propylene.
  • alkynyl refers to a branched or straight-chain monovalent unsaturated aliphatic radical containing at least one carbon-carbon triple bond and only C and H when unsubstituted. Monovalency of an alkynyl group does not include the optional substituents on the alkynyl group. For example, if an alkynyl group is attached to a compound, monovalency of the alkynyl group refers to its attachment to the compound and does not include any additional substituents that may be present on the alkynyl group.
  • the alkynyl group may contain, e.g., 2-20, 2-18, 2-16, 2-14, 2-12, 2-10, 2-8, 2-6, or 2-4 carbon atoms (e.g., C2-C20, C2-C18, C2-C16, C2-C14, C2-C12, C2-C10, C2-C8, C2-C6, or C2-C4).
  • Examples include ethynyl, 1-propynyl, and 3-butynyl.
  • amino acid refers to a molecular fragment having an amino functional group and a carboxylic functional group.
  • Amino acids include natural amino acids and unnatural amino acids.
  • a "natural amino acid” refers to an amino acid that is naturally produced or found in a mammal. Natural amino acids can be encoded by the standard genetic code or may result from, for example, post- translational modifications.
  • Natural amino acids include the twenty proteinogenic L-amino acids (Alanine (A), Cysteine (C), Serine (S), Threonine (T), Aspartic Acid (D), Glutamic Acid (E), Asparagine (N), Glutamine (Q), Histidine (H), Arginine (R), Lysine (K), Isoleucine (I), Leucine (L), Methionine (M), Valine (V), Phenylalanine (F), Tyrosine (Y), Tryptophan (W), Glycine (G), and Proline (P)).
  • GABA gamma-aminobutyric acid
  • L- DOPA 3,4-dihydroxy-L-phenylalanine
  • carnitine ornithine
  • citrulline homoserine
  • lanthionine 2-aminoisobutyric acid
  • dehydroalanine dehydroalanine.
  • An "unnatural amino acid” is an amino acid that is not naturally produced (e.g., encoded by the genetic code or resulting from a posttranslational modification) or naturally found in a mammal.
  • Unnatural amino acids include amino acids that normally do not occur in proteins (e.g., an a-amino acid having the D-configuration, or a (D,L)-isomeric mixture thereof), homologues of naturally occurring amino acids (e.g., a p- or y-amino acid analogue), an a,a-disubstituted analogue of a naturally occurring amino acid, or an a-amino acid in which the amino acid side chain has been shortened by one or two methylene groups or lengthened to up to 10 carbon atoms.
  • proteins e.g., an a-amino acid having the D-configuration, or a (D,L)-isomeric mixture thereof
  • homologues of naturally occurring amino acids e.g., a p- or y-amino acid analogue
  • an a,a-disubstituted analogue of a naturally occurring amino acid e.g., a-disubstit
  • y-amino acids that are GABA analogues, such as (S)-3-(aminomethyl)-5-methylhexanoic acid (pregabalin), 2-[l- (aminomethyl)cyclohexyl]acetic acid (gabapentin), orthose described in Yogeeswari et al., Recent Patents on CNS Drug Discovery 2006;l: 113-118, the disclosure of which is incorporated by reference herein in its entirety.
  • GABA analogues such as (S)-3-(aminomethyl)-5-methylhexanoic acid (pregabalin), 2-[l- (aminomethyl)cyclohexyl]acetic acid (gabapentin), orthose described in Yogeeswari et al., Recent Patents on CNS Drug Discovery 2006;l: 113-118, the disclosure of which is incorporated by reference herein in its entirety.
  • amino acids include "a-amino acids,” in which the amino and carboxylic groups are attached to the same carbon.
  • p-amino acids the carbon to which the amino group is attached is adjacent to the carbon to which the carboxylic group is attached, and in “y-amino acids,” there is an additional intervening carbon.
  • Amino acids can have the L-configuration (for example, natural amino acids have the L-configuration) or the D-configuration.
  • An amino acid can be attached to a compound of the disclosure through a covalent attachment to, for example, the carboxylic functional group ("C-terminal linked") or through the amino functional group ("N-terminal linked").
  • aryl refers to any monocyclic or fused ring bicyclic or multicyclic system containing only carbon atoms in the ring(s), which has the characteristics of aromaticity in terms of electron distribution throughout the ring system, e.g., phenyl, naphthyl, or phenanthryl.
  • An aryl group may have, e.g., six to sixteen carbons or six to fourteen carbons (e.g., six carbons, ten carbons, thirteen carbons, fourteen carbons, or sixteen carbons).
  • arylalkyl refers to a monovalent radical of formula -RR’, in which R is alkylene, and R’ is aryl.
  • carbocycle refers to a monovalent, saturated (“cycloalkyl”) or unsaturated, non-aromatic cyclic group containing only C and H when unsubstituted.
  • a carbocycle may have, e.g., three to twenty carbons (e.g., a C3-C7, C3-C8, C3-C9, C3-C10, C3-C11, C3-C12, C3-C14, C3-C16, C3- Cis, or C3-C20 carbocycle).
  • cycloalkyl refers to a monovalent, saturated cyclic group containing only C and H when unsubstituted.
  • a cycloalkyl may have, e.g., three to twenty carbons (e.g., a C3-C7, C3- Cs, C3-C9, C3-C10, C3-C11, C3-C12, C3-C14, C3-C16, C3-C18, or C3-C20 cycloalkyl).
  • Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • cycloalkyl also includes cyclic groups having a bridged multicyclic structure in which one or more carbons bridges two non-adjacent members of a monocyclic ring, e.g., bicyclo[2.2.1]heptyl and adamantyl.
  • cycloalkyl also includes bicyclic, tricyclic, and tetracyclic fused ring structures, e.g., decalin and spiro-cyclic compounds.
  • cycloalkenyl refers to a monovalent, unsaturated carbocyclic ring system that includes at least one carbon-carbon double bond, only C and H when unsubstituted, and is not aromatic across the whole ring system.
  • a cycloalkenyl may have, e.g., four to twenty carbons (e.g., a C4-C7, C4-C8, C4-C9, C4-C10, C4-C11, C4-C12, C4-C13, C4-C14, C4-C16, C4-C18, or C4-C20 cycloalkenyl).
  • cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and cycloheptenyl.
  • cycloalkenyl also includes cyclic groups having a bridged multicyclic structure in which one or more carbons bridges two non-adjacent members of a monocyclic ring, e.g., bicyclo[2.2.2]oct-2-ene.
  • cycloalkenyl also includes fused bicyclic and multicyclic nonaromatic, carbocyclic ring systems containing one or more double bonds.
  • halo refers to a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical.
  • heterocycle represents a monocyclic or fused ring bicyclic or multicyclic system having at least one heteroatom as a ring atom.
  • a heterocycle ring may have, e.g., one to fifteen carbons ring atoms (e.g., a C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, C1-C7, Ci-Cs, C1- C9, C1-C10, C1-C11, C1-C12, C1-C13, C1-C14, or C1-C15 heterocycle) and one or more (e.g., one, two, three, four, or five) ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
  • Heterocycle groups may or may not include a ring that is aromatic.
  • An aromatic heterocycle group is referred to as a “heteroaryl” group.
  • a heterocycle group is a 3- to 8-membered ring, a 3- to 6-membered ring, a 4- to 6-membered ring, a 6- to 10-membered ring, a 6- to 12-membered ring, a 5-membered ring, or a 6-membered ring.
  • Exemplary 5-membered heterocycle groups may have zero to two double bonds
  • exemplary 6-membered heterocycle groups may have zero to three double bonds.
  • Exemplary 5-membered groups include, for example, optionally substituted pyrrole, optionally substituted pyrazole, optionally substituted isoxazole, optionally substituted pyrrolidine, optionally substituted imidazole, optionally substituted thiazole, optionally substituted thiophene, optionally substituted thiolane, optionally substituted furan, optionally substituted tetrahydrofuran, optionally substituted diazole, optionally substituted triazole, optionally substituted tetrazole, optionally substituted oxazole, optionally substituted 1 ,3,4-oxadiazole, optionally substituted 1 ,3,4-thiadiazole, optionally substituted 1 ,2,3,4-oxatriazole, and optionally substituted 1 ,2,3,4-thiatriazole.
  • Exemplary 6- membered heterocycle groups include, for example, optionally substituted pyridine, optionally substituted piperidine, optionally substituted piperazine, optionally substituted pyrimidine, optionally substituted pyrazine, optionally substituted pyridazine, optionally substituted triazine, optionally substituted 2/7-pyran, optionally substituted 4/7-pyran, and optionally substituted tetrahydropyran.
  • Exemplary 7-membered heterocycle groups include optionally substituted azepine, optionally substituted 1 ,4-diazepine, optionally substituted thiepine, and optionally substituted 1 ,4-thiazepine.
  • neurological disorder refers to any damage or dysfunction of one or more nerves in a subject.
  • a neurological disorder may include any damage or dysfunction that prevents and/or inhibits one or more electrical and/or chemical transmissions of a sensory and/or motor function signal.
  • a neurological disorder may include any damage or dysfunction that results in a transmission of one or more electrical and/or chemical transmissions of a nerve cell uncontrollably by the subject.
  • a neurological disorder may include damage or dysfunction of one or more nerves located within the central nervous system and/or peripheral nervous system of a subject.
  • a neurological disorder may include damage or dysfunction of a somatic, autonomic, and/or enteric nervous system of a subject.
  • a neurological disorder may include damage or dysfunction of an afferent and/or efferent nervous system of a subject.
  • a neurological disorder may include damage or dysfunction of a sympathetic and/or parasympathetic nervous system of a subject.
  • a neurological disorder may include damage of dysfunction of one or more cranial nerves (e.g., the olfactory nerve, optic nerve, oculomotor nerve, trochlear nerve, trigeminal nerve, abducens nerve, facial nerve, vestibulocochlear nerve, glossopharyngeal nerve, vagus nerve, accessory nerve, and/or hypoglossal nerve) of a subject.
  • cranial nerves e.g., the olfactory nerve, optic nerve, oculomotor nerve, trochlear nerve, trigeminal nerve, abducens nerve, facial nerve, vestibulocochlear nerve, glossopharyngeal nerve, vagus nerve, accessory nerve, and/or hypoglossal nerve
  • a neurological disorder may be a neurotraumatic disorder, which may include a spinal cord injury, traumatic brain injury, stroke, peripheral nerve injury, multiple sclerosis, ischemia, amyotrophic lateral sclerosis, Parkinson’s disease, Alzheimer’s disease, myelopathy, hypoxic-ischemic encephalopathy, tumor- associated epilepsy, spasticity, or peripheral neuropathy
  • a neurological disorder may be a neurodevelopmental disorder, which may include an autism spectrum disorder, Rett syndrome, Fragile X syndrome, Tuberous Sclerosis Complex (TSC), Angelman syndrome, cerebral palsy, Down syndrome, pain (e.g., neuropathic pain, chronic pain, or inflammatory pain), Dravet syndrome, epilepsy (e.g., temporal lobe epilepsy), or sudden unexpected death in epilepsy.
  • the pain is neuropathic pain, inflammation, inflammatory pain, arthritic pain, diabetic pain, or neuralgia.
  • a neurological disorder may include an affective disorder, which may include schizophrenia, bipolar-disorder, anxiety disorder, major depressive disorder, and the like thereof.
  • Alkyl, alkylene, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, and heterocycle groups may be substituted with carbocycle (e.g., cycloalkyl); aryl; heterocycle; halo; OR a , in which R a is H, alkyl, alkenyl, alkynyl, carbocycle (e.g., cycloalkyl), aryl, or heterocycle; SR a , in which R a is as defined herein; CN; NO2; N3; NR b R c , in which each of R b and R c is, independently, H, alkyl, alkenyl, alkynyl, carbocycle (e.g., cycloalkyl), aryl, or heterocycle; SC>2R d , in which R d
  • Aryl, carbocycle (e.g., cycloalkyl), heteroaryl, and heterocycle groups may also be substituted with alkyl, alkenyl, or alkynyl.
  • a substituent is further substituted as described herein.
  • Ci alkyl group i.e., methyl
  • a Ci alkyl group may be substituted with oxo to form a formyl group and further substituted with -OH or -NR b R c to form a carboxyl group or an amido group.
  • FIG. 1 is a graph depicting the mean plasma concentration over time of Compound A in dogs following the oral administration of 5 mg/kg of Compound A or intravenous administration of 1 mg/kg of Compound A or an equivalent orally administered dose of Compounds 3, 6, 12, 13, 15, and 11 .
  • FIG. 2 is graph depicting a plurality of pharmacokinetic parameters for each of Compounds 3, 6, 12, 13, 15, 11 , and 27 when compared to Compound A following oral administration of 5 mg/kg of Compound A or an equivalent dose of Compounds 3, 6, 12, 13, 15, 1 1 , or 27.
  • FIG. 3 is a graph depicting the plasma concentration over time of Compound A and Compound 3 in dogs following oral administration of 744 mg/kg Compound 3.
  • FIG. 4. is a graph depicting the plasma profile of Compound B after administration of compound B (1 mg/kg) IV, compound B (5 mg/kg) PO, or compound 28 (7.6 mg/kg) in male Beagle dogs.
  • Fig 5. is a table depicting the PK parameters of Compound B and Compound 28 in male Beagle dogs.
  • Described herein are compounds, compositions, and methods for treating neurological disorders, e.g., neurotraumatic disorders, neurodevelopmental disorders, or affective disorders, in a subject.
  • the compounds described herein may function as orally-available prodrugs of potassium-chloride cotransporter 2 (KCC2) potentiators, such as Compound A or Compound B.
  • KCC2 potassium-chloride cotransporter 2
  • Compound B as well as compounds disclosed in U.S. Patents Nos. 9,040,538 and 9,315,521 , the contents of which are incorporated herein by reference in their entirety.
  • the compounds described herein are useful for treating neurological disorders, e.g., neurotraumatic disorders, neurodevelopmental disorders, or affective disorders.
  • the present disclosure provides compounds and compositions that can be administered to a subject (e.g., a human) in order to treat a neurological disorder (e.g., a neurotraumatic disorder, a neurodevelopmental disorder, or an affective disorder).
  • a neurological disorder e.g., a neurotraumatic disorder, a neurodevelopmental disorder, or an affective disorder.
  • the compound is a compound of formula (I-2): or a pharmaceutically acceptable salt thereof, wherein
  • V is O, S, NH, NZ, N-terminal linked amino acid, or CH2; which R a is -CH2NH- or -C(Rd)2Q-, in which each Rd is independently -H, -Ci-Cs alkyl, -Ci-Cs cycloalkyl, -Ci-Cs aryl, or -Ci-Cs heteroaryl; Rb is H, OH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -Ci-Cs alkoxy, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-C aryl, or -N(R e )2, and in which each R e is independently -H or -Ci-Cs alkyl;
  • R2 and R3 are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-C aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OZ, -N(Z)2, -C(NH)N(Z)2, -OCH2OZ, -O(CH 2 ) 2 OZ, -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z) 2 , -C(O)N(Z) 2 , -C(O)OZ
  • R4, Rs, RB, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Z) 2 , -C(NH)N(Z) 2I -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)OZ, -OC(O)N(Z) 2 , -C(O)N(Z) 2 , -C(O)OZ, -SZ, -S(O)Z, -S(O) 2 Z, -NHC(O)Z, -NHS(O) 2 Z
  • Q2, Q3, and Q4 are each, independently, N, N + -O-, or C, wherein Q2, Q4, and QB are not simultaneously C.
  • the compound is a compound of formula (II-2): or a pharmaceutically acceptable salt thereof, wherein:
  • V is O, S, NH, NZ, or CH 2 ; which R a ’ is -H, -OH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, or optionally substituted -Ce-Cu aryl; and R a is -CH2NH- or -C(Rd)2O-, in which each Rd is independently -H, -Ci-Cs alkyl, -Ci-Cs cycloalkyl, -Ci-Cs aryl, or -Ci-Cs heteroaryl; Rb is H, OH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C
  • R2’ and R3’ together with the atoms to which each is attached, join to form a 5- to 6-membered aromatic or non-aromatic carbocycle or heterocycle;
  • R4, Rs, RB, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Z) 2 , -C(NH)N(Z) 2I -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)OZ, -OC(O)N(Z) 2 , -C(O)N(Z) 2 , -C(O)OZ, -SZ, -S(O)Z, -S(O) 2 Z, -NHC(O)Z, -NHS(O) 2 Z
  • Q2, Q3, and Q4 are each, independently, N, N + -O-, or C, wherein Q2, Q4, and Qe are not simultaneously C.
  • a pharmaceutical composition of the disclosure contains one or more of the compounds disclosed herein (e.g., one or more of the compounds of any one of formulas (I), (I-2), (I-3), (I-4), (I-5), (II), (I I-2) , (I I-3) , (I I-4) , (I I-5) , and other compounds disclosed herein) as the therapeutic compound.
  • the pharmaceutical compositions also contain a pharmaceutically acceptable excipient, which can be formulated by methods known to those skilled in the art.
  • the compounds disclosed herein e.g., the compounds of formulas
  • the compounds disclosed herein may be used in the form of free base, or in the form of salts or solvates. All forms are within the scope of the disclosure.
  • Exemplary routes of administration of the pharmaceutical compositions include oral, sublingual, buccal, transdermal, intradermal, intramuscular, parenteral, intravenous, intra-arterial, intracranial, subcutaneous, intracerebroventricular, intraorbital, intraventricular, intrathecal (intraspinal), intraperitoneal, intranasal, inhalation, and topical administration.
  • oral dosage forms can be, for example, in the form of tablets, capsules, a liquid solution or suspension, a powder, or liquid or solid crystals, which contain the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients.
  • excipients may be, for example, inert diluents or fillers; granulating and disintegrating agents; binding agents; and lubricating agents, glidants, and antiadhesives.
  • Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, and the like.
  • compositions for oral administration may also be presented as chewable tablets, as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, or as soft gelatin capsules where the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.
  • Powders, granulates, and pellets may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or spray drying equipment.
  • liquid forms in which the compounds and compositions of the present disclosure can be incorporated for administration orally include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils, , as well as elixirs and similar pharmaceutical vehicles.
  • Neurological disorders are disorders that affect the brain, as well as nerves throughout the body and also the spinal cord. Common symptoms of neurological disorders include numbness, tingling, muscle weakness, loss of muscle tone, loss of sensation, disruption or loss of autonomic function, numbness, bowel, or bladder incontinence, paralysis, confusion, pain, altered levels of consciousness, mood disorders, and sexual dysfunction. Certain primary symptoms, such as impaired movement and sensation, can further lead to secondary symptoms including muscle atrophy, loss of voluntary motor control and spasticity at sites of the body innervated by the neurological disorder, pressure (e.g., bed) sores, infections, and respiratory problems.
  • pressure e.g., bed
  • cell death at the neurological disorder may continue long after the initial insult that precipitated the neurological disorder as a result of stress and inflammatory signaling that leads to further ischemia, inflammation, swelling, and disruption of synaptic signaling.
  • Neurological disorder may result in total loss of motor and sensory function distal to the neurological disorder, or incomplete, resulting in partial loss of motor and sensory function.
  • Neurological disorders may present as various distinct conditions, depending on the site and severity of the condition.
  • peripheral neurological disorder results from damage to peripheral nerves that extend to the extremities of an individual, leading to numbness and/or loss of sensory function.
  • Proximal neurological disorder results from damage to peripheral and/or central nerves, leading to muscle weakness in the upper part of the legs, buttocks, and/or hips in a subject.
  • Autonomic neurological disorder results from damage and/or dysfunction of autonomic nerves that least to reduced and/or uncontrolled body homeostasis of an individual.
  • Focal neurological disorder and/or polyneurological disorder results from damage to one nerve and/or a plurality of nerves, respectively.
  • Central cord syndrome frequently results from damage to the cervical spinal cord, resulting in weakness in the upper extremities with relative sparing of function in the legs and spared sensation in sacral dermatomes (e.g., urinary sphincter, anal sphincter, and genitalia).
  • sacral dermatomes e.g., urinary sphincter, anal sphincter, and genitalia.
  • neurological disorders include, but are not limited to neurotraumatic disorders such as spinal cord injury (SCI), traumatic brain injury (TBI), stroke (e.g., hemorrhagic or ischemic stroke), peripheral nerve injury (PNI), myelopathy, hypoxic-ischemic encephalopathy, tumor-associated epilepsy, spasticity, multiple sclerosis, ischemia, amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), Alzheimer’s disease (AD), and peripheral neuropathy (PN); neurodevelopmental disorders such as autism, Rett syndrome, Fragile X syndrome, Angelman syndrome, Tuberous Sclerosis Complex (TSC), cerebral palsy, Down syndrome, pain (e.g., neuropathic pain, inflammation, inflammatory pain, arthritic pain, diabetic pain, and neuralgia), Dravet syndrome, epilepsy (e.g., temporal lobe epilepsy, refractory epilepsy, neurotrauma associated epilepsy, status epilepticus, tumor associated epilepsy
  • Neurotraumatic disorders are disorders of the nervous system that result from neurological trauma, such as, e.g., TBI, SCI, PNI, PN, stroke, ischemia, hypoxic-ischemic encephalopathy, tumor- associated epilepsy, and spasticity.
  • neurological trauma such as, e.g., TBI, SCI, PNI, PN, stroke, ischemia, hypoxic-ischemic encephalopathy, tumor- associated epilepsy, and spasticity.
  • TBI neurological trauma
  • TBI also known as intracranial injury
  • TBI usually results from an external force suddenly impacting the head of an individual, with the severity of the from mild (e.g., concussion) to severe (e.g., penetrating injury, coma-inducing injury).
  • Sequalae of TBI often includes loss of consciousness, physical, cognitive, social, emotional, and behavioral impairments, but can also be fatal.
  • a SCI refers to any insult to the any region of the spinal cord, e.g., the cervical vertebrae, the thoracic vertebrae, the lumbar vertebrae, the sacral vertebrae, the sacrum, or the coccyx, that causes a negative effect on the function of the spinal cord, e.g., reduce mobility of feeling in limbs.
  • the severity of a spinal cord injury is measured in levels of the injury’s outcome, e.g., ranging from no effect on mobility, e.g., retained walking capacity, to paraplegia (e.g., paralysis of legs and lower region of body), and tetraplegia (e.g., loss of muscle strength in all four extremities).
  • PNI refers to any disorder resulting from a nerve injury caused by a traumatic event. Peripheral nerve injury is generally divided into three distinct events, namely, (1) Wallerian degeneration; (2) axon regeneration/growth; and (3) nerve innervation. Types of PNI include, from least severe to most severe: neurapraxia (axon remains intact, but myelin is damaged), axonotmesis (disruption of the axon with maintenance of the epineurium), and neurotmesis (loss of axon continuity/axon transection).
  • Stroke is a condition which occurs when the blood supply to a part of the brain is interrupted (i.e., ischemic stroke) by obstruction of a blood vessel by a blood clot, an embolism, systemic hypoperfusion, or cerebral venous sinus thrombosis or when a blood vessel in the brain bursts and releases blood into the spaces surrounding the brain cells (i.e., hemorrhagic stroke) as a result of an intracerebral or a subarachnoid hemorrhage. Stroke poses a substantial public burden as nearly 77.2 million people experienced an ischemic stroke, and 29.1 million people experienced a hemorrhagic stroke in 2019.
  • the symptoms of a stroke may include numbness or weakness, especially on one side of the body corresponding to the contralateral side of the stroke, muscle flaccidity or spasticity, confusion, trouble understanding or producing speech, impaired vision in both eyes, impaired mobility, dizziness, severe headache, or loss of balance or coordination.
  • Neurological trauma may also result from progressive neurodegenerative disorders that result in damage to neural tissue of the CNS.
  • Non-limiting examples of neurodegenerative disorders contemplated for treatment using the presently disclosed compositions and methods include, but are not limited to, ALS, PD, AD, and PN.
  • Neurodevelopmental disorders refer to neurological disorders resulting from abnormal development of the nervous system and are characterized by abnormal brain function, including, but not limited to, impairments in emotional regulation, learning and memory, impulse control, and cognition. This class of neurological disorders is characterized by diverse etiologies that may account for the crossity of symptoms and their degree of severity. Generally, neurodevelopmental disorders are caused by disruptions the neurotypical developmental trajectory of the nervous system, which can produce pathological anatomical architecture and connectivity in the nervous system. Causes of neurodevelopmental disorders may include genetic and metabolic diseases, social isolation, inflammatory and autoimmune disorders, infectious diseases, malnutrition, physical trauma, as well as environmental factors.
  • the present disclosure contemplates treatment of neurodevelopmental disorders such as, e.g., autism spectrum disorders, Rett syndrome, Fragile X syndrome, Angelman syndrome, Tuberous Sclerosis Complex (TSC), cerebral palsy, Down syndrome, pain (e.g., neuropathic pain, inflammation, inflammatory pain, arthritic pain, diabetic pain, and neuralgia), Dravet syndrome, epilepsy (e.g., epilepsy related to one or more KCC2 mutations or epilepsy of infancy with migrating focal seizures (EIMFS) or temporal lobe epilepsy, refractory epilepsy, neurotrauma associated epilepsy, status epilepticus, tumor associated epilepsy, and hypoxic-ischemic encephalopathy), and sudden unexpected death in epilepsy by administering a composition of the disclosure to the afflicted subject, thereby treating the subject.
  • epilepsy e.g., epilepsy related to one or more KCC2 mutations or epilepsy of infancy
  • Affective disorders are a class of neurological conditions characterized by dysregulation of normal affect and mood.
  • Disorders of affect may feature mania or hypomania (e.g., schizophrenia and bipolar disorder), depressed mood (e.g., schizophrenia, bipolar disorder, and MDD), and moods that cycle between mania and depression (e.g., bipolar disorder).
  • Affective disorders that may be treated using the disclosed methods and compositions include schizophrenia, bipolar disorder, and MDD.
  • Schizophrenia is a psychiatric disease characterized by recurrent psychosis.
  • Symptoms of schizophrenia may include (1) positive symptoms related to hallucinations and reality distortion; (2) disorganized symptoms characterized by attentional impairment and thought disorder; and (3) negative symptoms such as apathy, anhedonia, avolition and loss of verbal fluency.
  • Dysfunction of the limbic- cortical system may be implicated in all three types of symptoms.
  • causes of schizophrenia have been attributed to biological sex, genetic mutations, environmental factors, malnutrition during pregnancy, and age of parents, among other factors.
  • Several hypotheses exist as to the etiology of schizophrenia one being the glutamate hypothesis in which reduced glutamatergic drive to inhibitory interneurons is thought to result in reduced cortical inhibition and altered cortical network dynamics that lead to presentation of clinical symptoms.
  • Bipolar disorder is an affective disorder that features recurrent bouts of depression and mania (i.e., abnormally elevated mood) spanning from days to weeks each.
  • causes of bipolar disorder may be manifold, but genetic and environmental factors have been implicated.
  • bipolar I disorder in which there has been at least one manic episode with or without depressive episodes
  • bipolar II disorder in which there has been at least one hypomanic episode and one major depressive episode.
  • MDD is a neurological disorder that is often characterized by the patient having at least two weeks of sustained low mood, low self-esteem, loss of interest in routine activities, hyperalgesia, and low psychomotor activity. Depression in MDD may last for periods of time (weeks, days, months, or years) separated by years or may be continuous. MDD may pose a substantial risk to the afflicted patient as the patient may be at a substantially higher risk for suicide. Etiological causes of the disorder have been attributed to substance abuse, other medical conditions (e.g., neurological disorders, metabolic disorders, gastrointestinal disorders, endocrine disorders, cardiovascular disease, pulmonary disease, cancer, and autoimmune disease), and genetic and environmental factors.
  • other medical conditions e.g., neurological disorders, metabolic disorders, gastrointestinal disorders, endocrine disorders, cardiovascular disease, pulmonary disease, cancer, and autoimmune disease
  • a neurological disorder may also be caused by infection, ischemia, and tumors. Owing to the physiological barriers to regeneration in the central nervous system (CNS), neurological disorders have been a notoriously difficult condition to treat, with most treatments being palliative and rehabilitative. Most treatments involve imposing limitations to movement, maintenance of proper blood pressure by frequent repositioning of the subject, and physical and occupation therapy.
  • CNS central nervous system
  • the compounds disclosed herein are, in general, suitable for use in treating a neurological disorder, e.g., a neurotraumatic, neurodevelopmental, and/or affective disorder, or complications resulting therefrom.
  • a neurological disorder e.g., a neurotraumatic, neurodevelopmental, and/or affective disorder, or complications resulting therefrom.
  • Non-limiting examples of neurotraumatic disorders include spinal cord injury (SCI), traumatic brain injury (TBI), stroke (e.g., hemorrhagic, or ischemic stroke), peripheral nerve injury (PNI), multiple sclerosis (MS), ischemia, amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), Alzheimer’s disease (AD), peripheral neuropathy (PN), hypoxic-ischemic encephalopathy, tumor-associated epilepsy, and spasticity.
  • SCI spinal cord injury
  • TBI traumatic brain injury
  • stroke e.g., hemorrhagic, or ischemic stroke
  • PNI peripheral nerve injury
  • MS multiple sclerosis
  • ischemia amyotrophic lateral sclerosis
  • ALS amyotrophic lateral sclerosis
  • PD amyotrophic lateral sclerosis
  • AD Alzheimer’s disease
  • PN peripheral neuropathy
  • hypoxic-ischemic encephalopathy tumor-associated epilepsy, and spasticity.
  • Neurodevelopmental disorders may include, but are not limited to autism, Rett syndrome, Fragile X syndrome, Angelman syndrome, Tuberous Sclerosis Complex (TSC), cerebral palsy, Down syndrome, pain (e.g., neuropathic pain, inflammation, inflammatory pain, arthritic pain, diabetic pain, and neuralgia), Dravet syndrome, epilepsy (e.g., epilepsy related to one or more KCC2 mutations or epilepsy of infancy with migrating focal seizures (EIMFS) or temporal lobe epilepsy, refractory epilepsy, neurotrauma associated epilepsy, status epilepticus, tumor associated epilepsy, or hypoxic-ischemic encephalopathy), and sudden unexpected death in epilepsy.
  • Non-limiting examples of affective disorders include schizophrenia, bipolar disorder, anxiety disorder, and major depressive disorder (MDD).
  • the dosage of the pharmaceutical compositions of the disclosure depends on factors including, but are not limited to, the route of administration, the severity of the condition to be treated, and physical characteristics, e.g., age, weight, and general health, of the subject.
  • the amount of a compound disclosed herein e.g., a compound of any one of formulas (I), (I-2), (I-3), (I-4), (I-5), (II), (II-2), (II-3), (II-4), and (II-5), and other compounds disclosed herein
  • contained within a single dose may be an amount that effectively imparts the desired therapeutic effect without inducing significant toxicity.
  • the dosage may be adapted by the clinician in accordance with conventional factors such as the extent of the disease and different parameters of the subject.
  • compositions of the disclosure that contain a compound disclosed herein (e.g., a compound of any one of formulas (I), (I-2), (I-3), (I-4), (I-5), (II), (II-2), (II-3), (II-4), and (II-5), and other compounds disclosed herein may be administered to a subject in need thereof one or more times (e.g., 10 times or more) daily, or as medically necessary.
  • the timing between administrations may decrease as the medical condition improves or increase as the health of the subject declines.
  • 3,5-Dichloro-4-pyridinyl)methanethiol [CAS: 2229521-53-1] is mixed with 3-chloro-2, 5,6,7- tetrahydro-1 H-cyclopenta[c]pyridin-1-one [CAS: 178308-48-0] in the presence of a K2CO3 in N,N- dimethylformamide or diisopropylethylamine in ethanol.
  • the desired product is obtained in high yield following standard purification.
  • Step 2 Preparation of tert-butyl ((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6, 7-dihydro-5H-cyclopenta[d] -pyrimidin-4-yl)oxy)methyl) adipate
  • Step 3 Preparation of 6-(((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6, 7-dihydro-5H-cyclopenta[d]pyrimidin -4-yl)oxy)methoxy)-6-oxohexanoic acid
  • Step 1 Preparation of tert-butyl (((2-(((3-chloro-5-methylpyridin-4-yl)methyl)thio)-6,7-dihydro-5l-l-cyclo -penta[d]pyrimidin-4-yl)oxy)methyl) adipate
  • Step 2 Preparation of 6-(((2-(((3-chloro-5-methylpyridin-4-yl)methyl)thio)-6, 7-dihydro-5H-cyclopenta[d] -pyrimidin-4-yl)oxy)methoxy)-6-oxohexanoic acid
  • Step 1 Preparation of 1 -tert-butyl 6-(1 -chloroethyl) hexanedioate
  • Step 2 Preparation of ( ⁇ ) tert-butyl (1-((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6, 7-dihydro-5H-cyclo -penta[d]pyrimidin-4-yl)oxy)ethyl) adipate
  • Step 3 Preparation of ( ⁇ ) 6-(1-((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6, 7-dihydro-5H-cyclopenta[d] -pyrimidin-4-yl)oxy)ethoxy)-6-o-xohexanoic acid
  • Step 1 Preparation of 2-(((3, 5-dichloropyridin-4-yl)methyl)thio)-4-((methylthio)methoxy)-6, 7-dihydro-5H -cyclopenta[d]pyrimidine
  • Step 3 Preparation of tert-butyl (((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6, 7-dihydro-5l-l-cyclopenta[d] -pyrimidin-4-yl)oxy)methyl) malonate
  • Step 4 Preparation of 3-(((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6, 7-dihydro-5H-cyclopenta[d]pyrimidin -4-yl)oxy)methoxy)-3-oxopropanoic acid
  • Step 2 Preparation of 4-(((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6, 7-dihydro-5H-cyclopenta[d]pyrimidin -4-yl)oxy)methoxy)-4-oxobutanoic acid
  • Step 1 Preparation of tert-butyl (((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6, 7-dihydro-5l-l-cyclopenta -[d]pyrimidin-4-yl)oxy)methyl) glutarate
  • Step 2 Preparation of 5-(((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6, 7-dihydro-5H-cyclopenta[d]pyrimidin -4-yl)oxy)methoxy)-5-oxopentanoic acid
  • Step 1 Preparation of (S)-((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6, 7-dihydro-5H-cyclopenta[d]pyr -imidin-4-yl)oxy)methyl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate
  • Step 2 Preparation of (S)-((3-(((3,5-dichloropyridin-4-yl)methyl)thio)-6, 7-dihydro-5H-cyclopenta[c]pyr -idin-1-yl)oxy)methyl 2-amino-3-methylbutanoate formate salt
  • Step 1 Preparation of di-tert-butyl (((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6, 7-dihydro-5l-l-cyclopenta -[d]pyrimidin-4-yl)oxy)methyl) phosphate
  • Step 2 Preparation of ((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6, 7-dihydro-5H-cyclopenta[d]pyrimidin -4-yl)oxy)methyl dihydrogen phosphate
  • Step 2 Preparation of ( ⁇ ) 6-(tert-butyl) 1 -(chloromethyl) 2-methylhexaned ioate
  • Step 3 Preparation of ( ⁇ ) 6-tert-butyl 1-(((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5H-cyclo penta[d]pyrimidin-4-yl)oxy)methyl) 2-methylhexanedioate
  • Step 4 Preparation of ( ⁇ ) 6-(((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6, 7-dihydro-5H-cyclopenta[d] pyrimidin-4-yl)oxy)methoxy)-5-methyl-6-oxohexanoic acid
  • Step 2 Preparation of 6-(tert-butyl) 1 -(chloromethyl) 2,2-dimethylhexanedioate
  • Step 3 Preparation of 6-tert-butyl 1-(((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5H-cyclopenta [d]pyrimidin-4-yl)oxy)methyl) 2, 2-dimethylhexanedioate
  • Step 4 Preparation of 6-(((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6, 7-dihydro-5H-cyclopenta[d]pyrimidin -4-yl)oxy)methoxy)-5, 5-dimethyl-6-oxohexanoic acid
  • Example 23 In Vivo Pharmacokinetics of Compounds 3, 6, 12, 13, 15, 11 , and 27 in male Beagle Dogs
  • the half-life of Compound 3 was measured for the biological matrix of plasma, blood, intestinal S9, liver hepatocytes, and liver S9 for rats, dogs, monkeys, humans.
  • the results of the study are provided in Table 3.
  • Compound 3 was rapidly metabolized to Compound A in all matrices.
  • the half-life of Compound 28 was measured for the biological matrix of plasma, blood, intestinal microsomes, liver microsomes, and liver hepatocytes for rats, dogs, and humans.
  • the results of the study are provided in Table 5.
  • Compound 28 was rapidly metabolized to Compound B in all matrices.
  • V is O, S, NH, NZ, N-terminal linked amino acid, or CH 2 ; which R a is -CH2NH- or -C(Rd)20-, in which each Rd is independently -
  • Rb is H, OH, optionally substituted - Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -Ci-Cs alkoxy, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-C aryl, or - N(R e )2, and in which each R e is independently -H or -Ci-Cs alkyl;;
  • R2 and R3 are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-C aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OZ, -N(Z)2, -C(NH)N(Z)2, -OCH2OZ, -O(CH 2 ) 2 OZ, -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z) 2 , -C(O)N(Z) 2 , -C(O)OZ
  • A1 and A2 are each, independently, -H, -halo, -Ci-Cs alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C12 cycloalkyl, -Ce-Cu aryl, or -C7-C14 arylalkyl; and
  • A3 is a 3- to 9-membered aromatic or non-aromatic carbocycle or heterocycle.
  • V is O, S, NH, NZ, N-terminal linked amino acid, or CH2; which R a is -CH2NH- or -C(Rd)2O-, in which each Rd is independently -H, -Ci-Cs alkyl, -Ci-Cs cycloalkyl, -Ci-Cs aryl, or -Ci-Cs heteroaryl; Rb is H, OH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -Ci-Cs alkoxy, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-C aryl, or - N(R e )2, and in which each R e is independently -H or -Ci-Cs alkyl;
  • R2 and R3 are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-C aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OZ, -N(Z)2, -C(NH)N(Z)2, -OCH2OZ, -O(CH 2 ) 2 OZ, -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z) 2 , -C(O)N(Z) 2 , -C(O)OZ
  • R4, Rs, RB, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Z) 2 , -C(NH)N(Z) 2I -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)OZ, -OC(O)N(Z) 2 , -C(O)N(Z) 2 , -C(O)OZ, -SZ, -S(O)Z, - S(O) 2 Z, -NHC(O)Z, -NHS(O) 2 Z
  • Q2, Q3, and Q4 are each, independently, N, N + -O-, or C, in which Q2, Q4, and QB are not simultaneously C.
  • R4, Rs, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Cs-C aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OZ, -N(Z)2, -C(NH)N(Z)2, -O(CH 2 )nOZ, -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z) 2 , -C(O)N(Z) 2 , -C(O)OZ, -S
  • R4, Rs, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-Cu aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OZ, -N(Z)2, -C(NH)N(Z)2, -O(CH 2 )nOZ, -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z) 2 , -C(O)N(Z) 2 , -C(O)OZ, -S
  • R4, Rs, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-C aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OZ, -N(Z)2, -C(NH)N(Z)2, -O(CH 2 )nOZ, -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z) 2 , -C(O)N(Z) 2 , -C(O)OZ, -S
  • E36 The compound of any one of embodiments 1-34, in which R2 is selected from -H, -halo, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C5 alkenyl, optionally substituted -C2-C5 alkynyl, optionally substituted -C7-C14 arylalkyl, and -CN.
  • V is O, S, NH, NZ, or CH 2 ; which R a ’ is -H, -OH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, or optionally substituted -Ce-C aryl; and R a is -CH2NH- or -C(Rd)2O-, in which each Rd is independently -H, -Ci-Cs alkyl, -Ci-Cs cycloalkyl, -Ci-Cs aryl, or -Ci-Cs heteroaryl; Rb is H, OH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C
  • R2’ and R3’ together with the atoms to which each is attached, join to form a 5- to 6-membered aromatic or non-aromatic carbocycle or heterocycle;
  • Z is -H; optionally substituted -Ci-Cs alkyl; optionally substituted -C4-Ci2 alkcycloalkyl; optionally substituted -Cs-Cg alkheterocyclyl, in which the heterocycle is 3- to 9-membered; optionally substituted -C3-C12 cycloalkyl; optionally substituted -Ce-C aryl; optionally substituted optionally substituted -C7-C14 arylalkyl; optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle; optionally substituted -C2-C8 alkenyl; or optionally substituted -C2-C8 alkynyl;
  • A1 and A2 are each, independently, -H, -halo, -Ci-Cs alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C12 cycloalkyl, -Ce-Cu aryl, or -C7-C14 arylalkyl; and
  • A3 is a 3- to 9-membered aromatic or non-aromatic carbocycle or heterocycle.
  • V is O, S, NH, NZ, or CH 2 ; which R a ’ is -H, -OH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, or optionally substituted -Ce-Cu aryl; and R a is -CH2NH-, or -C(Rd)2O-, in which each Rd is independently -H, -Ci-Cs alkyl, -Ci-Cs cycloalkyl, -Ci-Cs aryl, or -Ci-Cs heteroaryl; Rb is H, OH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -
  • R2’ and R3’ together with the atoms to which each is attached, join to form a 5- to 6-membered aromatic or non-aromatic carbocycle or heterocycle;
  • R4, Rs, RB, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Z) 2 , -C(NH)N(Z) 2I -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)OZ, -OC(O)N(Z) 2 , -C(O)N(Z) 2 , -C(O)OZ, -SZ, -S(O)Z, -S(O) 2 Z, -NHC(O)Z, -NHS(O) 2 Z
  • R4, Rs, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-C aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OZ, -N(Z)2, -C(NH)N(Z)2, -O(CH 2 )nOZ, -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z) 2 , -C(O)N(Z) 2 , -C(O)OZ, -S
  • R4, Rs, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-C aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OZ, -N(Z)2, -C(NH)N(Z)2, -O(CH 2 )nOZ, -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z) 2 , -C(O)N(Z) 2 , -C(O)OZ, -S
  • R4, Rs, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-Cu aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OZ, -N(Z)2, -C(NH)N(Z)2, -O(CH 2 )nOZ, -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z) 2 , -C(O)N(Z) 2 , -C(O)OZ, -S
  • Q2, Q4, and Qe are each, independently, N, N + -O-, or C;
  • Q3 and Qs are each, independently, N, N + -O-, C, O, or S, in which only one of Q3 and Q4 can be O or S; in which Q2, Q3, Q4, Qs, and QB simultaneously are C only if R4 and Rs, Rs and Rs, RB and R7, or R7 and Rs, together with the atoms to which each is attached, join to form a 5- or 6-membered aromatic or non-aromatic heterocycle;
  • R4, Rs, RB, R7, and Rs are each, independently, absent, -H, -OH, -O', -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, optionally substituted -CB-Cu aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OY, N(Y) 2 , -C(NH)N(Y) 2I -O(CH 2 ) m OY, -C(O)Y, -OC(O)Y, -OC(O)OY, OC(O)N(Y) 2 , C(O)N(Y) 2 , -C
  • Each Y is, independently, -H, -C1-C5 alkyl, -C3-C7 cycloalkyl, phenyl, -C7-C9 arylalkyl, 3- to 7- membered aromatic or non-aromatic heterocycle, -C2-C5 alkenyl, or -C2-Cs alkynyl; or two Y, together with the atom to which each is attached, join to form a 3- to 7-membered aromatic or non-aromatic heterocycle; and m is 0 or 1 .
  • R4, Rs, RB, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted - C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, - N(Y) 2 , -C(NH)N(Y) 2I -C(O)Y, -OC(O)Y, -OC(O)OY, -OC(O)N(Y) 2I -C(O)N(Y) 2I
  • R4, Rs, Re, and R7 are each, independently, -H, -OH, -halo, -CN, NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Y) 2 , -C(NH)N(Y) 2I -C(O)Y, -OC(O)Y, -OC(O)OY, -OC(O)N(Y) 2I -C(O)N(Y) 2I -C(O)OY, -SY, -S(O)Y, -S(O) 2 Y, -NHC(O)Y, -NHS(O) 2 Y, -NHC(NH)N(Y) 2
  • R4 and Rs, Rs and Re, or Re and R7 together with the carbon atoms to which each is attached, join to form an optionally substituted 5- or 6-membered aromatic or non-aromatic carbocycle or heterocycle; and each Y is, independently, -H, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C7 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, optionally substituted -C2-C5 alkenyl, or optionally substituted -C2-C5 alkynyl; or two Y, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
  • R4, Rs, Re, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Y) 2 , -C(NH)N(Y) 2I -C(O)Y, -OC(O)Y, -OC(O)OY, -OC(O)N(Y) 2I -C(O)N(Y) 2I -C(O)OY, -SY, -S(O)Y, -S(O) 2 Y, -NHC(O)Y, -NHS(O) 2 Y, -NHC(NH)N(Y) 2
  • R4 and Rs or Rs and Re together with the carbon atoms to which each is attached, join to form an optionally substituted 5- or 6-membered aromatic or non-aromatic carbocycle or heterocycle; and each Y is, independently, -H, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C7 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, optionally substituted -C2-C5 alkenyl, or optionally substituted -C2-C5 alkynyl; or two Y, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
  • R4, Rs, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Y) 2 , -C(NH)N(Y) 2I -C(O)Y, -OC(O)Y, -OC(O)OY, -OC(O)N(Y) 2I -C(O)N(Y) 2I -C(O)OY, -SY, -S(O)Y, -S(O) 2 Y, -NHC(O)Y, -NHS(O) 2 Y, -NHC(NH)N(Y)
  • R4 and Rs or R7 and Rs together with the carbon atoms to which each is attached, join to form an optionally substituted 5- or 6-membered aromatic or non-aromatic carbocycle or heterocycle; and each Y is, independently, -H, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C7 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, optionally substituted -C2-C5 alkenyl, or optionally substituted -C2-C5 alkynyl; or two Y, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
  • R4, Rs, Re, and R7 are each, independently, -H, -OH, halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Y) 2 , -C(NH)N(Y) 2I -C(O)Y, -OC(O)Y, -OC(O)OY, -OC(O)N(Y) 2I -C(O)N(Y) 2I -C(O)OY, -SY, -S(O)Y, -S(O) 2 Y, -NHC(O)Y, -NHS(O) 2 Y, -NHC(NH)N(Y) 2
  • each Y is, independently, -H, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C7 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, optionally substituted -C2-C5 alkenyl, or optionally substituted -C2-C5 alkynyl; or two Y, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle; and
  • Q3, Q4, Qs, and Qe are each, independently, N , N+-0-,or C.
  • R4, Rs, Re, and R7 are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Y) 2 , -C(NH)N(Y) 2I -C(O)Y, -OC(O)Y, -OC(O)OY, -OC(O)N(Y) 2I -C(O)N(Y) 2I -C(O)OY, -SY, -S(O)Y, -S(O) 2 Y, -NHC(O)Y, -NHS(O) 2 Y, -NHC(NH)N(Y)
  • each Y is, independently, -H, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C7 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, optionally substituted -C2-C5 alkenyl, or optionally substituted -C2-C5 alkynyl; or two Y, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle; and
  • Q3 and Qe are each, independently, N, N + -O-, or C.
  • Rs is -H, -OH, -CN, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7- membered aromatic or non-aromatic heterocycle, -N(Y)2, -C(NH)N(Y)2, -C(O)Y, -C(O)N(Y)2, -C(O)OY, -S(O) 2 Y, -NHC(O)Y, -NHS(O) 2 Y, -NHC(NH)N(Y) 2 , -NYC(NH)N(Y) 2 , -NHC(NCN)N(Y) 2 , or -NYC(NCN)N(Y) 2 ;
  • Re and R7 are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OZ, -N(Y)2, -C(NH)N(Y) 2 , -C(O)Y, -OC(O)Y, -OC(O)OY, -OC(O)N(Y) 2I -C(O)N(Y) 2I -C(O)OY, -SY, -S(O)Y, -S(O) 2 Y, -NHC(O)Y, -NHS(O) 2 Y, -NHC(NH)N(Y) 2 , -NY
  • each Y is, independently, -H, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C7 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, optionally substituted -C2-C5 alkenyl, or optionally substituted -C2-C5 alkynyl; or two Y, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
  • R4 is -H, -OH, -CN, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7- membered aromatic or non-aromatic heterocycle, -N(Y)2, -C(NH)N(Y)2, -C(O)Y, -C(O)N(Y)2, -C(O)OY, -S(O) 2 Y, -NHC(O)Y, -NHS(O) 2 Y, -NHC(NH)N(Y) 2 , -NYC(NH)N(Y) 2 , -NHC(NCN)N(Y) 2 , or -NZC(NCN)N(Y) 2 ; Re and R7 are each, independently, -H, -OH, -halo,
  • Re and R7 together with the carbon atoms to which each is attached, join to form an optionally substituted 5- or 6-membered aromatic or non-aromatic carbocycle or heterocycle; and each Y is, independently, -H, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C7 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, optionally substituted -C2-C5 alkenyl, or optionally substituted -C2-C5 alkynyl; or two Y, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
  • R4 is -H, -OH, -CN, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7- membered aromatic or non-aromatic heterocycle, -N(Y)2, -C(NH)N(Y)2, -C(O)Y, -C(O)N(Y)2, -C(O)OY, -S(O) 2 Y, -NHC(O)Y, -NHS(O) 2 Y, -NHC(NH)N(Y) 2 , -NYC(NH)N(Y) 2 , -NHC(NCN)N(Y) 2 , or -NYC(NCN)N(Y) 2 ;
  • Rs and R7 are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Y)2, -C(NH)N(Y) 2 , -C(O)Y, -OC(O)Y, -OC(O)OY, -OC(O)N(Y) 2I -C(O)N(Y) 2I -C(O)OY, -SY, -S(O)Y, -S(O) 2 Y, -NHC(O)Y, -NHS(O) 2 Y, -NHC(NH)N(Y) 2 , -NY
  • each Y is, independently, -H, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C7 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, optionally substituted -C2-C5 alkenyl, or optionally substituted -C2-C5 alkynyl; or two Y, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
  • R4 is -H, -OH, -CN, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7- membered aromatic or non-aromatic heterocycle, -N(Y)2, -C(NH)N(Y)2, -C(O)Y, -C(O)N(Y)2, -C(O)OY, -S(O) 2 Y, -NHC(O)Y, -NHS(O) 2 Y, -NHC(NH)N(Y) 2 , -NYC(NH)N(Y) 2 , -NHC(NCN)N(Y) 2 , or -NYC(NCN)N(Y) 2 ;
  • Rs and Re are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Y)2, -C(NH)N(Y) 2 , -C(O)Y, -OC(O)Y, -OC(O)OY, -OC(O)N(Y) 2I -C(O)N(Y) 2I -C(O)OY, -SY, -S(O)Y, -S(O) 2 Y, -NHC(O)Y, -NHS(O) 2 Y, -NHC(NH)N(Y) 2 , -NYC
  • R4 and Rs or Rs and Re together with the carbon atoms to which each is attached, join to form an optionally substituted 5- or 6-membered aromatic or non-aromatic carbocycle or heterocycle; and each Y is, independently, -H, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C7 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, optionally substituted -C2-C5 alkenyl, or optionally substituted -C2-C5 alkynyl; or two Y, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
  • R4 is -H, -OH, -CN, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7- membered aromatic or non-aromatic heterocycle, -N(Y)2, -C(NH)N(Y)2, -C(O)Y, -C(O)N(Y)2, -C(O)OY, -S(O) 2 Y, -NHC(O)Y, -NHS(O) 2 Y, -NHC(NH)N(Y) 2 , -NYC(NH)N(Y) 2 , -NHC(NCN)N(Y) 2 , or -NYC(NCN)N(Y) 2 ;
  • Rs, Re, and R7 are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Y)2, -C(NH)N(Y) 2 , -C(O)Y, -OC(O)Y, -OC(O)OY, -OC(O)N(Y) 2I -C(O)N(Y) 2I -C(O)OY, -SY, -S(O)Y, -S(O) 2 Y, -NHC(O)Y, -NHS(O) 2 Y, -NHC(NH)N(Y) 2 ,
  • each Y is, independently, -H, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C7 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, optionally substituted -C2-C5 alkenyl, or optionally substituted -C2-C5 alkynyl; or two Y, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
  • Rs and Re are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Y)2, -C(NH)N(Y) 2 , -C(O)Y, -OC(O)Y, -OC(O)OY, -OC(O)N(Y) 2I -C(O)N(Y) 2I -C(O)OY, -SY, -S(O)Y, -S(O) 2 Y, -NHC(O)Y, -NHS(O) 2 Y, -NHC(NH)N(Y) 2 , -NYC
  • each Y is, independently, -H, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C7 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, optionally substituted -C2-C5 alkenyl, or optionally substituted -C2-C5 alkynyl; or two Y, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
  • Rs and R7 are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Y)2, -C(NH)N(Y) 2 , -C(O)Y, -OC(O)Y, -OC(O)OY, -OC(O)N(Y) 2I -C(O)N(Y) 2I -C(O)OY, -SY, -S(O)Y, -S(O) 2 Y, -NHC(O)Y, -NHS(O) 2 Y, -NHC(NH)N(Y) 2 , -NY
  • R4 and R7 are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Y)2, -C(NH)N(Y) 2 , -C(O)Y, -OC(O)Y, -OC(O)OY, -OC(O)N(Y) 2I -C(O)N(Y) 2I -C(O)OY, -SY, -S(O)Y, -S(O) 2 Y, -NHC(O)Y, -NHS(O) 2 Y, -NHC(NH)N(Y) 2 , -
  • Re and R7 are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Y)2, -C(NH)N(Y) 2 , -C(O)Y, -OC(O)Y, -OC(O)OY, -OC(O)N(Y) 2I -C(O)N(Y) 2I -C(O)OY, -SY, -S(O)Y, -S(O) 2 Y, -NHC(O)Y, -NHS(O) 2 Y, -NHC(NH)N(Y) 2 , -NY
  • each Y is, independently, -H, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C7 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, optionally substituted -C2-C5 alkenyl, or optionally substituted -C2-C5 alkynyl; or two Y, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
  • A3 is: in which
  • Rs and Re are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Y)2, -C(NH)N(Y) 2 , -C(O)Y, -OC(O)Y, -OC(O)OY, -OC(O)N(Y) 2I -C(O)N(Y) 2I -C(O)OY, -SY, -S(O)Y, -S(O) 2 Y, NHC(O)Y, -NHS(O) 2 Y, -NHC(NH)N(Y) 2 , -NYC(NH
  • each Y is, independently, -H, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C7 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, optionally substituted -C2-C5 alkenyl, or optionally substituted -C2-C5 alkynyl; or two Y, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
  • Rs and R7 are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Y)2, -C(NH)N(Y) 2 , -C(O)Y, -OC(O)Y, -OC(O)OY, -OC(O)N(Y) 2I -C(O)N(Y) 2I -C(O)OY, -SY, -S(O)Y, -S(O) 2 Y, -NHC(O)Y, -NHS(O) 2 Y, -NHC(NH)N(Y) 2 , -NY
  • R4, Rs, and R7 are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Y)2, -C(NH)N(Y) 2 , -C(O)Y, -OC(O)Y, -OC(O)OY, -OC(O)N(Y) 2I -C(O)N(Y) 2I -C(O)OY, -SY, -S(O)Y, -S(O) 2 Y, -NHC(O)Y, -NHS(O) 2 Y, -NHC(NH)N(Y) 2 ,
  • R4 and Rs together with the carbon atoms to which each is attached, join to form an optionally substituted 5- or 6-membered aromatic or non-aromatic carbocycle or heterocycle; and each Y is, independently, -H, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C7 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, optionally substituted -C2-C5 alkenyl, or optionally substituted -C2-C5 alkynyl; or two Y, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
  • R4, Rs, Re, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-C aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OY, -N(Y) 2 , -C(NH)N(Y) 2I -O(CH 2 ) n OY, -C(O)Y, -OC(O)Y, -OC(O)OY, -OC(O)N(Y) 2 , -C(O)N(Y) 2 , -C(O)
  • E122 The compound of any one of embodiments 1 , 14-37, and 51-120, in which Qi is -S(O)-.
  • a pharmaceutically composition including a compound of any one of embodiments 1-124 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • E126 A method for treating a neurological disorder, including administering to a subject in need thereof a therapeutically effective amount of a compound of any one of embodiments 1 -124 or a pharmaceutically acceptable salt thereof.
  • E127 The method of embodiment 126, in which the neurological disorder is a neurotraumatic disorder, a neurodevelopmental disorder, or an affective disorder.
  • E128 The method of embodiment 127, in which the neurological disorder is a neurotraumatic disorder.
  • E129 The method of embodiment 128, in which the neurotraumatic disorder is selected from the group consisting of spinal cord injury, traumatic brain injury, stroke, peripheral nerve injury, multiple sclerosis, ischemia, amyotrophic lateral sclerosis, Parkinson’s disease, Alzheimer’s disease, myelopathy, hypoxic-ischemic encephalopathy, tumor-associated epilepsy, spasticity, and peripheral neuropathy.
  • the neurotraumatic disorder is selected from the group consisting of spinal cord injury, traumatic brain injury, stroke, peripheral nerve injury, multiple sclerosis, ischemia, amyotrophic lateral sclerosis, Parkinson’s disease, Alzheimer’s disease, myelopathy, hypoxic-ischemic encephalopathy, tumor-associated epilepsy, spasticity, and peripheral neuropathy.
  • E130 The method of embodiment 127, in which the neurological disorder is a neurodevelopmental disorder.
  • E131 The method of embodiment 130, in which the neurodevelopmental disorder is selected from an autism spectrum disorder, Rett syndrome, Fragile X syndrome, Angelman syndrome, Tuberous Sclerosis Complex (TSC), cerebral palsy, Down syndrome, pain, Dravet syndrome, epilepsy, and sudden unexpected death in epilepsy.
  • the neurodevelopmental disorder is selected from an autism spectrum disorder, Rett syndrome, Fragile X syndrome, Angelman syndrome, Tuberous Sclerosis Complex (TSC), cerebral palsy, Down syndrome, pain, Dravet syndrome, epilepsy, and sudden unexpected death in epilepsy.
  • TSC Tuberous Sclerosis Complex
  • E132 The method of embodiment 131 , in which the pain is selected from neuropathic pain, inflammation, inflammatory pain, arthritic pain, diabetic pain, and neuralgia.
  • E133 The method of embodiment 131 , in which the epilepsy is selected from temporal lobe epilepsy, refractory epilepsy, neurotrauma associated epilepsy, status epilepticus, tumor associated epilepsy, and hypoxic-ischemic encephalopathy.
  • E134 The method of embodiment 127, in which the neurological disorder is an affective disorder.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The disclosure provides compounds of Formulas (I), (I-2), (I-3), (I-4), (I-5), (II), (II-2), (II-3), (II-4), and (II-5) and pharmaceutically acceptable salts thereof. Also provided are compositions and methods of using the compounds, e.g., for the treatment of neurological disorders.

Description

METHODS AND COMPOUNDS FOR TREATING NEUROLOGICAL DISORDERS
Background
Neurological disorders are detrimental to individuals due to the impact on a number of neurological functions such as sensory, motor, cognitive, and/or developmental functions in the affected individual. These disorders often result in profound and irreversible neurological effects that pose severe challenges to an afflicted patient’s everyday life. Few therapeutics have been studied or utilized to treat these neurological disorders, which causes severe challenges and suffering for these patients. Additionally, the few that have been studied or utilized are not adequately sufficient to reduce the individual’s suffering or improve recovery from these neurological disorders.
Accordingly, there is a need for novel therapeutic agents for the treatment of neurological disorders.
Summary of the Disclosure
The present disclosure provides compounds, compositions, and methods for treating or preventing neurological disorders in a patient. The disclosed methods include administration to a subject suffering from a neurological disorder of a compound disclosed herein in an amount effective. The disclosure further provides pharmaceutical compositions containing one of the compounds described herein.
In a first aspect, the disclosure provides a compound of formula (1-2):
Figure imgf000002_0001
V is O, S, NH, NZ, N-terminal linked amino acid,
Figure imgf000002_0002
which Ra is -CH2NH- or -C(Rd)2Q-, in which each Rd is independently -H, -Ci-Cs alkyl, -Ci-Cs cycloalkyl, -Ci-Cs aryl, or -Ci-Cs heteroaryl; Rb is -H, -OH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -Ci-Cs alkoxy, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-C aryl, or -N(Re)2, and each Re is independently -H or -Ci-Cs alkyl;
R2 and R3 are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-Cu aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OZ, -N(Z)2, -C(NH)N(Z)2, -OCH2OZ, -O(CH2)2OZ, -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z)2I -C(O)N(Z)2I -C(O)OZ, -SZ, -SOZ, -S(O)2Z, -NHC(O)Z, -NHS(O)2Z, -NHC(NH)N(Z)2, -NZC(NH)N(Z)2, -NHC(NCN)N(Z)2, -NZC(NCN)N(Z)2, or -PO(OZ)2;
R4, Rs, Re, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted - C1-C5 alkyl, optionally substituted -Cs-Ce cycloalkyl, optionally substituted phenyl, optionally substituted - C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, - N(Z)2, -C(NH)N(Z)2I -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z)2I -C(O)N(Z)2I -C(O)OZ, -SZ, -S(O)Z, -S(O)2Z, -NHC(O)Z, -NHS(O)2Z, -NHC(NH)N(Z)2, -NYC(NH)N(Z)2, -NHC(NCN)N(Z)2, or -NZC(NCN)N(Z)2; each Z is, independently, -H; optionally substituted -Ci-Cs alkyl; optionally substituted -C4-C12 alkcycloalkyl; optionally substituted -Cs-Cg alkheterocyclyl, in which the heterocycle is 3- to 9-membered; optionally substituted -C3-C12 cycloalkyl; optionally substituted -Ce-C aryl; optionally substituted -C7-C14 arylalkyl; optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle; optionally substituted -C2-C8 alkenyl; or optionally substituted -C2-C8 alkynyl; or two Z, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle; and Q2, Q3, and Q4 are each, independently, N, N+-O_, or C, in which Q2, Q4, and Qe are not simultaneously C.
In some embodiments, the compound is a compound of formula (I-3):
Figure imgf000003_0001
or a pharmaceutically acceptable salt thereof, in which
R4, Rs, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-C aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OZ, -N(Z)2, -C(NH)N(Z)2, -O(CH2)nOZ, -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z)2, -C(O)N(Z)2I -C(O)OZ, -SZ, -S(O)Z, -S(O)2Z, -NHC(O)Z, -NHS(O)2Z, -NHC(NH)N(Z)2, -NYC(NH)N(Z)2, -NHC(NCN)N(Z)2, -NYC(NCN)N(Z)2, or -PO(OZ)2; and each Z is, independently, -H; optionally substituted -Ci-Cs alkyl; optionally substituted -C4-C12 alkcycloalkyl; optionally substituted -Cs-Cg alkheterocyclyl, in which the heterocycle is 3- to 9- membered; optionally substituted -C3-C12 cycloalkyl; optionally substituted -Ce-Cu aryl; optionally substituted -C7-C14 arylalkyl; 3- to 9-membered optionally substituted aromatic or non-aromatic heterocycle; optionally substituted -C2-C8 alkenyl; or optionally substituted -C2-C8 alkynyl; or two Z, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
In some embodiments of any of the aspects described herein (e.g., formula (1-3)), R4 is -halo, e.g., -Cl.
In some embodiments of any of the aspects described herein (e.g., formula (1-3)), Rs is -halo, e.g., -Cl.
In some embodiments of any of the aspects described herein (e.g. formula (1-3)), Rs is Ci-Cs alkyl, e.g., methyl.
In some embodiments of any of the aspects described herein (e.g., formula (I-3)), Rs is -H.
In some embodiments of any of the aspects described herein (e.g., formula (I-3)), R7 is -H.
In some embodiments, the compound is a compound of formula (I-4):
Figure imgf000004_0001
or a pharmaceutically acceptable salt thereof, in which R4, Rs, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Cs-Cu aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OZ, -N(Z)2, -C(NH)N(Z)2, -O(CH2)nOZ, -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z)2, -C(O)N(Z)2I -C(O)OZ, -SZ, -S(O)Z, -S(O)2Z, -NHC(O)Z, -NHS(O)2Z, -NHC(NH)N(Z)2, -NYC(NH)N(Z)2, -NHC(NCN)N(Z)2, -NYC(NCN)N(Z)2, or -PO(OZ)2; and each Z is, independently, -H; optionally substituted -Ci-Cs alkyl; optionally substituted -C4-Ci2 alkcycloalkyl; optionally substituted -C3-C9 alkheterocyclyl, in which the heterocycle is 3- to 9- membered; optionally substituted -C3-C12 cycloalkyl; optionally substituted -Cs-Cu aryl; optionally substituted -C7-C14 arylalkyl; 3- to 9-membered optionally substituted aromatic or non-aromatic heterocycle; optionally substituted -C2-C8 alkenyl; or optionally substituted -C2-C8 alkynyl; or two Z, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
In some embodiments, the compound is a compound of formula (I-5):
Figure imgf000004_0002
or a pharmaceutically acceptable salt thereof, in which R4, Rs, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-Cu aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OZ, -N(Z)2, -C(NH)N(Z)2, -O(CH2)nOZ, -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z)2,-C(O)N(Z)2, -C(O)OZ, -SZ, -S(O)Z, -S(O)2Z, -NHC(O)Z, -NHS(O)2Z, -NHC(NH)N(Z)2, -NYC(NH)N(Z)2, NHC(NCN)N(Z)2, -NYC(NCN)N(Z)2, or -PO(OZ)2; and each Z is, independently, -H; optionally substituted -Ci-Cs alkyl; optionally substituted -C4-Ci2 alkcycloalkyl; optionally substituted -C3-C9 alkheterocyclyl, in which the heterocycle is 3- to 9- membered; optionally substituted -C3-C12 cycloalkyl; optionally substituted -Ce-Cu aryl; optionally substituted -C7-C14 arylalkyl; 3- to 9-membered optionally substituted aromatic or non-aromatic heterocycle; optionally substituted -C2-C8 alkenyl; or optionally substituted -C2-C8 alkynyl; or two Z, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
In some embodiments, Rb is optionally substituted -Ci-Cs alkyl, e.g., -(CH2)sCH3, -CH3, -C(CH3)3, or -CH(CH3)2.
In some embodiments, Rb is carboxyl substituted -Ci-Cs alkyl, e.g., -(CH2)4COOH, -CH2COOH, -(CH2)2COOH, -(CH2)3COOH, -CH(CH3)(CH2)3COO 2)3COOH.
In some embodiments, Rb is an amino acid,
Figure imgf000005_0001
alanine, phenylalanine, glycine, N,N- dimethylglycine, lysine, glutamic acid, aspartic acid, leucine, or isoleucine.
In some embodiments, Rb is optionally substituted -Ci-Cs alkoxy, e.g., -OCH2CH3 or
Figure imgf000005_0002
In some embodiments, Rb is -N(Re)2, e.g., -NHCH2CH3.
In some embodiments, Ra is -CH2NH-.
In some embodiments, Ra is -C(Rd)2O-, in which Rd is -CH2O- or -CH(CH3)O-.
In some embodiments, R2 is selected from -H, -halo, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C5 alkenyl, optionally substituted -C2-C5 alkynyl, optionally substituted -C7-C14 arylalkyl, and -CN.
In some embodiments, R3 is selected from -H, -halo, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C5 alkenyl, optionally substituted -C2-C5 alkynyl, optionally substituted -C7-C14 arylalkyl, and -CN. In another aspect, the disclosure provides a compound of formula (11-2):
Figure imgf000006_0001
or a pharmaceutically acceptable salt thereof, in which V is O, S, NH, NZ, or CH2;
Figure imgf000006_0002
which
Ra’ is -H, -OH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, or optionally substituted -Ce-Cu aryl; and Ra is -CH2NH- or -C(Rd)2O-, ‘in which each Rd is independently -H, -Ci-Cs alkyl, -Ci-Cs cycloalkyl, -Ci-Cs aryl, or -Ci-Cs heteroaryl; Rb is H, OH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -Ci-Cs alkoxy, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-C aryl, or -N(Re)2, in which each Re is independently -H or -Ci-Cs alkyl; and Rc is H, Ci-Cs alkyl, or Ce-Cu aryl; R2’ and R3’, together with the atoms to which each is attached, join to form a 5- to 6-membered aromatic or non-aromatic carbocycle or heterocycle; R4, Rs, Re, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Z)2, -C(NH)N(Z)2, -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z)2, -C(O)N(Z)2, -C(O)OZ, -SZ, -S(O)Z, -S(O)2Z, -NHC(O)Z, -NHS(O)2Z, -NHC(NH)N(Z)2, -NYC(NH)N(Z)2, -NHC(NCN)N(Z)2, or -NZC(NCN)N(Z)2; each Z is, independently, -H; optionally substituted -Ci-Cs alkyl; optionally substituted -C4-Ci2 alkcycloalkyl; optionally substituted -Cs-Cg alkheterocyclyl, in which the heterocycle is 3- to 9-membered; optionally substituted -C3-C12 cycloalkyl; optionally substituted -Ce-Cu aryl; optionally substituted -C7-C14 arylalkyl; optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle; optionally substituted -C2-C8 alkenyl; or optionally substituted -C2-C8 alkynyl; or two Z, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle; and Q2, Q3, and Q4 are each, independently, N, N+-O-, or C, wherein Q2, Q4, and Q3 are not simultaneously C. In some embodiments, the compound is a compound of formula (11-3):
Figure imgf000007_0001
or a pharmaceutically acceptable salt thereof, in which R4, Rs, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-Cu aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OZ, -N(Z)2, -C(NH)N(Z)2, -O(CH2)nOZ, -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z)2, -C(O)N(Z)2I -C(O)OZ, -SZ, -S(O)Z, -S(O)2Z, -NHC(O)Z, -NHS(O)2Z, -NHC(NH)N(Z)2, -NYC(NH)N(Z)2, -NHC(NCN)N(Z)2, -NYC(NCN)N(Z)2, or -PO(OZ)2; and each Z is, independently, -H; optionally substituted -Ci-Cs alkyl; optionally substituted -C4-Ci2 alkcycloalkyl; optionally substituted -C3-C9 alkheterocyclyl, in which the heterocycle is 3- to 9- membered; optionally substituted -C3-C12 cycloalkyl; optionally substituted -Ce-Cu aryl; optionally substituted -C7-C14 arylalkyl; 3- to 9-membered optionally substituted aromatic or non-aromatic heterocycle; optionally substituted -C2-C8 alkenyl; or optionally substituted -C2-C8 alkynyl; or two Z, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
In some embodiments of any of the aspects described herein (e.g., formula (II-3)), R4 is -halo, e.g., -Cl.
In some embodiments of any of the aspects described herein (e.g., formula (II-3)), Rs is -halo, e.g., -Cl.
In some embodiments of any of the aspects described herein (e.g., formula (II-3)), Rs is C1-C6 alkyl, e.g., methyl.
In some embodiments of any of the aspects described herein (e.g., formula (II-3)), Rs is -H. In some embodiments of any of the aspects described herein (e.g., formula (II-3)), R7 is -H. In some embodiments, the compound is a compound of formula (II-4):
Figure imgf000007_0002
or a pharmaceutically acceptable salt thereof, in which R4, Rs, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-Ci2 cycloalkyl, optionally substituted -Ce-Cu aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OZ, -N(Z)2, -C(NH)N(Z)2, -O(CH2)nOZ, -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z)2, -C(O)N(Z)2I -C(O)OZ, -SZ, -S(O)Z, -S(O)2Z, -NHC(O)Z, -NHS(O)2Z, -NHC(NH)N(Z)2, -NYC(NH)N(Z)2, -NHC(NCN)N(Z)2, -NYC(NCN)N(Z)2, or -PO(OZ)2; and each Z is, independently, -H; optionally substituted -Ci-Cs alkyl; optionally substituted -C4-Ci2 alkcycloalkyl; optionally substituted -C3-Cg alkheterocyclyl, in which the heterocycle is 3- to 9- membered; optionally substituted -C3-Ci2 cycloalkyl; optionally substituted -Ce-Cu aryl; optionally substituted -C7-C14 arylalkyl; 3- to 9-membered optionally substituted aromatic or non-aromatic heterocycle; optionally substituted -C2-C8 alkenyl; or optionally substituted -C2-C8 alkynyl; or two Z, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
In some embodiments, the compound is a compound of formula (II-5):
Figure imgf000008_0001
or a pharmaceutically acceptable salt thereof, in which R4, Rs, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-Ci2 cycloalkyl, optionally substituted -Ce-Cu aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OZ, -N(Z)2, -C(NH)N(Z)2, -O(CH2)nOZ, -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z)2, -C(O)N(Z)2I -C(O)OZ, -SZ, -S(O)Z, -S(O)2Z, -NHC(O)Z, -NHS(O)2Z, -NHC(NH)N(Z)2, -NYC(NH)N(Z)2, -NHC(NCN)N(Z)2,-NYC(NCN)N(Z)2, or -PO(OZ)2; and each Z is, independently, -H; optionally substituted -Ci-Cs alkyl; optionally substituted -C4-Ci2 alkcycloalkyl; optionally substituted -C3-Cg alkheterocyclyl, in which the heterocycle is 3- to 9- membered; optionally substituted -C3-Ci2 cycloalkyl; optionally substituted -Ce-Cu aryl; optionally substituted -C7-C14 arylalkyl; 3- to 9-membered optionally substituted aromatic or non-aromatic heterocycle; optionally substituted -C2-C8 alkenyl; or optionally substituted -C2-C8 alkynyl; or two Z, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
In some embodiments, R1’ is -C(O)Ra’. In some embodiments, Ra’ is optionally substituted -Ci-Cs
Figure imgf000008_0002
o
In some embodiments, R1’ is
Figure imgf000009_0001
. In some embodiments, Rb is optionally substituted -Ci-Cs alkyl, e.g., -(CH2)sCH3, -CH3, -C(CH3)3, or -CH(CH3)2. In some embodiments, Rb is carboxyl substituted -Ci-C8 alkyl, e.g, -(CH2)4COOH, -CH2COOH, -(CH2)2COOH, -(CH2)3COOH, -CH(CH3)(CH2)3COOH, -C(CH3)2(CH2)3COOH.
Figure imgf000009_0002
In some embodiments, Rb is an amino acid, e.g., NH2 , alanine, phenylalanine, glycine, N,N- dimethylglycine, lysine, glutamic acid, aspartic acid, leucine, or isoleucine.
In some embodiments, Rb is optionally substituted -Ci-Cs alkoxy, e.g., -OCH2CH3 or
Figure imgf000009_0003
In some embodiments, CH2CH3.
In some embodiments,
Figure imgf000009_0004
n some embodiments, each Rc is independently
-H or -C(CH3)3.
In some embodiments, R2’ and R3’, together with the atoms to which each is attached, form optionally substituted cyclopentyl or optionally substituted cyclohexyl. In some embodiments, R2’ and R3’, together with the atom to which each is attached, join to form cyclopentyl.
In some embodiments of any of the aspects described herein (e.g., formula (I-2), (I-3), (I-4), (-5), 11-2), (I I-3), (I I-4), or (I I-5), V is O, S, or NH.
In another aspect, the disclosure provides a compound of formula (I) or formula (II), as is described herein.
In another aspect, the present disclosure provides compounds of Table 1 .
Table 1
Figure imgf000009_0005
Figure imgf000009_0006
Figure imgf000010_0001
Figure imgf000010_0002
Figure imgf000011_0002
Figure imgf000011_0001
Figure imgf000012_0001
Figure imgf000012_0002
Figure imgf000013_0001
In another aspect, the disclosure provides a pharmaceutically composition including a compound described herein (e.g., any one of the compounds of Formulas (I), (I-2), (I-3), (I-4), (I-5), (II), (II-2), (II-3), (I I-4) , (I I-5) and Table 1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
In another aspect, the disclosure provides a method for treating a neurological disorder, which includes administering to a subject in need thereof a therapeutically effective amount of a compound described herein (e.g., any one of the compounds of Formulas (I), (I-2), (I-3), (I-4), (I-5), (II), (II-2), (II-3), (I I-4) , (I I-5) and Table 1) or a pharmaceutically acceptable salt thereof.
In some embodiments, the neurological disorder is a neurotraumatic disorder, a neurodevelopmental disorder, or an affective disorder.
In some embodiments, the neurological disorder is a neurotraumatic disorder, e.g., spinal cord injury, traumatic brain injury, stroke, peripheral nerve injury, multiple sclerosis, ischemia, amyotrophic lateral sclerosis, Parkinson’s disease, Alzheimer’s disease, myelopathy, hypoxic-ischemic encephalopathy, tumor-associated epilepsy, spasticity, or peripheral neuropathy.
In some embodiments, the neurological disorder is a neurodevelopmental disorder, e.g., an autism spectrum disorder, Rett syndrome, Fragile X syndrome, Angelman syndrome, Tuberous Sclerosis Complex (TSC), cerebral palsy, Down syndrome, pain (e.g., neuropathic pain, chronic pain, or inflammatory pain), Dravet syndrome, epilepsy (e.g., temporal lobe epilepsy), or sudden unexpected death in epilepsy.
In some embodiments, the pain is neuropathic pain, inflammation, inflammatory pain, arthritic pain, diabetic pain, or neuralgia.
In some embodiments, the epilepsy is temporal lobe epilepsy, refractory epilepsy, neurotrauma associated epilepsy, status epilepticus, tumor associated epilepsy, hypoxic-ischemic encephalopathy and sudden unexpected death in epilepsy.
In some embodiments, the neurological disorder is an affective disorder, e.g., schizophrenia, bipolar disorder, anxiety disorder, or major depressive disorder.
Definitions
To facilitate the understanding of the present disclosure, a number of terms are defined below. Terms defined herein have meanings as commonly understood by a person of ordinary skill in the areas relevant to the disclosure. Terms such as "a," "an," and "the" are not intended to refer to only a singular entity, but include the general class of which a specific example may be used for illustration. The terminology herein is used to describe specific embodiments of the disclosure, but their usage does not limit the disclosure, except as outlined in the claims. As used herein, the term “about” is used to indicate that a value includes the standard deviation of error for the method being employed to determine the value. In certain embodiments, the term “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11 %, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1 %, or less in either direction (greater than or less than) of a stated value, unless otherwise stated or otherwise evident from the context (e.g., where such number would exceed 100% of a possible value).
Those skilled in the art will appreciate that certain compounds described herein can exist in one or more different isomeric (e.g., stereoisomers, geometric isomers, atropisomers, tautomers) or isotopic (e.g., in which one or more atoms has been substituted with a different isotope of the atom, such as hydrogen substituted for deuterium) forms. Unless otherwise indicated or clear from context, a depicted structure can be understood to represent any such isomeric or isotopic form, individually or in combination.
Compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present disclosure that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present disclosure. Cis and trans geometric isomers of the compounds of the present disclosure are described and may be isolated as a mixture of isomers or as separated isomeric forms.
In some embodiments, one or more compounds depicted herein may exist in different tautomeric forms. As will be clear from context, unless explicitly excluded, references to such compounds encompass all such tautomeric forms. In some embodiments, tautomeric forms result from the swapping of a single bond with an adjacent double bond and the concomitant migration of a proton. In certain embodiments, a tautomeric form may be a prototropic tautomer, which is an isomeric protonation states having the same empirical formula and total charge as a reference form. Examples of moieties with prototropic tautomeric forms are ketone — enol pairs, amide — imidic acid pairs, lactam — lactim pairs, amide — imidic acid pairs, enamine — imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, such as, 1 H- and 3H-imidazole, 1 H-, 2H- and 4H-1 ,2,4-triazole, 1 H- and 2H-isoindole, and 1 H- and 2H-pyrazole. In some embodiments, tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. In certain embodiments, tautomeric forms result from acetal interconversion.
Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopica lly enriched atoms. Exemplary isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 180, 32P, 33P, 35S, 18F, 36CI, 123l and 125l. Isotopically-labeled compounds (e.g., those labeled with 3H and 14C) can be useful in compound or substrate tissue distribution assays. Tritiated (i.e., ,sup.3H) and carbon-14 (i.e., 14C)) isotopes can be useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, one or more hydrogen atoms are replaced by 2H, D, or 3H, or one or more carbon atoms are replaced by 13C- or 14C-enriched carbon. Positron emitting isotopes such as 15O, 13N, 11C, and 18F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Preparations of isotopically labelled compounds are known to those of skill in the art. For example, isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed for compounds of the present invention described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
As is known in the art, many chemical entities can adopt a variety of different solid forms such as, for example, amorphous forms or crystalline forms (e.g., polymorphs, hydrates, solvate). In some embodiments, compounds of the present invention may be utilized in any such form, including in any solid form. In some embodiments, compounds described or depicted herein may be provided or utilized in hydrate or solvate form.
At various places in the present specification, substituents of compounds of the present disclosure are disclosed in groups or in ranges. It is specifically intended that the present disclosure include each and every individual subcombination of the members of such groups and ranges. For example, the term “Ci-Ce alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and Ce alkyl. Furthermore, where a compound includes a plurality of positions at which substituents are disclosed in groups or in ranges, unless otherwise indicated, the present disclosure is intended to cover individual compounds and groups of compounds (e.g., genera and subgenera) containing each and every individual subcombination of members at each position.
The term “optionally substituted X” (e.g., “optionally substituted alkyl”) is intended to be equivalent to “X, wherein X is optionally substituted” (e.g., “alkyl, wherein said alkyl is optionally substituted”). It is not intended to mean that the feature “X” (e.g., alkyl) per se is optional. As described herein, certain compounds of interest may contain one or more “optionally substituted” moieties. In general, the term “substituted”, whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent, e.g., any of the substituents or groups described herein. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. For example, in the term “optionally substituted Ci-Ce alkyl-C2-Cg heteroaryl,” the alkyl portion, the heteroaryl portion, or both, may be optionally substituted. Combinations of substituents envisioned by the present disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable”, as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein. The term “optionally substituted,” as used herein, refers to having 0, 1 , or more substituents (e.g., 0-25, 0-20, 0-10, or 0-5 substituents).
As used herein, any values provided in a range of values include both the upper and lower bounds, and any values contained within the upper and lower bounds.
As used herein, the terms “administer” and “administering” are used to indicate the process of providing a therapeutic, pharmaceutical, housing compartment, medication, or the like thereof to a subject. In some embodiments, a pharmaceutical is provided via oral administration. As used herein, the terms “improve” and “improving,” in reference to recovery from a disease or condition, e.g., a neurological disorder, refer to an enhancement of recovery in one or more parameters measuring or quantifying the severity of the neurological disorder relative to the recovery in these parameters in or prior to treatment with the compounds or compositions described herein. Alternatively, improvement may be measured with respect to a reference subject having the same diagnosis as the subject but that did not receive treatment with a compound or composition of the disclosure. For neurological disorders, such parameters may include motor and sensory function in a subject. Methods for assessing motor and sensory function in a subject suffering from a neurological disorder are known in the art and are further described herein.
As used herein, the term “pharmaceutical composition” refers to an active compound, formulated together with one or more pharmaceutically acceptable excipients. In some embodiments, a compound of the disclosure is present in unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions) or tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, or pastes for application to the tongue.
The term “pharmaceutically acceptable excipient,” as used herein, refers to any inactive ingredient (for example, a vehicle capable of suspending or dissolving the active compound) having the properties of being nontoxic and non-inflammatory in a subject. Typical excipients include, for example: antiadherents, antioxidants, binders, coatings, compression aids, dis integrants, dyes, emollients, emulsifiers, diluents, film formers or coatings, flavors, fragrances, glidants, lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, or waters of hydration. Excipients include, but are not limited to: butylated optionally substituted hydroxytoluene (e.g., BHT), calcium carbonate, calcium phosphate dibasic, calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, optionally substituted hydroxypropyl cellulose, optionally substituted hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch, stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. Those of ordinary skill in the art are familiar with a variety of agents and materials useful as excipients.
As used herein, the term “pharmaceutically acceptable salt” represents those salts of the compounds described that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. These salts may be acid addition salts involving inorganic or organic acids. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable acid. Methods for preparation of the appropriate salts are well-established in the art.
The term “subject,” as used herein, can be a human, non-human primate, or other mammal, such as but not limited to dog, cat, horse, cow, pig, goat, monkey, rat, mouse, and sheep. In preferred embodiments, the subject is a human.
As used herein, the term “therapeutically effective amount” refers to an amount sufficient to effect beneficial or desired results, such as clinical results, and, as such, a “therapeutically effective amount” depends upon the context in which it is being applied. For example, in the context of administering a compound disclosed herein (e.g., a compounds of any one of formulas (I), (1-2), (1-3), (1-4), (1-5), (II), (11-2), (11-3), (11-4), and (11-5), and other compounds disclosed herein) to treat a neurological disorder, a therapeutically effective amount of a compound is, for example, an amount sufficient to reverse alleviate the neurological disorder.
As used herein, the term “treat,” or “treating,” refers to a therapeutic treatment of a neurological disorder in a subject. The effect of treatment can include reversing, alleviating, reducing severity of, inhibiting the progression of, reducing the likelihood of recurrence of the neurological disorder or one or more symptoms or manifestations of the neurological disorder, stabilizing (i.e., not worsening) the state of the neurological disorder as compared to the state and/or the condition of the disease or disorder in the absence of the therapeutic treatment.
The term “alkcycloalkyl,” as used herein, refers to monovalent radical of formula -RR’, in which R is alkylene, and R’ is cycloalkyl.
The term “alkenyl,” as used herein, refers to a branched or straight-chain monovalent unsaturated aliphatic radical containing at least one carbon-carbon double bond and no carbon-carbon triple bonds, and only C and H when unsubstituted. Monovalency of an alkenyl group does not include the optional substituents on the alkenyl group. For example, if an alkenyl group is attached to a compound, monovalency of the alkenyl group refers to its attachment to the compound and does not include any additional substituents that may be present on the alkenyl group. In some embodiments, the alkenyl group may contain, e.g., 2-20, 2-18, 2-16, 2-14, 2-12, 2-10, 2-8, 2-6, or 2-4 carbon atoms (e.g., C2-C20, C2-C18, C2-C16, C2-C14, C2-C12, C2-C10, C2-C8, C2-C6, or C2-C4). Examples include, but are not limited to, ethenyl, 1 -propenyl, 2-propenyl, 1 -methylethenyl, 1 -butenyl, 2-butenyl, 3-butenyl, and the like.
The term “alkheterocyclyl,” as used herein, refers to a monovalent radical of formula -RR’, in which R is alkylene, and R’ is heterocycle.
The term “alkoxy,” as used herein, refers to a monovalent radical of formula -OR, in which R is alkyl.
The term “alkyl,” as used herein, refers to a branched or straight-chain monovalent saturated aliphatic radical containing only C and H when unsubstituted. The monovalency of an alkyl group does not include the optional substituents on the alkyl group. For example, if an alkyl group is attached to a compound, monovalency of the alkyl group refers to its attachment to the compound and does not include any additional substituents that may be present on the alkyl group. In some embodiments, the alkyl group may contain, e.g., 1-20, 1-18, 1-16, 1-14, 1-12, 1-10, 1-8, 1-6, 1-4, or 1-2 carbon atoms (e.g., C1- C20, C1-C18, C1-C16, C1-C14, C1-C12, C1-C10, Ci-Cs, C1-C6, C1-C4, or C1-C2). Examples include, but are not limited to, methyl, ethyl, isobutyl, sec-butyl, and tert-butyl. The term “alkylene,” as used herein, refers to a divalent radical obtained by removing a hydrogen atom from a carbon atom of an alkyl group. The divalency of an alkylene group does not include the optional substituents on the alkylene group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, and n-propylene.
The term “alkynyl,” as used herein, refers to a branched or straight-chain monovalent unsaturated aliphatic radical containing at least one carbon-carbon triple bond and only C and H when unsubstituted. Monovalency of an alkynyl group does not include the optional substituents on the alkynyl group. For example, if an alkynyl group is attached to a compound, monovalency of the alkynyl group refers to its attachment to the compound and does not include any additional substituents that may be present on the alkynyl group. In some embodiments, the alkynyl group may contain, e.g., 2-20, 2-18, 2-16, 2-14, 2-12, 2-10, 2-8, 2-6, or 2-4 carbon atoms (e.g., C2-C20, C2-C18, C2-C16, C2-C14, C2-C12, C2-C10, C2-C8, C2-C6, or C2-C4). Examples include ethynyl, 1-propynyl, and 3-butynyl.
The term “amino acid,” as used herein, refers to a molecular fragment having an amino functional group and a carboxylic functional group. Amino acids include natural amino acids and unnatural amino acids. A "natural amino acid" refers to an amino acid that is naturally produced or found in a mammal. Natural amino acids can be encoded by the standard genetic code or may result from, for example, post- translational modifications. Natural amino acids include the twenty proteinogenic L-amino acids (Alanine (A), Cysteine (C), Serine (S), Threonine (T), Aspartic Acid (D), Glutamic Acid (E), Asparagine (N), Glutamine (Q), Histidine (H), Arginine (R), Lysine (K), Isoleucine (I), Leucine (L), Methionine (M), Valine (V), Phenylalanine (F), Tyrosine (Y), Tryptophan (W), Glycine (G), and Proline (P)). Other natural amino acids include gamma-aminobutyric acid (GABA; a y-amino acid), 3,4-dihydroxy-L-phenylalanine (L- DOPA), carnitine, ornithine, citrulline, homoserine, lanthionine, 2-aminoisobutyric acid, and dehydroalanine. An "unnatural amino acid" is an amino acid that is not naturally produced (e.g., encoded by the genetic code or resulting from a posttranslational modification) or naturally found in a mammal. Unnatural amino acids include amino acids that normally do not occur in proteins (e.g., an a-amino acid having the D-configuration, or a (D,L)-isomeric mixture thereof), homologues of naturally occurring amino acids (e.g., a p- or y-amino acid analogue), an a,a-disubstituted analogue of a naturally occurring amino acid, or an a-amino acid in which the amino acid side chain has been shortened by one or two methylene groups or lengthened to up to 10 carbon atoms. Other unnatural amino acids include y-amino acids that are GABA analogues, such as (S)-3-(aminomethyl)-5-methylhexanoic acid (pregabalin), 2-[l- (aminomethyl)cyclohexyl]acetic acid (gabapentin), orthose described in Yogeeswari et al., Recent Patents on CNS Drug Discovery 2006;l: 113-118, the disclosure of which is incorporated by reference herein in its entirety.
Types of amino acids include "a-amino acids," in which the amino and carboxylic groups are attached to the same carbon. In "p-amino acids," the carbon to which the amino group is attached is adjacent to the carbon to which the carboxylic group is attached, and in "y-amino acids," there is an additional intervening carbon. Amino acids can have the L-configuration (for example, natural amino acids have the L-configuration) or the D-configuration. An amino acid can be attached to a compound of the disclosure through a covalent attachment to, for example, the carboxylic functional group ("C-terminal linked") or through the amino functional group ("N-terminal linked").
The term “aryl,” as used herein, refers to any monocyclic or fused ring bicyclic or multicyclic system containing only carbon atoms in the ring(s), which has the characteristics of aromaticity in terms of electron distribution throughout the ring system, e.g., phenyl, naphthyl, or phenanthryl. An aryl group may have, e.g., six to sixteen carbons or six to fourteen carbons (e.g., six carbons, ten carbons, thirteen carbons, fourteen carbons, or sixteen carbons).
The term “arylalkyl,” as used herein, refers to a monovalent radical of formula -RR’, in which R is alkylene, and R’ is aryl.
The term “carbocycle,” as used herein, refers to a monovalent, saturated (“cycloalkyl”) or unsaturated, non-aromatic cyclic group containing only C and H when unsubstituted. A carbocycle may have, e.g., three to twenty carbons (e.g., a C3-C7, C3-C8, C3-C9, C3-C10, C3-C11, C3-C12, C3-C14, C3-C16, C3- Cis, or C3-C20 carbocycle).
The term “cycloalkyl,” as used herein, refers to a monovalent, saturated cyclic group containing only C and H when unsubstituted. A cycloalkyl may have, e.g., three to twenty carbons (e.g., a C3-C7, C3- Cs, C3-C9, C3-C10, C3-C11, C3-C12, C3-C14, C3-C16, C3-C18, or C3-C20 cycloalkyl). Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term “cycloalkyl” also includes cyclic groups having a bridged multicyclic structure in which one or more carbons bridges two non-adjacent members of a monocyclic ring, e.g., bicyclo[2.2.1]heptyl and adamantyl. The term “cycloalkyl” also includes bicyclic, tricyclic, and tetracyclic fused ring structures, e.g., decalin and spiro-cyclic compounds.
The term “cycloalkenyl,” as used herein, refers to a monovalent, unsaturated carbocyclic ring system that includes at least one carbon-carbon double bond, only C and H when unsubstituted, and is not aromatic across the whole ring system. A cycloalkenyl may have, e.g., four to twenty carbons (e.g., a C4-C7, C4-C8, C4-C9, C4-C10, C4-C11, C4-C12, C4-C13, C4-C14, C4-C16, C4-C18, or C4-C20 cycloalkenyl). Exemplary cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and cycloheptenyl. The term “cycloalkenyl” also includes cyclic groups having a bridged multicyclic structure in which one or more carbons bridges two non-adjacent members of a monocyclic ring, e.g., bicyclo[2.2.2]oct-2-ene. The term “cycloalkenyl” also includes fused bicyclic and multicyclic nonaromatic, carbocyclic ring systems containing one or more double bonds.
The term “halo,” as used herein, refers to a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical.
The term “heterocycle,” as used herein, represents a monocyclic or fused ring bicyclic or multicyclic system having at least one heteroatom as a ring atom. For example, a heterocycle ring may have, e.g., one to fifteen carbons ring atoms (e.g., a C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, C1-C7, Ci-Cs, C1- C9, C1-C10, C1-C11, C1-C12, C1-C13, C1-C14, or C1-C15 heterocycle) and one or more (e.g., one, two, three, four, or five) ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Heterocycle groups may or may not include a ring that is aromatic. An aromatic heterocycle group is referred to as a “heteroaryl” group. In preferred embodiments of the disclosure, a heterocycle group is a 3- to 8-membered ring, a 3- to 6-membered ring, a 4- to 6-membered ring, a 6- to 10-membered ring, a 6- to 12-membered ring, a 5-membered ring, or a 6-membered ring. Exemplary 5-membered heterocycle groups may have zero to two double bonds, and exemplary 6-membered heterocycle groups may have zero to three double bonds. Exemplary 5-membered groups include, for example, optionally substituted pyrrole, optionally substituted pyrazole, optionally substituted isoxazole, optionally substituted pyrrolidine, optionally substituted imidazole, optionally substituted thiazole, optionally substituted thiophene, optionally substituted thiolane, optionally substituted furan, optionally substituted tetrahydrofuran, optionally substituted diazole, optionally substituted triazole, optionally substituted tetrazole, optionally substituted oxazole, optionally substituted 1 ,3,4-oxadiazole, optionally substituted 1 ,3,4-thiadiazole, optionally substituted 1 ,2,3,4-oxatriazole, and optionally substituted 1 ,2,3,4-thiatriazole. Exemplary 6- membered heterocycle groups include, for example, optionally substituted pyridine, optionally substituted piperidine, optionally substituted piperazine, optionally substituted pyrimidine, optionally substituted pyrazine, optionally substituted pyridazine, optionally substituted triazine, optionally substituted 2/7-pyran, optionally substituted 4/7-pyran, and optionally substituted tetrahydropyran. Exemplary 7-membered heterocycle groups include optionally substituted azepine, optionally substituted 1 ,4-diazepine, optionally substituted thiepine, and optionally substituted 1 ,4-thiazepine.
As used herein, the term “neurological disorder” refers to any damage or dysfunction of one or more nerves in a subject. A neurological disorder may include any damage or dysfunction that prevents and/or inhibits one or more electrical and/or chemical transmissions of a sensory and/or motor function signal. A neurological disorder may include any damage or dysfunction that results in a transmission of one or more electrical and/or chemical transmissions of a nerve cell uncontrollably by the subject. A neurological disorder may include damage or dysfunction of one or more nerves located within the central nervous system and/or peripheral nervous system of a subject. A neurological disorder may include damage or dysfunction of a somatic, autonomic, and/or enteric nervous system of a subject. A neurological disorder may include damage or dysfunction of an afferent and/or efferent nervous system of a subject. A neurological disorder may include damage or dysfunction of a sympathetic and/or parasympathetic nervous system of a subject. A neurological disorder may include damage of dysfunction of one or more cranial nerves (e.g., the olfactory nerve, optic nerve, oculomotor nerve, trochlear nerve, trigeminal nerve, abducens nerve, facial nerve, vestibulocochlear nerve, glossopharyngeal nerve, vagus nerve, accessory nerve, and/or hypoglossal nerve) of a subject. A neurological disorder may be a neurotraumatic disorder, which may include a spinal cord injury, traumatic brain injury, stroke, peripheral nerve injury, multiple sclerosis, ischemia, amyotrophic lateral sclerosis, Parkinson’s disease, Alzheimer’s disease, myelopathy, hypoxic-ischemic encephalopathy, tumor- associated epilepsy, spasticity, or peripheral neuropathy A neurological disorder may be a neurodevelopmental disorder, which may include an autism spectrum disorder, Rett syndrome, Fragile X syndrome, Tuberous Sclerosis Complex (TSC), Angelman syndrome, cerebral palsy, Down syndrome, pain (e.g., neuropathic pain, chronic pain, or inflammatory pain), Dravet syndrome, epilepsy (e.g., temporal lobe epilepsy), or sudden unexpected death in epilepsy. The pain is neuropathic pain, inflammation, inflammatory pain, arthritic pain, diabetic pain, or neuralgia. The method of claim 64, wherein the epilepsy is temporal lobe epilepsy, refractory epilepsy, neurotrauma associated epilepsy, status epilepticus, tumor associated epilepsy, hypoxic-ischemic encephalopathy and sudden unexpected death in epilepsy. A neurological disorder may include an affective disorder, which may include schizophrenia, bipolar-disorder, anxiety disorder, major depressive disorder, and the like thereof.
The term “oxo,” as used herein, refers to a divalent oxygen atom represented by the structure =O. Alkyl, alkylene, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, and heterocycle groups may be substituted with carbocycle (e.g., cycloalkyl); aryl; heterocycle; halo; ORa, in which Ra is H, alkyl, alkenyl, alkynyl, carbocycle (e.g., cycloalkyl), aryl, or heterocycle; SRa, in which Ra is as defined herein; CN; NO2; N3; NRbRc, in which each of Rb and Rc is, independently, H, alkyl, alkenyl, alkynyl, carbocycle (e.g., cycloalkyl), aryl, or heterocycle; SC>2Rd, in which Rd is H, alkyl or aryl; SC>2NReRf, in which each of Re and Rf is, independently, H, alkyl, or aryl; SOR9, in which R9 is H, alkyl, or aryl; or P(O)(ORh)2,in which each Rh is, independently, H or alkyl. Aryl, carbocycle (e.g., cycloalkyl), heteroaryl, and heterocycle groups may also be substituted with alkyl, alkenyl, or alkynyl. Alkyl, alkylene, alkenyl, alkynyl, carbocycle (e.g., cycloalkyl), and heterocycle groups may also be substituted with oxo or =NRj, in which Rj is H or alkyl. In some embodiments, a substituent is further substituted as described herein. For example, a Ci alkyl group, i.e., methyl, may be substituted with oxo to form a formyl group and further substituted with -OH or -NRbRc to form a carboxyl group or an amido group.
Brief Description of the Drawings
FIG. 1 is a graph depicting the mean plasma concentration over time of Compound A in dogs following the oral administration of 5 mg/kg of Compound A or intravenous administration of 1 mg/kg of Compound A or an equivalent orally administered dose of Compounds 3, 6, 12, 13, 15, and 11 .
FIG. 2 is graph depicting a plurality of pharmacokinetic parameters for each of Compounds 3, 6, 12, 13, 15, 11 , and 27 when compared to Compound A following oral administration of 5 mg/kg of Compound A or an equivalent dose of Compounds 3, 6, 12, 13, 15, 1 1 , or 27.
FIG. 3 is a graph depicting the plasma concentration over time of Compound A and Compound 3 in dogs following oral administration of 744 mg/kg Compound 3.
FIG. 4. is a graph depicting the plasma profile of Compound B after administration of compound B (1 mg/kg) IV, compound B (5 mg/kg) PO, or compound 28 (7.6 mg/kg) in male Beagle dogs.
Fig 5. is a table depicting the PK parameters of Compound B and Compound 28 in male Beagle dogs.
Detailed Description
Described herein are compounds, compositions, and methods for treating neurological disorders, e.g., neurotraumatic disorders, neurodevelopmental disorders, or affective disorders, in a subject. Without wishing to be bound by theory, the compounds described herein may function as orally-available prodrugs of potassium-chloride cotransporter 2 (KCC2) potentiators, such as Compound A or Compound B.
Figure imgf000021_0001
Compound B as well as compounds disclosed in U.S. Patents Nos. 9,040,538 and 9,315,521 , the contents of which are incorporated herein by reference in their entirety. The compounds described herein are useful for treating neurological disorders, e.g., neurotraumatic disorders, neurodevelopmental disorders, or affective disorders.
Compounds
The present disclosure provides compounds and compositions that can be administered to a subject (e.g., a human) in order to treat a neurological disorder (e.g., a neurotraumatic disorder, a neurodevelopmental disorder, or an affective disorder).
In some embodiments, the compound is a compound of formula (I-2):
Figure imgf000022_0001
or a pharmaceutically acceptable salt thereof, wherein
V is O, S, NH, NZ, N-terminal linked amino acid, or CH2;
Figure imgf000022_0002
which Ra is -CH2NH- or -C(Rd)2Q-, in which each Rd is independently -H, -Ci-Cs alkyl, -Ci-Cs cycloalkyl, -Ci-Cs aryl, or -Ci-Cs heteroaryl; Rb is H, OH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -Ci-Cs alkoxy, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-C aryl, or -N(Re)2, and in which each Re is independently -H or -Ci-Cs alkyl;
R2 and R3 are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-C aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OZ, -N(Z)2, -C(NH)N(Z)2, -OCH2OZ, -O(CH2)2OZ, -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z)2, -C(O)N(Z)2, -C(O)OZ, -SZ, -SOZ, -S(O)2Z, -NHC(O)Z, -NHS(O)2Z, -NHC(NH)N(Z)2, -NZC(NH)N(Z)2, -NHC(NCN)N(Z)2, -NZC(NCN)N(Z)2, or -PO(OZ)2;
R4, Rs, RB, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Z)2, -C(NH)N(Z)2I -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z)2, -C(O)N(Z)2, -C(O)OZ, -SZ, -S(O)Z, -S(O)2Z, -NHC(O)Z, -NHS(O)2Z, -NHC(NH)N(Z)2, -NYC(NH)N(Z)2, -NHC(NCN)N(Z)2, or -NZC(NCN)N(Z)2; each Z is, independently, -H; optionally substituted -Ci-Cs alkyl; optionally substituted -C4-C12 alkcycloalkyl; optionally substituted -Cs-Cg alkheterocyclyl, in which the heterocycle is 3- to 9-membered; optionally substituted -C3-C12 cycloalkyl; optionally substituted -Ce-C aryl; optionally substituted -C7-C14 arylalkyl; optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle; optionally substituted -C2-C8 alkenyl; or optionally substituted -C2-C8 alkynyl; or two Z, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle; and
Q2, Q3, and Q4 are each, independently, N, N+-O-, or C, wherein Q2, Q4, and QB are not simultaneously C.
In some embodiments, the compound is a compound of formula (II-2):
Figure imgf000023_0001
or a pharmaceutically acceptable salt thereof, wherein:
V is O, S, NH, NZ, or CH2;
Figure imgf000023_0002
which Ra’ is -H, -OH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, or optionally substituted -Ce-Cu aryl; and Ra is -CH2NH- or -C(Rd)2O-, in which each Rd is independently -H, -Ci-Cs alkyl, -Ci-Cs cycloalkyl, -Ci-Cs aryl, or -Ci-Cs heteroaryl; Rb is H, OH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -Ci-Cs alkoxy, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-Cu aryl, or -N(Re)2, and each Re is independently -H or -Ci-Cs alkyl; and Rc is H, Ci-Cs alkyl, or Ce-Cu aryl;
R2’ and R3’, together with the atoms to which each is attached, join to form a 5- to 6-membered aromatic or non-aromatic carbocycle or heterocycle;
R4, Rs, RB, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Z)2, -C(NH)N(Z)2I -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z)2, -C(O)N(Z)2, -C(O)OZ, -SZ, -S(O)Z, -S(O)2Z, -NHC(O)Z, -NHS(O)2Z, -NHC(NH)N(Z)2, -NYC(NH)N(Z)2, -NHC(NCN)N(Z)2, or -NZC(NCN)N(Z)2; each Z is, independently, -H, optionally substituted -Ci-Cs alkyl, optionally substituted -C4-C12 alkcycloalkyl, optionally substituted -Cs-Cg alkheterocyclyl, in which the heterocycle is 3- to 9-membered; optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-C aryl; optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, optionally substituted -C2-C8 alkenyl, or optionally substituted -C2-C8 alkynyl; or two Z, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle; and
Q2, Q3, and Q4 are each, independently, N, N+-O-, or C, wherein Q2, Q4, and Qe are not simultaneously C.
Exemplary compounds are provided in Table 1.
Pharmaceutical Compositions
A pharmaceutical composition of the disclosure contains one or more of the compounds disclosed herein (e.g., one or more of the compounds of any one of formulas (I), (I-2), (I-3), (I-4), (I-5), (II), (I I-2) , (I I-3) , (I I-4) , (I I-5) , and other compounds disclosed herein) as the therapeutic compound. In addition to a therapeutically effective amount of the compound, the pharmaceutical compositions also contain a pharmaceutically acceptable excipient, which can be formulated by methods known to those skilled in the art. The compounds disclosed herein (e.g., the compounds of formulas
(I), (I-2), (I-3), (I-4), (I-5), (II), (II-2), (II-3), (II-4), (II-5), and other compounds disclosed herein) may also be administered with or without other therapeutics for a particular condition, formulated in the same composition or different compositions for administration via the same or different routes.
The compounds disclosed herein (e.g., the compounds of formulas (I), (I-2), (I-3), (I-4), (I-5), (II), (II-2), (II-3), (II-4), (II-5), and the compounds of Table 1) may be used in the form of free base, or in the form of salts or solvates. All forms are within the scope of the disclosure.
Exemplary routes of administration of the pharmaceutical compositions (or the compounds of the composition) include oral, sublingual, buccal, transdermal, intradermal, intramuscular, parenteral, intravenous, intra-arterial, intracranial, subcutaneous, intracerebroventricular, intraorbital, intraventricular, intrathecal (intraspinal), intraperitoneal, intranasal, inhalation, and topical administration.
Formulations for oral administration
The pharmaceutical compositions of the disclosure include those formulated for oral administration (“oral dosage forms”). Oral dosage forms can be, for example, in the form of tablets, capsules, a liquid solution or suspension, a powder, or liquid or solid crystals, which contain the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers; granulating and disintegrating agents; binding agents; and lubricating agents, glidants, and antiadhesives. Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, and the like.
Pharmaceutical compositions for oral administration may also be presented as chewable tablets, as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, or as soft gelatin capsules where the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil. Powders, granulates, and pellets may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or spray drying equipment. The liquid forms in which the compounds and compositions of the present disclosure can be incorporated for administration orally include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils, , as well as elixirs and similar pharmaceutical vehicles.
Neurological Disorders
Neurological disorders are disorders that affect the brain, as well as nerves throughout the body and also the spinal cord. Common symptoms of neurological disorders include numbness, tingling, muscle weakness, loss of muscle tone, loss of sensation, disruption or loss of autonomic function, numbness, bowel, or bladder incontinence, paralysis, confusion, pain, altered levels of consciousness, mood disorders, and sexual dysfunction. Certain primary symptoms, such as impaired movement and sensation, can further lead to secondary symptoms including muscle atrophy, loss of voluntary motor control and spasticity at sites of the body innervated by the neurological disorder, pressure (e.g., bed) sores, infections, and respiratory problems. Furthermore, cell death at the neurological disorder may continue long after the initial insult that precipitated the neurological disorder as a result of stress and inflammatory signaling that leads to further ischemia, inflammation, swelling, and disruption of synaptic signaling. Neurological disorder may result in total loss of motor and sensory function distal to the neurological disorder, or incomplete, resulting in partial loss of motor and sensory function.
Neurological disorders may present as various distinct conditions, depending on the site and severity of the condition. For example, peripheral neurological disorder results from damage to peripheral nerves that extend to the extremities of an individual, leading to numbness and/or loss of sensory function. Proximal neurological disorder results from damage to peripheral and/or central nerves, leading to muscle weakness in the upper part of the legs, buttocks, and/or hips in a subject. Autonomic neurological disorder results from damage and/or dysfunction of autonomic nerves that least to reduced and/or uncontrolled body homeostasis of an individual. Focal neurological disorder and/or polyneurological disorder results from damage to one nerve and/or a plurality of nerves, respectively. Central cord syndrome frequently results from damage to the cervical spinal cord, resulting in weakness in the upper extremities with relative sparing of function in the legs and spared sensation in sacral dermatomes (e.g., urinary sphincter, anal sphincter, and genitalia).
Examples of neurological disorders include, but are not limited to neurotraumatic disorders such as spinal cord injury (SCI), traumatic brain injury (TBI), stroke (e.g., hemorrhagic or ischemic stroke), peripheral nerve injury (PNI), myelopathy, hypoxic-ischemic encephalopathy, tumor-associated epilepsy, spasticity, multiple sclerosis, ischemia, amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), Alzheimer’s disease (AD), and peripheral neuropathy (PN); neurodevelopmental disorders such as autism, Rett syndrome, Fragile X syndrome, Angelman syndrome, Tuberous Sclerosis Complex (TSC), cerebral palsy, Down syndrome, pain (e.g., neuropathic pain, inflammation, inflammatory pain, arthritic pain, diabetic pain, and neuralgia), Dravet syndrome, epilepsy (e.g., temporal lobe epilepsy, refractory epilepsy, neurotrauma associated epilepsy, status epilepticus, tumor associated epilepsy, and hypoxic- ischemic encephalopathy), and sudden unexpected death in epilepsy); and affective disorders, such as schizophrenia, bipolar disorder, anxiety disorder, and major depressive disorder (MDD).
Neurotraumatic disorders are disorders of the nervous system that result from neurological trauma, such as, e.g., TBI, SCI, PNI, PN, stroke, ischemia, hypoxic-ischemic encephalopathy, tumor- associated epilepsy, and spasticity. In the U.S., roughly 1.7 million people are estimated to suffer TBI every year from causes such as falls, motor vehicle-related incidents, sports injuries, and violence, roughly 52,000 of which succumb to such injuries. Survivors of neurological trauma often face prolonged or indefinite disability.
TBI (also known as intracranial injury) usually results from an external force suddenly impacting the head of an individual, with the severity of the from mild (e.g., concussion) to severe (e.g., penetrating injury, coma-inducing injury). Sequalae of TBI often includes loss of consciousness, physical, cognitive, social, emotional, and behavioral impairments, but can also be fatal.
A SCI refers to any insult to the any region of the spinal cord, e.g., the cervical vertebrae, the thoracic vertebrae, the lumbar vertebrae, the sacral vertebrae, the sacrum, or the coccyx, that causes a negative effect on the function of the spinal cord, e.g., reduce mobility of feeling in limbs. The severity of a spinal cord injury is measured in levels of the injury’s outcome, e.g., ranging from no effect on mobility, e.g., retained walking capacity, to paraplegia (e.g., paralysis of legs and lower region of body), and tetraplegia (e.g., loss of muscle strength in all four extremities).
PNI refers to any disorder resulting from a nerve injury caused by a traumatic event. Peripheral nerve injury is generally divided into three distinct events, namely, (1) Wallerian degeneration; (2) axon regeneration/growth; and (3) nerve innervation. Types of PNI include, from least severe to most severe: neurapraxia (axon remains intact, but myelin is damaged), axonotmesis (disruption of the axon with maintenance of the epineurium), and neurotmesis (loss of axon continuity/axon transection).
Stroke is a condition which occurs when the blood supply to a part of the brain is interrupted (i.e., ischemic stroke) by obstruction of a blood vessel by a blood clot, an embolism, systemic hypoperfusion, or cerebral venous sinus thrombosis or when a blood vessel in the brain bursts and releases blood into the spaces surrounding the brain cells (i.e., hemorrhagic stroke) as a result of an intracerebral or a subarachnoid hemorrhage. Stroke poses a substantial public burden as nearly 77.2 million people experienced an ischemic stroke, and 29.1 million people experienced a hemorrhagic stroke in 2019. Depending on the area of the brain affected by the stroke, the symptoms of a stroke may include numbness or weakness, especially on one side of the body corresponding to the contralateral side of the stroke, muscle flaccidity or spasticity, confusion, trouble understanding or producing speech, impaired vision in both eyes, impaired mobility, dizziness, severe headache, or loss of balance or coordination.
Neurological trauma may also result from progressive neurodegenerative disorders that result in damage to neural tissue of the CNS. Non-limiting examples of neurodegenerative disorders contemplated for treatment using the presently disclosed compositions and methods include, but are not limited to, ALS, PD, AD, and PN.
Neurodevelopmental disorders refer to neurological disorders resulting from abnormal development of the nervous system and are characterized by abnormal brain function, including, but not limited to, impairments in emotional regulation, learning and memory, impulse control, and cognition. This class of neurological disorders is characterized by diverse etiologies that may account for the multeity of symptoms and their degree of severity. Generally, neurodevelopmental disorders are caused by disruptions the neurotypical developmental trajectory of the nervous system, which can produce pathological anatomical architecture and connectivity in the nervous system. Causes of neurodevelopmental disorders may include genetic and metabolic diseases, social isolation, inflammatory and autoimmune disorders, infectious diseases, malnutrition, physical trauma, as well as environmental factors. The present disclosure contemplates treatment of neurodevelopmental disorders such as, e.g., autism spectrum disorders, Rett syndrome, Fragile X syndrome, Angelman syndrome, Tuberous Sclerosis Complex (TSC), cerebral palsy, Down syndrome, pain (e.g., neuropathic pain, inflammation, inflammatory pain, arthritic pain, diabetic pain, and neuralgia), Dravet syndrome, epilepsy (e.g., epilepsy related to one or more KCC2 mutations or epilepsy of infancy with migrating focal seizures (EIMFS) or temporal lobe epilepsy, refractory epilepsy, neurotrauma associated epilepsy, status epilepticus, tumor associated epilepsy, and hypoxic-ischemic encephalopathy), and sudden unexpected death in epilepsy by administering a composition of the disclosure to the afflicted subject, thereby treating the subject.
Affective disorders (also known as mood disorders) are a class of neurological conditions characterized by dysregulation of normal affect and mood. Disorders of affect may feature mania or hypomania (e.g., schizophrenia and bipolar disorder), depressed mood (e.g., schizophrenia, bipolar disorder, and MDD), and moods that cycle between mania and depression (e.g., bipolar disorder). Affective disorders that may be treated using the disclosed methods and compositions include schizophrenia, bipolar disorder, and MDD.
Schizophrenia is a psychiatric disease characterized by recurrent psychosis. Symptoms of schizophrenia may include (1) positive symptoms related to hallucinations and reality distortion; (2) disorganized symptoms characterized by attentional impairment and thought disorder; and (3) negative symptoms such as apathy, anhedonia, avolition and loss of verbal fluency. Dysfunction of the limbic- cortical system may be implicated in all three types of symptoms. Causes of schizophrenia have been attributed to biological sex, genetic mutations, environmental factors, malnutrition during pregnancy, and age of parents, among other factors. Several hypotheses exist as to the etiology of schizophrenia, one being the glutamate hypothesis in which reduced glutamatergic drive to inhibitory interneurons is thought to result in reduced cortical inhibition and altered cortical network dynamics that lead to presentation of clinical symptoms.
Bipolar disorder is an affective disorder that features recurrent bouts of depression and mania (i.e., abnormally elevated mood) spanning from days to weeks each. Causes of bipolar disorder may be manifold, but genetic and environmental factors have been implicated. Generally, two types of bipolar disorder exist, namely, bipolar I disorder, in which there has been at least one manic episode with or without depressive episodes, and bipolar II disorder, in which there has been at least one hypomanic episode and one major depressive episode.
MDD is a neurological disorder that is often characterized by the patient having at least two weeks of sustained low mood, low self-esteem, loss of interest in routine activities, hyperalgesia, and low psychomotor activity. Depression in MDD may last for periods of time (weeks, days, months, or years) separated by years or may be continuous. MDD may pose a substantial risk to the afflicted patient as the patient may be at a substantially higher risk for suicide. Etiological causes of the disorder have been attributed to substance abuse, other medical conditions (e.g., neurological disorders, metabolic disorders, gastrointestinal disorders, endocrine disorders, cardiovascular disease, pulmonary disease, cancer, and autoimmune disease), and genetic and environmental factors.
A neurological disorder may also be caused by infection, ischemia, and tumors. Owing to the physiological barriers to regeneration in the central nervous system (CNS), neurological disorders have been a notoriously difficult condition to treat, with most treatments being palliative and rehabilitative. Most treatments involve imposing limitations to movement, maintenance of proper blood pressure by frequent repositioning of the subject, and physical and occupation therapy.
Method of Treating a Neurological Disorder
The compounds disclosed herein (e.g., the compounds of Table 1 and formulas (I), (I-2), (I-3), (I- 4), (I-5), (II), (II-2), (II-3), (II-4), and (II-5), and other compounds disclosed herein) are, in general, suitable for use in treating a neurological disorder, e.g., a neurotraumatic, neurodevelopmental, and/or affective disorder, or complications resulting therefrom. Non-limiting examples of neurotraumatic disorders include spinal cord injury (SCI), traumatic brain injury (TBI), stroke (e.g., hemorrhagic, or ischemic stroke), peripheral nerve injury (PNI), multiple sclerosis (MS), ischemia, amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), Alzheimer’s disease (AD), peripheral neuropathy (PN), hypoxic-ischemic encephalopathy, tumor-associated epilepsy, and spasticity. Neurodevelopmental disorders may include, but are not limited to autism, Rett syndrome, Fragile X syndrome, Angelman syndrome, Tuberous Sclerosis Complex (TSC), cerebral palsy, Down syndrome, pain (e.g., neuropathic pain, inflammation, inflammatory pain, arthritic pain, diabetic pain, and neuralgia), Dravet syndrome, epilepsy (e.g., epilepsy related to one or more KCC2 mutations or epilepsy of infancy with migrating focal seizures (EIMFS) or temporal lobe epilepsy, refractory epilepsy, neurotrauma associated epilepsy, status epilepticus, tumor associated epilepsy, or hypoxic-ischemic encephalopathy), and sudden unexpected death in epilepsy. Non-limiting examples of affective disorders include schizophrenia, bipolar disorder, anxiety disorder, and major depressive disorder (MDD).
The dosage of the pharmaceutical compositions of the disclosure depends on factors including, but are not limited to, the route of administration, the severity of the condition to be treated, and physical characteristics, e.g., age, weight, and general health, of the subject. Typically, the amount of a compound disclosed herein (e.g., a compound of any one of formulas (I), (I-2), (I-3), (I-4), (I-5), (II), (II-2), (II-3), (II-4), and (II-5), and other compounds disclosed herein) contained within a single dose may be an amount that effectively imparts the desired therapeutic effect without inducing significant toxicity. The dosage may be adapted by the clinician in accordance with conventional factors such as the extent of the disease and different parameters of the subject.
Pharmaceutical compositions of the disclosure that contain a compound disclosed herein (e.g., a compound of any one of formulas (I), (I-2), (I-3), (I-4), (I-5), (II), (II-2), (II-3), (II-4), and (II-5), and other compounds disclosed herein may be administered to a subject in need thereof one or more times (e.g., 10 times or more) daily, or as medically necessary. The timing between administrations may decrease as the medical condition improves or increase as the health of the subject declines.
The following examples are merely illustrative and should not be construed as limiting the scope of this disclosure in any way as many variations and equivalents will become apparent to those skilled in the art upon reading the present disclosure. The contents of all references, patents, and patent applications cited throughout this application are expressly incorporated herein by reference.
Examples
The following examples are put forth so as to provide those of ordinary skill in the art with a description of how the compositions and methods described herein may be used, made, and evaluated, and are intended to be purely exemplary of the disclosure and are not intended to limit the scope of what the inventors regard as their disclosure.
Example 1. Synthesis of Compound A
Method A
Figure imgf000029_0001
4-(Bromomethyl)-3,5-dichloropyridine [CAS: 159783-45-6] is mixed with 2-mercapto-6,7-dihydro -3H-cyclopentapyrimidin-4(5H)-one [CAS: 35563-27-0] in the presence of a K2CO3 and acetone or triethylamine and ethanol. The desired product is obtained in high yield following standard purification.
Method B
Figure imgf000029_0002
3,5-Dichloro-4-pyridinyl)methanethiol [CAS: 2229521-53-1] is mixed with 3-chloro-2, 5,6,7- tetrahydro-1 H-cyclopenta[c]pyridin-1-one [CAS: 178308-48-0] in the presence of a K2CO3 in N,N- dimethylformamide or diisopropylethylamine in ethanol. The desired product is obtained in high yield following standard purification.
Example 2. Synthesis of 6-(((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5Hcyclopenta[d]
Figure imgf000029_0003
Step 1: Preparation of 1-tert-butyl 6-chloromethyl hexanedioate
To a mixture of 6-(fe/Y-butoxy)-6-oxohexanoic acid (100 g, 494 mmol), H2O (500 mL) and DCM (500 mL) at 0 °C was added NaHCOs (199.4 g, 2.4 mol) and n-Bu4NHSC>4 (10.07 g, 29.7 mmol). The mixture was stirred at 0 °C for 10 min, then chloromethyl sulfurochloridate (293.7 g, 1 .8 mol) was added dropwise, the mixture was warmed to rt and stirred overnight. The mixture was extracted with DCM (3 x 500 mL) and the combined organic layers were washed with brine, dried over Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to give 1 -tert-butyl 6-chloromethyl hexanedioate (125 g) as an oil, which was used directly in the next step without further purification.
Step 2: Preparation of tert-butyl ((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6, 7-dihydro-5H-cyclopenta[d] -pyrimidin-4-yl)oxy)methyl) adipate
To a mixture of 2-{[(3,5-dichloropyridin-4-yl)methyl]sulfanyl}-3/7,5H,6/7,7/7-cyclopenta[d]pyrimidin- 4-one (109 g, 332 mmol), CS2CO3 (131.45 g, 402.2 mmol) and DMF (1 L) was added 1 -tert-butyl 6- chloromethyl hexanedioate (125 g, 499 mmol) in DMF (300 mL). The mixture was stirred at rt overnight, then diluted with H2O (500 mL) and extracted with DCM (3 x 1 L). The combined organic layers were washed with H2O and brine, then dried over Na2SC , filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE/EtOAc 1 :0 to 4:1) to give tert-butyl (((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5/7-cyclopenta[c(] -pyrimidin-4-yl)oxy)methyl) adipate (160 g, 89%) as an oil. LC/MS: m/z = 542.10 [M+H]+.
Step 3: Preparation of 6-(((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6, 7-dihydro-5H-cyclopenta[d]pyrimidin -4-yl)oxy)methoxy)-6-oxohexanoic acid
To a mixture of tert-butyl (((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5/7-cyclopenta[c(] -pyrimidin-4-yl)oxy)methyl) adipate (10.0 g, 18.4 mmol) and DCM (100 mL) at 0 °C was TFA (20 mL) dropwise. The mixture was warmed to rt and stirred overnight, then diluted with DCM (100 mL), washed with H2O (3 x 100 mL), dried over anhydrous Na2SC , and filtered. The filtrate was concentrated under reduced pressure. The reaction was repeated for 12 batches, each on a 10 g scale (a total of 130 g of starting material was used). This resulted in 6-(((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro -5/7-cyclopenta[c(]pyrimidin-4-yl)oxy)methoxy)-6-oxohexanoic acid (105 g, 90%) as a solid. LC/MS: m/z = 486.05 [M+H]+; HRMS: [M+H]+ cal for C20H21CI2N3O5S 486.0663; found, 486.0664; 1H NMR (300 MHz, DMSO-de) 6 11.99 (s, 1 H), 8.62 (s, 2H), 6.10 (s, 2H), 4.68 (s, 2H), 2.86 (t, J = 7.7 Hz, 2H), 2.72 (t, J = 7.4 Hz, 2H), 2.37 (t, J = 6.8 Hz, 2H), 2.16 (t, J = 6.8 Hz, 2H), 2.11-1 .95 (m, 2H), 1 .60-1 .37 (m, 4H); 13C NMR (75 MHz, DMSO-de) 6 177.3, 174.2, 171.8, 166.7, 163.2, 147.8, 141 .7, 132.2, 115.9, 81.1 , 33.6, 33.2, 33.0, 29.7, 25.7, 23.8, 23.7, 21.4.
Single crystal X-Ray structure of 6-(((2-(((3, 5-dichloropyridin-4-yl)methyl)thio)-6, 7-dihydro-5H-cyclopenta -[d]pyrimidin-4-yl)oxy)methoxy)-6-oxohexanoic acid
A sample of 6-(((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5/7-cyclopenta[d]pyrimidin -4-yl)oxy)methoxy)-6-oxohexanoic acid (11 .2 mg) was dissolved in acetone (400 mL) and n-heptane (800 mL) was added. The mixture was left to evaporate at rt to provide a single crystal for x-ray structure determination, crystallized as triclinic in P-1 space group with the formula unit of C20H21N3O5SCI2. Data for the x-ray structure is presented in Table 2. Table 2
Figure imgf000031_0001
Example 3. Synthesis of 6-(((2-(((3-chloro-5-methylpyridin-4-yl)methyl)thio)-6,7-dihydro-5H-cyclo
-penta[d]pyrimidin-4-yl)oxy)methoxy)-6-oxohexanoic acid (Compound 28)
Figure imgf000032_0001
Step 1: Preparation of tert-butyl (((2-(((3-chloro-5-methylpyridin-4-yl)methyl)thio)-6,7-dihydro-5l-l-cyclo -penta[d]pyrimidin-4-yl)oxy)methyl) adipate
To a mixture of 2-{[(3-chloro-5-methylpyridin-4-yl)methyl]sulfanyl}-3/7,5/7,6/7,7/7-cyclopenta[c(] -pyrimidin-4-one (815 mg, 2.6 mmol) and CS2CO3 (1.08 g, 3.3 mmol) and DMF (8 mL) was added 1-fert- butyl 6-chloromethyl hexanedioate (831 mg, 3.3 mmol) in DMF (2 mL). The mixture was stirred at rt overnight, then diluted with H2O and extracted with DCM (3 x 10 mL). The combined organic layers were washed with H2O (x 5) and brine, dried over Na2SC , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE/EtOAc 1 :0 to 52:48) to give tert-butyl (((2-(((3-chloro-5-methylpyridin-4-yl)methyl)thio)-6,7-dihydro-5/7-cyclopenta[c(] pyrimidin-4-yl)oxy)methyl) adipate (1.1 g, 80%) as an oil.
Step 2: Preparation of 6-(((2-(((3-chloro-5-methylpyridin-4-yl)methyl)thio)-6, 7-dihydro-5H-cyclopenta[d] -pyrimidin-4-yl)oxy)methoxy)-6-oxohexanoic acid
To a mixture of fe/7-butyl (((2-(((3-chloro-5-methylpyridin-4-yl)methyl)thio)-6,7-dihydro-5/7-cyclo -penta[cf]pyrimidin-4-yl)oxy)methyl) adipate (1.1 g, 2.1 mmol) in DCM (10mL) was added TFA (2 mL) dropwise. The mixture was heated to 30 °C and stirred overnight, then concentrated under reduced pressure and the residue was purified by preparative-HPLC to give 6-(((2-(((3-chloro-5-methylpyridin-4-yl) methyl)thio)-6,7-dihydro-5/7-cyclopenta[c(]pyrimidin-4-yl)oxy)methoxy)-6-oxohexanoic acid (0.53 g, 54%) as a solid. LC/MS: m/z = 466.05 [M+H]+; 1H NMR (300 MHz, DMSO-d6) 6 1 1 .99 (s, 1 H), 8.49 (s, 1 H), 8.39 (s, 1 H), 6.10 (s, 2H), 4.57 (s, 2H), 2.88 (t, J = 7.7 Hz, 2H), 2.74 (t, J = 7.4 Hz, 2H), 2.42 (s, 3H), 2.38 (t, J = 6.8 Hz, 2H), 2.16 (t, J = 6.9 Hz, 2H), 2.11-1 .97 (m, 2H), 1 .57-1 .43 (m, 4H).
Example 4. Synthesis of (±) 6-(1-((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5H-cyclo
-penta[d]pyrimidin-4-yl)oxy)ethoxy)-6-oxohexanoic acid (Compound 15)
Figure imgf000032_0002
Step 1: Preparation of 1 -tert-butyl 6-(1 -chloroethyl) hexanedioate
To a mixture of 1 -chloroethyl sulfurochloridate (1 .7 g, 9.5 mmol) and 6-(tert-butoxy)-6-oxohexa -noic acid (1 .29 g, 6.38 mmol) in DCM (10 mL) and H2O (10 mL) at 0 °C was added NaHCOs (2.15 g, 25.6 mmol) and BU4NHSO4 (0.22 g, 0.65 mmol). The mixture was stirred at 0 °C for 12 h, then extracted with DCM (3 x 10 mL). The combined organic layers were dried over Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to give 1 -tert-butyl 6-(1 -chloroethyl) hexanedioate. The product was used directly in the next step without further purification.
Step 2: Preparation of (±) tert-butyl (1-((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6, 7-dihydro-5H-cyclo -penta[d]pyrimidin-4-yl)oxy)ethyl) adipate
To a mixture of 1-tert-butyl 6-(1 -chloroethyl) hexanedioate (2.52 g, 9.5 mmol) and 2-{[(3,5-dichlor -opyridin-4-yl)methyl]sulfanyl}-3/7,5/7,6/7,7/7-cyclopenta[c(]pyrimidin-4-one (1.4 g, 4.3 mmol) in DMF (30 mL) was added CS2CO3 (695 mg, 2.13 mmol). The mixture was heated to 30 °C and stirred for 12 h, then diluted with H2O and extracted with DCM (3 x 10 mL). The combined organic layers were washed with H2O (x 5) and brine, dried over Na2SC , filtered and the filtrate was concentrated under reduced pressure. The residue was :purified by column chromatography on silica gel (PE/EtOAc 1 :0 to 7:3) to give (±) tert -butyl (1-((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5/7-cyclopenta[c(]pyrimidin-4-yl)oxy)ethyl) adipate as a solid. LC/MS: m/z = 578.20 [M+Na]+.
Step 3: Preparation of (±) 6-(1-((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6, 7-dihydro-5H-cyclopenta[d] -pyrimidin-4-yl)oxy)ethoxy)-6-o-xohexanoic acid
A mixture of (±) tert-butyl (1-((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5/7-cyclopenta -[c(]pyrimidin-4-yl)oxy)ethyl) adipate (1 .2 g, 2.2 mmol), TFA (5 mL) and DCM (15 mL) was heated to 30 °C and stirred for 12 h. The mixture was purified by preparative-HPLC (0% to 100% CH3CN in H2O containing 0.05% TFA) to give (±) 6-(1-((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5/7-cyclo -penta[c(]pyrimidin-4-yl)oxy)ethoxy)-6-oxohexanoic acid (402 mg, 37%) as a solid. LC/MS: m/z = 500.05 [M+H]+; 1H-NMR (300 MHz, CDCI3) 6 8.48 (s, 2H), 7.40-7.30 (m, 1 H), 4.85-4.51 (m, 2H), 2.93 (t, J = 7.8 Hz, 2H), 2.87-2.77 (m, 2H), 2.41-2.29 (m, 4H), 2.20-2.05 (m, 2H), 1.71-1.58 (m, 7H).
Example 5. Synthesis of 3-(((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5H-cyclopenta -[d]pyrimidin-4-yl)oxy)methoxy)-3-oxopropanoic acid (Compound 11)
Figure imgf000033_0001
Step 1: Preparation of 2-(((3, 5-dichloropyridin-4-yl)methyl)thio)-4-((methylthio)methoxy)-6, 7-dihydro-5H -cyclopenta[d]pyrimidine
A mixture of 2-{[(3,5-dichloropyridin-4-yl)methyl]sulfanyl}-3/7,5/7,6/7,7/7-cyclopenta[c(]pyrimidin -4-one (3.5 g, 10.7 mmol) of CS2CO3 (10.42 g, 32.0 mmol) and DMF (100 mL) at 0 °C was stirred for 5-10 min, then chloromethyl methyl sulfide (2.06 g, 21 .3 mmol) was added dropwise. The mixture was warmed to rt and stirred overnight, then diluted with H2O and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine, dried over Na2SC , filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE/EtOAc 1 :0 to 78:22) to give 2-(((3,5-dichloropyridin-4-yl)methyl)thio)-4-((methylthio)methoxy)-6,7- dihydro-5/7-cyclo-penta[c(]pyrimidine (1.96 g, 44%) as a solid. LC/MS: m/z = 388.00 [M+H]+. Step 2: Preparation of 4-(chloromethoxy)-2-(((3, 5-dichloropyridin-4-yl)methyl)thio)-6, 7-dihydro-5H-cyclo -penta[d]pyrimidine
To a mixture of 2-(((3,5-dichloropyridin-4-yl)methyl)thio)-4-((methylthio)methoxy)-6,7-dihydro-5/7 -cyclopenta[cf]pyrimidine (1 .96 g, 4.9 mmol) and EtsN (1 .23 g, 12.3 mmol) in DCM (60 mL) at 0 °C was added SO2CI2 (0.96 g, 7.1 mmol) in DCM (0.5 mL) dropwise. The mixture was warmed to rt and stirred for 2 h, then concentrated under reduced pressure to give 4-(chloromethoxy)-2-(((3,5-dichloropyridin-4-yl) -methyl)thio)-6,7-dihydro-5/7-cyclopenta[c(]pyrimidine (1.96 g, 99%) as an oil, which was used in the next step without further purification. LC/MS: m/z = 375.90 [M+H]+.
Step 3: Preparation of tert-butyl (((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6, 7-dihydro-5l-l-cyclopenta[d] -pyrimidin-4-yl)oxy)methyl) malonate
To a mixture of 3-(te/Y-butoxy)-3-oxopropanoic acid (1 .33 g, 8.3 mmol) and CS2CO3 (2.04 g, 6.25 mmol) in DMF (20 mL) was added 4-(chloromethoxy)-2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro -5/7-cyclopenta[c(]pyrimidine (1 .90 g, 5.04 mmol) in DMF (5 mL) dropwise. The mixture was stirred at rt overnight, then diluted with H2O and extracted with DCM (3 x 30 mL). The combined organic layers were washed with H2O (x 5) and brine, then dried over Na2SC , filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE/EtOAc 1 :0 to 3:1) to give te/Y-butyl (((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5/7-cyclopenta[c(]pyrimidin -4-yl)oxy)methyl) malonate (1 .3 g, 52%) as an oil. LC/MS: m/z = 500.00 [M+H]+.
Step 4: Preparation of 3-(((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6, 7-dihydro-5H-cyclopenta[d]pyrimidin -4-yl)oxy)methoxy)-3-oxopropanoic acid
To a mixture of te/Y-butyl (((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5/7-cyclopenta -[d]pyrimidin-4-yl)oxy)methyl) malonate (1 .7 g, 3.4 mmol) in DCM (26 mL) was added TFA (5.5 g). The mixture was heated to 30 °C and stirred overnight, then concentrated under reduced pressure and the residue was purified by preparative-HPLC to give 3-(((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7- dihydro-5/7-cyclopenta[c(]pyrimidin-4-yl)oxy)methoxy)-3-oxopropanoic acid (509 mg, 33%) as a solid. LC/MS: m/z = 443.95 [M+H]+; 1H NMR (300 MHz, DMSO-d6) 6 12.80 (s, 1 H), 8.67 (s, 2H), 6.15 (s, 2H), 4.72 (s, 2H), 3.32 (s, 2H), 2.90 (t, J = 7.7 Hz, 2H), 2.76 (t, J = 7.4 Hz, 2H), 2.15-1 .99 (m, 2H).
Example 6. Synthesis of 4-(((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5H-cyclopenta -[d]pyrimidin-4-yl)oxy)methoxy)-4-oxobutanoic acid (Compound 12)
Figure imgf000034_0001
Step 1: Preparation of tert-butyl (((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6, 7-dihydro-5l-l-cyclopenta -[d]pyrimidin-4-yl)oxy)methyl) succinate
To a mixture of 2-{[(3,5-dichloropyridin-4-yl) methyl]sulfanyl}-3/7,5/7,6/7,7/7-cyclopenta[cf] -pyrimidin-4-one (1.0 g, 3.0 mmol) CS2CO3 (1.0 g, 3.1 mmol) and DMF (15 mL) was added tert-butyl (chloromethyl) succinate [CAS No: 432037-43-9; W02009108704] (1.0 g, 4.5 mmol) in DMF (5 mL). The mixture was stirred at rt overnight then diluted with H2O and extracted with DCM (3 x 20 mL). The combined organic layers were washed with H2O (x 5) and brine, dried over Na2SC , filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE/EtOAc 1 :0 to 62:38) to give tert-butyl (((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7 -dihydro-5/7-cyclopenta[c(]pyrimidin-4-yl)oxy)methyl) succinate (1.36 g, 87%) as an oil.
Step 2: Preparation of 4-(((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6, 7-dihydro-5H-cyclopenta[d]pyrimidin -4-yl)oxy)methoxy)-4-oxobutanoic acid
To a mixture of tert-butyl (((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5/7-cyclopenta[c(] -pyrimidin-4-yl)oxy)methyl) succinate (1 .3 g, 2.5 mmol) in DCM (20 mL) was added TFA (5 mL). The mixture was heated to 30 °C and stirred overnight, then concentrated under reduced pressure and the residue was purified by preparative-HPLC to give 4-(((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7- dihydro -5/7-yclopenta[c(]pyrimidin-4-yl)oxy)methoxy)-4-oxobutanoic acid (581 mg, 50%) as a solid, m/z = 457.95 [M+H]+; 1H NMR (300 MHz, DMSO-d6) 6 12.22 (s, 1 H), 8.66 (s, 2H), 6.11 (s, 2H), 4.71 (s, 2H), 2.88 (t, J = 7.7 Hz, 2H), 2.75 (t, J = 7.4 Hz, 2H), 2.58 (dd, J = 7.5, 4.8 Hz, 2H), 2.50-2.45 (m, 3H), 2.14-1.98 (m, 2H).
Example 7. Synthesis of 5-(((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5H-cyclopenta -[d]pyrimidin-4-yl)oxy)methoxy)-5-oxopentanoic acid (Compound 13)
Figure imgf000035_0001
Step 1: Preparation of tert-butyl (((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6, 7-dihydro-5l-l-cyclopenta -[d]pyrimidin-4-yl)oxy)methyl) glutarate
To a mixture of 2-{[(3,5-dichloropyridin-4-yl) methyl]sulfanyl}-3/7,5/7,6/7,7/7-cyclopenta[c(]pyrimidin -4-one (815 mg, 2.48 mmol), CS2CO3 (974 mg, 2.97 mmol) and DMF (10 mL) was added 1 -fe/7-butyl 5- chloromethyl pentanedioate (895 mg, 3.78 mmol) in DMF (0.5 mL). The mixture was stirred at rt overnight, then diluted with H2O and extracted with DCM (3 x 20 mL). The combined organic layers were washed with H2O (x 5) and brine, dried over Na2SC>4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (PE/EtOAc 1 :0 to 71 :29) to give tert-butyl (((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5/7-cyclopenta[c(]pyrimidin -4-yl)oxy)methyl) glutarate (1.13 g, 86%) as an oil. Step 2: Preparation of 5-(((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6, 7-dihydro-5H-cyclopenta[d]pyrimidin -4-yl)oxy)methoxy)-5-oxopentanoic acid
To a mixture of fe/7-butyl (((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5/7-cyclopenta -[cf]pyrimidin-4-yl)oxy)methyl) glutarate (1 .13 g, 2.1 mmol) and DCM (20 mL) was added TFA (4 mL). The mixture was heated to 30 °C and stirred overnight, then concentrated under reduced pressure and the residue was purified by preparative-HPLC to give 5-(((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7- dihydro -5/7-cyclopenta[c(]pyrimidin-4-yl)oxy)methoxy)-5-oxopentanoic acid (0.54 g, 53%) as a solid, m/z = 472.00 [M+H]+; 1H NMR (300 MHz, DMSO-d6) 6 12.08 (s, 1H), 8.66 (s, 2H), 6.10 (s, 2H), 4.70 (s, 2H), 2.88 (t, J = 7.7 Hz, 2H), 2.74 (t, J = 7.4 Hz, 2H), 2.40 (t, J = 7.4 Hz, 2H), 2.23 (t, J = 7.4 Hz, 2H), 2.13- 1 .97 (m, 2H), 1 .79-1 .64 (m, 2H).
Example 8. Synthesis of (S)-((3-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5H-cyclopenta
-[d]pyridin-1 -yl)oxy)methyl 2-amino-3-methylbutanoate (Compound 4)
Figure imgf000036_0001
Step 1: Preparation of (S)-((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6, 7-dihydro-5H-cyclopenta[d]pyr -imidin-4-yl)oxy)methyl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate
To a mixture of 2-{[(3,5-dichloropyridin-4-yl)methyl]sulfanyl}-3/7,5/7,6/7,7/7-cyclopenta[d]pyr -imidin-4-one (300 mg, 0.9 mmol) in DMF (3.5 mL) was added CS2CO3 (300 mg, 0.9 mmol) and /V-[(1 ,1- dimethylethoxy)carbonyl]-L-valine chloromethyl ester [CAS No: 0224-39-3] (365 mg, 0.14 mmol) in DMF (0.5 mL). The mixture was stirred at rt for 1 h, then diluted with H2O and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with H2O (x 5) and brine, dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by preparative-HPLC to give (S)-((2- (((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5/7-cyclopenta[c(]pyrimidin-4-yl)oxy)methyl 2-((tert- butoxycarbonyl)amino)-3-methylbutanoate (250 mg) as an oil.
Step 2: Preparation of (S)-((3-(((3,5-dichloropyridin-4-yl)methyl)thio)-6, 7-dihydro-5H-cyclopenta[c]pyr -idin-1-yl)oxy)methyl 2-amino-3-methylbutanoate formate salt
To a mixture of (S)-((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5/7-cyclopenta[c(] -pyrimidin-4-yl)oxy)methyl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (250 mg, 0.45 mmol) in DCM (5 mL) was added TFA (1 mL) dropwise. The mixture was warmed to rt and stirred for 2 h, then diluted with H2O and extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine, concentrated under reduced pressure and the residue was purified by preparative-HPLC to give (S)-((3-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5/7-cyclopenta[c]pyridin-1-yl)oxy)methyl 2- amino-3-methylbutanoate formate salt (151 mg, 66%) as an oil. LC/MS: m/z = 457.05 [M+H]+; 1H NMR (300 MHz, DMSO-de) 6 8.67 (s, 2H), 8.52-8.46 (m, 3H), 6.31 (d, J = 6.0 Hz, 1 H), 6.18 (d, J = 6.0 Hz, 1 H), 4.71 (s, 2H), 4.04 (d, J = 4.2 Hz, 1 H), 2.91 (t, J = 7.7 Hz, 2H), 2.74 (t, J = 7.6 Hz, 2H), 2.21-1 .99 (m, 3H), 1.02-0.85 (m, 6H).
Example 9. Synthesis of ((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5H-cyclopenta[d]
-pyrimidin-4-yl)oxy)methyl heptanoate (Compound 2)
Figure imgf000037_0001
To a mixture of 2-{[(3,5-dichloropyridin-4-yl)methyl]sulfanyl}-3/7,5/7,6/7,7/7-cyclopenta[d]pyrimidin -4-one (200 mg, 0.6 mmol) and CS2CO3 (200 mg, 0.6 mmol) in DMF (2.5 mL) was added chloromethyl heptanoate [CAS No: 76068-79-6; WO 2020/077038] (164 mg, 0.92 mmol) in DMF (0.5 mL). The mixture was stirred at rt for 1 h, then diluted with H2O and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, concentrated under reduced pressure and the residue was purified by preparative-HPLC to give ((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5/7-cyclopenta -[c(]pyrimidin-4-yl)oxy)methyl heptanoate (108 mg, 38%) as an oil. LC/MS: m/z = 470.05 [M+H]+; 1H NMR (300 MHz, DMSO-de) 6 8.66 (s, 2H), 6.11 (s, 2H), 4.70 (s, 2H), 2.88 (t, J = 7.7 Hz, 2H), 2.75 (t, J = 7.4 Hz, 2H), 2.35 (t, J = 7.2 Hz, 2H), 2.14-1 .98 (m, 2H), 1 .57-1 .41 (m, 2H), 1 .28-1 .11 (m, 6H), 0.89-0.74 (m, 4H).
Example 10. Synthesis of (±) 1-((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5H-cyclo
-penta[d]pyrimidin-4-yl)oxy)ethyl acetate (Compound 5)
Figure imgf000037_0002
To a mixture of 2-{[(3,5-dichloropyridin-4-yl)methyl]sulfanyl}-3/7,5/7,6/7,7/7-cyclopenta[d]pyrimidin -4-one (0.5 g, 1 .5 mmol) in DMF (5 mL) was added CS2CO3 (0.75 g, 2.3 mmol) and 1 -bromoethyl acetate (1 .02 g, 6.1 mmol). The mixture was stirred at rt for 2 h, then diluted with H2O (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE/EtOAc 1 :0 to 1 :1) to give (±) 1-((2-(((3,5-dichloropyridin-4-yl) -methyl)thio)-6,7-dihydro-5/7-cyclopenta[c(]pyrimidin-4-yl)oxy)ethyl acetate (50 mg, 8%). LC/MS: m/z = 414.00 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 6 8.66 (s, 2H), 7.22 (q, J = 4.0 Hz, 1 H), 4.59-4.71 (m, 2H), 2.88 (t, J = 8.0 Hz, 2H), 2.74 (t, J = 8.0 Hz, 2H), 1 .99-2.10 (m, 5H), 1 .56 (d, J = 8.0 Hz, 3H). Example 11. Synthesis of ((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5H-cyclopenta [d]pyrimidin-4-yl)oxy)methyl pivalate (Compound 6)
Figure imgf000038_0001
To a mixture of 2-{[(3,5-dichloropyridin-4-yl)methyl]sulfanyl}-3/7,5/7,6/7,7/7-cyclopenta[d]pyrimidin -4-one (200 mg, 0.6 mmol) in DMF (10 mL) at rt was added chloromethyl 2,2-dimethylpropanoate (138 mg, 0.9 mmol) and K2CO3 (253 mg, 1 .8 mmol). The mixture was stirred at rt for 2 h, then diluted with H2O (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SC , filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica (PE/EtOAc 1 :0 to 1 :1) and preparative- HPLC to give ((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5/7-cyclopenta[c(]pyri -midin-4-yl)oxy)methyl pivalate (67 mg, 25%) as a solid. LC/MS: m/z = 442.05 [M+H]+; 1H HNMR (300 MHz, DMSO-de) 6 8.67 (s, 2H), 6.12 (s, 2H), 4.70 (s, 2H), 2.89 (t, J = 7.5 Hz, 2H), 2.76 (t, J = 7.5Hz, 2H), 2.01-2.12 (m, 2H), 1.13 (s, 9H).
Example 12. Synthesis of (±) 1-((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5H-cyclo
-penta[d]pyrimidin-4-yl)oxy)ethyl pivalate (16)
Figure imgf000038_0002
To a mixture of 2-{[(3,5-dichloropyridin-4-yl)methyl]sulfanyl}-3/7,5/7,6/7,7/7-cyclopenta[d]pyrim -idin-4-one (700 mg, 2.1 mmol) and CS2CO3 (700 mg, 2.2 mmol) in DMF (10 mL) was added 1 -chloroethyl 2,2-dimethylpropanoate (550 mg, 3.3 mmol). The mixture was stirred at rt overnight then diluted with H2O and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative-HPLC (0% to 70% CH3CN in H2O containing 0.05% TFA) to give (±) 1 -((2-(((3,5-dichloropyr -idin-4-yl)methyl)thio)-6,7-dihydro-5/7-cyclopenta[d]pyrimidin-4-yl)oxy)ethyl pivalate (500 mg, 55%) as a solid. LC/MS: m/z = 456.05 [M+H]+; 1H NMR (300 MHz, DMSO-d6) 6 8.66 (s, 2H), 7.15 (q, J = 5.3 Hz, 1 H), 4.68 (d, J = 12.5 Hz, 1 H), 4.56 (d, J = 12.5 Hz, 1 H), 2.88 (t, J = 7.7 Hz, 2H), 2.75 (t, J = 7.5 Hz, 2H), 2.07 (q, J = 7.6 Hz, 2H), 1 .55 (d, J = 5.4 Hz, 3H), 1 .08 (s, 9H). Example 13. Synthesis of ((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5H-cyclopenta -[d]pyrimidin-4-yl)oxy)methyl isobutyrate (Compound 10)
Figure imgf000039_0001
A mixture of 2-{[(3,5-dichloropyridin-4-yl)methyl]sulfanyl}-3/7,5/7,6H,7/7-cyclopenta[c(]pyrimidin -4-one (800 mg, 2.4 mmol) and CS2CO3 (800 mg, 2.5 mmol) in DMF (10 mL) was stirred at rt for 10 min, then chloromethyl 2-methylpropanoate (501 mg, 3.7 mmol) was added. The mixture was stirred at rt overnight then diluted with H2O and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried over Na2SC , filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative-HPLC (0% to 70% CH3CN in H2O containing 0.05% TFA) to give ((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5/7-cyclopenta[c(]pyrimidin-4-yl)oxy)methyl isobutyrate (500 mg, 48%) as a solid. LC/MS: m/z = 427.95 [M+H]+; 1H NMR (300 MHz, DMSO-d6) 6 8.67 (s, 2H), 6.11 (s, 2H), 4.70 (s, 2H), 2.89 (t, J = 7.7 Hz, 2H), 2.75 (t, J = 7.4 Hz, 2H), 2.69-2.51 (m, 1 H), 2.14-1 .98 (m, 2H), 1.07 (d, J = 7.0 Hz, 6H).
Example 14. Synthesis of ((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5H-cyclopenta[d]
-pyrimidin-4-yl)oxy)methyl ethyl carbonate (Compound 8)
Figure imgf000039_0002
A mixture of 2-{[(3,5-dichloropyridin-4-yl)methyl]sulfanyl}-3/7,5/7,6/7,7/7-cyclopenta[cf]pyrimidin -4-one (800 mg, 2.4 mmol) and CS2CO3 (794 mg, 2.4 mmol) in DMF (15 mL) was stirred at rt for 10 min, then chloromethyl ethyl carbonate (505 mg, 3.66 mmol) was added. The mixture was stirred at rt for 2 h, then purified by preparative-HPLC (0% to 70% CH3CN in H2O containing 0.05% TFA) to give ((2-(((3,5- dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5/7-cyclopenta[c(]pyrimidin-4-yl)oxy)methyl ethyl carbonate (520 mg, 49%) as a solid. LC/M: m/z = 430.00 [M+H]+; 1H NMR (300 MHz, DMSO-d6) 6 8.64 (s, 2H), 6.09 (s, 2H), 4.68 (s, 2H), 4.15 (q, J = 7.1 Hz, 2H), 2.87 (t, J = 7.7 Hz, 2H), 2.74 (t, J = 7.4 Hz, 2H), 2.12- 1.96 (m, 2H), 1 .19 (t, J = 7.1 Hz, 3H). Example 15. Synthesis of ((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5H-cyclopenta[d]
-pyrimidin-4-yl)oxy)methyl ((5-methyl-2-oxo-1 ,3-dioxol-4-yl)methyl) carbonate (Compound 9)
Figure imgf000040_0001
A mixture of 2-{[(3,5-dichloropyridin-4-yl)methyl]sulfanyl}-3/7,5/7,6/7,7/7-cyclopenta[c(]pyrimidin -4-one (1 .0 g, 3.0 mmol) and CS2CO3 (993 mg, 3.0 mmol) in DMF (20 mL) was stirred at rt for 15 min then chloromethyl ((5-methyl-2-oxo-1 , 3-d ioxol-4-y I) methyl) carbonate [CAS No: 2097531 -05-8; US 9,650,332] (1 .36 g, 6.11 mmol) was added. The mixture was stirred at rt for 48 h, then purified by preparative-HPLC (5% to 89% CH3CN in H2O containing 0.05% TFA) to give ((2-(((3,5-dichloropyridin-4- yl)methyl)thio)-6,7-dihydro-5/7-cyclopenta[c(]pyrimidin-4-yl)oxy)methyl ((5-methyl-2-oxo-1 ,3-dioxol-4- yl)methyl) carbonate (547 mg, 34%) as a solid. LC/M: m/z = 513.95 [M+H]+; 1H NMR (300 MHz, DMSO- cfe) 6 8.64 (s, 2H), 6.13 (s, 2H), 5.08 (s, 2H), 4.70 (s, 2H), 2.89 (t, J = 7.7 Hz, 2H), 2.75 (t, J = 7.4 Hz, 2H), 2.24-1.98 (m, 7H).
Example 16. Synthesis of ((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5H-cyclopenta[d]
-pyrimidin-4-yl)oxy)methyl ethylcarbamate (Compound 14)
Figure imgf000040_0002
A mixture of chloromethyl A/-ethylcarbamate [CAS No: 1427204-92-9; US20130064794] (1.73 g,
12.6 mmol), K2CO3 (1.31 g, 9.4 mmol) and 2-{[(3,5-dichloropyridin-4-yl)methyl]sulfanyl}-3/7,5/7,6/7,7/7 -cyclopenta[c(]pyrimidin-4-one (2.06 g, 6.3 mmol) in DMF (15 mL) was stirred at rt for 1 h. The mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with H2O, dried over Na2SC , filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE/EtOAc 1 :0 to 3:2) to give ((2-(((3,5-dichloropyridin -4-yl)methyl)thio)-6,7-dihydro-5/7-cyclopenta[c(]pyrimidin-4-yl)oxy)methyl ethylcarbamate (572 mg, 21 %) as a solid. LC/MS m/z = 429.00 [M+H]+; 1H NMR (300 MHz, DMSO-d6) 6 8.65 (s, 2H), 7.51 (t, J =
5.6 Hz, 1 H), 6.02 (s, 2H), 4.69 (s, 2H), 3.08-2.93 (m, 2H), 2.87 (t, J = 7.7 Hz, 2H), 2.73 (t, J = 7.4 Hz, 2H), 2.12-1 .95 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H). Example 17. Synthesis of di-tert-butyl (((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5H -cyclopenta[d]pyrimidin-4-yl)oxy)methyl) phosphate (Compound 7) and ((2-(((3,5-dichloropyridin- 4-yl)methyl)thio)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)oxy)methyl dihydrogen phosphate (Compound 1)
Figure imgf000041_0001
Step 1: Preparation of di-tert-butyl (((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6, 7-dihydro-5l-l-cyclopenta -[d]pyrimidin-4-yl)oxy)methyl) phosphate
To a mixture of 2-{[(3,5-dichloropyridin-4-yl)methyl]sulfanyl}-3/7,5/7,6/7,7/7-cyclopenta[d]pyrimidin -4-one (0.7 g, 2.1 mmol) in DMF (10 mL) was added CS2CO3 (1.05 g, 3.2 mmol). The mixture was stirred at rt for 1 h, then di-te/Y-butyl chloromethyl phosphate (2.21 g, 8.5 mmol) was added and the mixture was stirred at rt for a further 1 h. The mixture was diluted with H2O (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (PE/EtOAc 1 :0 to 1 :1) to give di-te/Y-butyl (((2-(((3,5-dichl -oropyridin-4-yl)methyl)thio)-6,7-dihydro-5/7-cyclopenta[c(]pyrimidin-4-yl)oxy)methyl) phosphate (1 g, 85%) as a solid. LC/MS: m/z = 550.10 [M+H]+; 1H NMR (300 MHz, DMSO-d6) 6 8.67 (s, 2H), 5.94 (d, J = 15.0 Hz, 2H), 4.73 (s, 2H), 2.91 (t, J = 9.0 Hz, 2H), 2.78 (t, J = 6.0 Hz, 2H), 2.02-2.16 (m, 2H), 1.38 (s, 18H).
Step 2: Preparation of ((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6, 7-dihydro-5H-cyclopenta[d]pyrimidin -4-yl)oxy)methyl dihydrogen phosphate
To a mixture of di-te/Y-butyl (((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5/7-cyclopenta [cf]pyrimidin-4-yl)oxy)methyl) phosphate (200 mg, 0.36 mmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at rt for 1 h, then concentrated under reduced pressure and the residue was purified by preparative-HPLC to give ((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5/7- cyclopenta[c(] -pyrimidin-4-yl)oxy)methyl dihydrogen phosphate (51 mg, 31 %) as a solid. LC/MS: m/z = 437.95 [M+H]+; 1H NMR (300 MHz, DMSO-d6) 6 8.65 (s, 2H), 5.85 (d, J = 12.0 Hz, 2H), 4.71 (s, 2H), 2.88 (t, J = 6.0 Hz, 2H), 2.77 (t, J = 6.0 Hz, 2H), 1 .96-2.13 (m, 2H).
Example 18. Synthesis of 2-{[(3,5-dichloropyridin-4-yl)methyl]sulfanyl}-5H,6H,7H-cyclopenta[d]pyr
-imidin-4-yl 2-methylpropanoate (Compound 25)
Figure imgf000041_0002
To a mixture of 2-{[(3,5-dichloropyridin-4-yl)methyl]sulfanyl}-3/7,5/7,6H,7/7-cyclopenta[d]pyrimidin -4-one (500 mg, 1 .5 mmol) in DCM (5 mL) was added EtsN (0.64 mL, 4.6 mmol). The mixture was stirred at rt for 20 min, then isobutyryl chloride (179 mg, 1.7 mmol) was added and the mixture stirred at rt for 1 h. The mixture was diluted with H2O (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (PE/EtOAc 1 :0 to 7:3) to give 2-{[(3,5-dichloropyridin-4-yl)methyl]sulfanyl} -5/7,6/7,7/7-cyclopenta[d]pyrimidin-4-yl 2-methylpropanoate (506 mg, 82%) as a solid. LC/MS: m/z = 398.00 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 6 8.65 (s, 2H), 4.68 (s, 2H), 2.98 (t, J = 7.7 Hz, 2H), 2.86- 2.94 (m, 1 H), 2.71 (t, J = 7.5 Hz, 2H), 2.02-2.14 (m, 2H), 1.25 (d, J = 5.4 Hz, 6H).
Example 19. Synthesis of 2-{[(3,5-dichloropyridin-4-yl)methyl]sulfanyl}-5H,6H,7H-cyclopenta[d]
-pyrimidin-4-yl propanoate (Compound 26)
Figure imgf000042_0001
Prepared in a manner similar to 2-{[(3,5-dichloropyridin-4-yl)methyl]sulfanyl}-5/7,6/7,7/7-cyclo -penta[c(]pyrimidin-4-yl 2-methylpropanoate to give 2-{[(3,5-dichloropyridin-4-yl)methyl]sulfanyl}-5/7,6/7,7/7 -cyclopenta[c(]pyrimidin-4-yl propanoate (557 mg, 47%) as a solid. LC/MS: m/z = 384.00 [M+H]+; 1H NMR (300 MHz, DMSO-d6) 6 8.65 (s, 2H), 4.67 (s, 2H), 2.98 (t, J = 7.7 Hz, 2H), 2.62-2.83 (m, 4H), 2.01- 2.15 (m, 2H), 1 .15 (t, J = 7.4 Hz, 3H).
Example 20. Synthesis of 2-{[(3,5-dichloropyridin-4-yl)methyl]sulfanyl}-5H,6H,7H-cyclopenta[d]
-pyrimidin-4-yl 2,2-dimethylpropanoate (Compound 27)
Figure imgf000042_0002
Prepared in a manner similar to 2-{[(3,5-dichloropyridin-4-yl)methyl]sulfanyl}-5/7,6/7,7/7-cyclo -penta[c(]pyrimidin-4-yl 2-methylpropanoate to give 2-{[(3,5-dichloropyridin-4-yl)methyl]sulfanyl} -5/7,6/7,7/7-cyclopenta[d]pyrimidin-4-yl 2,2-dimethylpropanoate (541 mg, 61 %) as a solid. LC/MS: m/z = 412.00 [M+H]+; 1H NMR (300 MHz, DMSO-d6) 6 8.65 (s, 2H), 4.69 (s, 2H), 2.98 (t, J = 7.5 Hz, 2H), 2.71 (t, J = 7.5 Hz, 2H), 2.08 (p, J = 7.5 Hz, 2H), 1 .32 (s, 9H) Example 21. Synthesis of (±) 6-(((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5H-cyclo -penta[d]pyrimidin-4-yl)oxy)methoxy)-5-methyl-6-oxohexanoic acid (Compound 17)
Figure imgf000043_0001
Step 1: Preparation of (±) 6-(tert-butoxy)-2-methyl-6-oxohexanoic acid
A mixture of 2-methylhexanedioic acid [CAS No: 626-70-0] (2.5 g, 15.6 mmol) and tert-butyl (Z)- /V,/V-diisopropylcarbamimidate (3.43 g, 17.1 mmol) in DCM (30 mL) was stirred at rt overnight. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (PE/EtOAc 1 :0 to 1 :1) to give (±) 6-(tert-butoxy)-2-methyl-6-oxohexanoic acid (1 .3 g, 39%) as an oil.
Step 2: Preparation of (±) 6-(tert-butyl) 1 -(chloromethyl) 2-methylhexaned ioate
To a mixture of 6-(tert-butoxy)-2-methyl-6-oxohexanoic acid (1.2 g, 5.6 mmol) in DCM (12 mL) and H2O (12 mL) at 0 °C was added NaHCOs (1 .63 g, 19.4 mmol) and n-Bu4NHSC>4 (0.1g, 0.3 mmol). The mixture was stirred at 0 °C for 10 min then chloromethyl sulfurochloridate (3.2 g, 19.4 mmol) was added portion-wise. The mixture was warmed to rt and stirred overnight, then extracted with DCM (3 x 40 mL). The combined organic layers were washed with brine, dried over Na2SC , filtered and the filtrate was concentrated under reduced pressure to give (±) 6-(tert-butyl) 1 -(chloromethyl) 2- methylhexanedioate (1 .3 g) as an oil (used in the next step without further purification).
Step 3: Preparation of (±) 6-tert-butyl 1-(((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5H-cyclo penta[d]pyrimidin-4-yl)oxy)methyl) 2-methylhexanedioate
To a mixture of 2-{[(3,5-dichloropyridin-4-yl)methyl]sulfanyl}-3/7,5/7,6/7,7/7-cyclopenta[d]pyrimidin -4-one (1 .5 g, 4.6 mmol), CS2CO3 (1 .67 g, 5.1 mmol) and DMF (25 mL) was added (±) 1 -tert- butyl 6- chloromethyl hexanedioate (1 .3 g, 4.9 mmol) in DMF (5 mL). The mixture was stirred at rt overnight, then diluted with H2O (100 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with H2O, brine, dried over Na2SC>4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (PE/EtOAc 1 :0 to 1 :1) to give (±) 6-te/Y-butyl 1-(((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5/7-cyclopenta[cf]pyrimidin -4-yl)oxy)methyl) 2-methylhexanedioate (1 .6 g, 62%) as an oil. LC/MS: m/z = 556.20 [M+H]+.
Step 4: Preparation of (±) 6-(((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6, 7-dihydro-5H-cyclopenta[d] pyrimidin-4-yl)oxy)methoxy)-5-methyl-6-oxohexanoic acid
To a mixture (±) 6-te/Y-butyl 1-(((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5/7-cyclo -penta[c(]pyrimidin-4-yl)oxy)methyl) 2-methylhexanedioate (1.0 g, 1.8 mmol) in DCM (10 mL) at 0 °C was added TFA (3 mL) dropwise. The mixture was warmed to rt and stirred for 2 h, then concentrated under reduced pressure and the residue was purified by preparative-HPLC (5% to 60% CH3CN in H2O containing 0.05% TFA) and then preparative-SFC to give (±) 6-(((2-(((3,5-dichloropyridin-4-yl)methyl)thio) -6,7-dihydro-5/7-cyclopenta[c(]pyrimidin-4-yl)oxy)methoxy)-5-methyl-6-oxohexanoic acid (321 mg, 36%) as a solid. LC/MS: m/z = 500.05 [M+H]+; 1H-NMR (300 MHz, d6-DMSO) 6 8.66 (s, 2H), 6.11 (d, J = 4.9 Hz, 2H), 4.70 (s, 2H), 2.84 - 2.92 (m, 2H), 2.70 - 2.79 (m, 2H), 2.42 - 2.45 (m, 1 H), 2.00 - 2.13 (m, 4H), 1 .35 - 1 .58 (m, 4H), 1.01 - 1 .09 (m, 3H).
Example 22. Synthesis of 6-(((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)oxy)methoxy)-5,5-dimethyl-6-oxohexanoic acid (Compound 18)
Figure imgf000044_0001
Step 1: Preparation of 6-(tert-butoxy)-2,2-dimethyl-6-oxohexanoic acid
A mixture of 2,2-dimethylhexanedioic acid [CAS No: 763-06-4] (5.0 g, 28.7 mmol) and te/Y-butyl (Z)-A/,A/'-diisopropylcarbamimidate (5.74 g, 28.7 mmol) in DCM (100 mL) was stirred at rt overnight. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (PE/EtOAc 1 :0 to 1 :1) to give 6-(te/Y-butoxy)-2,2-dimethyl-6-oxohexanoic acid (1 .9 g, 29%) as an oil.
Step 2: Preparation of 6-(tert-butyl) 1 -(chloromethyl) 2,2-dimethylhexanedioate
To a mixture of 6-(te/Y-butoxy)-2,2-dimethyl-6-oxohexanoic acid (1 .8 g, 7.8 mmol) in DCM (25 mL) and H2O (25 mL) at 0 °C was added NaHCOs (3.64 g, 43.33 mmol) and n-Bu4NHSC>4 (0.25 g, 0.74 mmol). The mixture was stirred at 0 °C for 10 min then chloromethyl sulfurochloridate (7.15 g, 43.3 mmol) was added portion-wise. The mixture was warmed to rt and stirred overnight, then extracted with DCM (3 x 40 mL). The combined organic layers were washed with brine, dried over Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to give 6-(tert-butyl) 1 -(chloromethyl) 2,2- dimethylhexanedioate (1 .8 g) as an oil (used in the next step without further purification).
Step 3: Preparation of 6-tert-butyl 1-(((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5H-cyclopenta [d]pyrimidin-4-yl)oxy)methyl) 2, 2-dimethylhexanedioate
To a mixture of 2-{[(3,5-dichloropyridin-4-yl)methyl]sulfanyl}-3/7,5/7,6/7,7/7-cyclopenta[d]pyrimidin -4-one (2.0 g, 6.0 mmol), CS2CO3 (2.35 g, 7.2 mmol) and DMF (25 mL) was added 1 -tert-butyl 6- chloromethyl hexanedioate (2.17 g, 7.8 mmol) in DMF (5 mL). The mixture was stirred at rt overnight, then diluted with H2O (100 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with H2O and brine, dried over Na2SC , and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (PE/EtOAc 1 :0 to 1 :1) to give 6-tert-butyl 1 -(((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5/7-cyclopenta[d]pyrimidin-4-yl) oxy)methyl) 2, 2-dimethylhexanedioate (1.3 g, 42%) as an oil.
Step 4: Preparation of 6-(((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6, 7-dihydro-5H-cyclopenta[d]pyrimidin -4-yl)oxy)methoxy)-5, 5-dimethyl-6-oxohexanoic acid
To a mixture of 6-tert-butyl 1-(((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5/7-cyclo penta[c(]pyrimidin-4-yl)oxy)methyl) 2, 2-dimethylhexanedioate (1.2 g, 2.1 mmol) and DCM (10 mL) at 0 °C was added TFA (3 mL) dropwise. The mixture was warmed to rt and stirred for 2 h, then concentrated under reduced pressure and the residue was purified by preparative-HPLC (5% to 60% CH3CN in H2O containing 0.05% TFA) to give 6-(((2-(((3,5-dichloropyridin-4-yl)methyl)thio)-6,7-dihydro-5/7-cyclopenta [c(]pyrimidin-4-yl)oxy)methoxy)-5,5-dimethyl-6-oxohexanoic acid (527 mg, 49%) as a solid. LC/MS: m/z = 514.05 [M+H]+; 1H-NMR (300 MHz; d6-DMSO) 6 8.65 (s, 2H), 6.10 (s, 2H), 4.69 (s, 2H), 2.86 (t, J = 7.7 Hz, 2H), 2.72 (t, J = 7.4 Hz, 2H), 1 .94 - 2.12 (m, 4H), 1 .39 - 1 .47 (m, 2H), 1 .23 - 1 .35 (m, 2H), 1 .08 (s, 6H).
Example 23. In Vivo Pharmacokinetics of Compounds 3, 6, 12, 13, 15, 11 , and 27 in male Beagle Dogs
A study was conducted to determine the pharmacokinetics of Compounds 3, 6, 12, 13, 15, 11 , and 27 in male Beagle dogs as compared to formulations of Compound A.
In non-naive male Beagle dogs, 5 mg/kg of Compound A or an equivalent dose of the other compounds were orally administered in 0.5% methylcellulose in saline (0.5-1 mg/mL). At 0.083, 0.25, 0.5, 1 , 2, 4, 8, 10, 12, and 24 hours after dosing, blood was serially drawn, and concentration measured in plasma. Food was available ad libitum. For comparison, 1 mg/kg of Compound A was administered via intravenous injection.
The results of the study are provided in FIG. 1 and FIG. 2.
It was found that Compounds 3, 12, 13, 15, and 11 unexpectedly exhibited higher oral bioavailability in dogs, as compared to formulations of Compound A. Example 24. In Vitro Pharmacokinetics of Compound 3
A study was conducted to determine the pharmacokinetics of Compound 3 in vitro in a plurality of biological matrices. The half-life of Compound 3 was measured for the biological matrix of plasma, blood, intestinal S9, liver hepatocytes, and liver S9 for rats, dogs, monkeys, humans. The results of the study are provided in Table 3. Compound 3 was rapidly metabolized to Compound A in all matrices.
Table 3. In Vitro pharmacokinetic parameters for biological matrices
Figure imgf000046_0001
Additionally, the half-life of Compound 3 when in the presence of hCES 1 b, hCES 1c, and hCES2c enzymes was measured. The results are of the study are provided in Table 4. Compound 3 was rapidly metabolized to Compound A via human CES enzymes.
Table 4. In Vitro pharmacokinetic parameters for enzymes
Figure imgf000046_0002
Example 25. In Vivo Pharmacokinetics of Compound 3 in male Beagle Dogs
A study was conducted to determine the pharmacokinetics of Compound 3 in vivo in male Beagle dogs as compared to Compound A, after oral dosing with Compound 3.
In non-naive male Beagle dogs, 744 mg/kg of Compound 3 was orally administered in 0.5% methylcellulose in saline (0.5-1 mg/mL). At 0.083, 0.25, 0.5, 1 , 2, 4, 8, 10, 12, and 24 hours after dosing, blood was serially drawn, and concentration of compounds A and 3 measured in plasma. Food was available ad libitum. The results of the study are provided in FIG. 3. Compound 3 was rapidly and completely converted to Compound A in the dog in vivo.
Example 26. In Vivo Pharmacokinetics of Compound 28 in male Beagle Dogs
A study was conducted to determine the pharmacokinetics of Compound 28 in male Beagle dogs as compared to formulations of Compound B.
In non-naive male Beagle dogs, 5 mg/kg of Compound B or an equivalent dose of compound 28 (7.6 mg/kg) were orally administered in 0.5% methylcellulose in saline (0.5-1 mg/mL). At 0.083, 0.25, 0.5, 1 , 2, 4, 8, and 24 hours after dosing, blood was serially drawn, and concentration of compound B and, where applicable, Compound 28, measured in plasma. Food was available ad libitum. For comparison, 1 mg/kg of Compound B was administered via intravenous injection.
The results of the study are provided in FIG. 4. It was found that Compound B, similar to Compound A, had very low bioavailability in dog, and Compound 28 exhibited higher oral bioavailability in dogs, as compared to formulations of Compound B.
Example 27. In Vitro Pharmacokinetics of Compound 28
A study was conducted to determine the pharmacokinetics of Compound 28 in vitro in a plurality of biological matrices. The half-life of Compound 28 was measured for the biological matrix of plasma, blood, intestinal microsomes, liver microsomes, and liver hepatocytes for rats, dogs, and humans. The results of the study are provided in Table 5. Compound 28 was rapidly metabolized to Compound B in all matrices.
Table 5. In Vitro pharmacokinetic parameters for biological matrices
Figure imgf000047_0002
Additionally, the half-life of Compound 28 when in the presence of hCES 1 b, hCES 1 c, and hCES2c enzymes was measured. The results are of the study are provided in Table 6. Compound 28 was rapidly metabolized to Compound B via human CES enzymes.
Table 6. In Vitro pharmacokinetic parameters for enzymes
Figure imgf000047_0003
Enumerated Embodiments
E1 . A compound of formula (I):
Figure imgf000047_0001
or a pharmaceutically acceptable salt thereof, in which
Qi is -O-, -S-, -S(O)-, -S(O)2-, -CH2-, -CH2CH2-, -CH=CH-, -OCH2-, -SCH2-, -S(O)CH2-, or -S(O2)CH2-;
V is O, S, NH, NZ, N-terminal linked amino acid, or CH2;
Figure imgf000048_0001
which Ra is -CH2NH- or -C(Rd)20-, in which each Rd is independently -
H, -Ci-Cs alkyl, -Ci-Cs cycloalkyl, -Ci-Cs aryl, or -Ci-Cs heteroaryl; Rb is H, OH, optionally substituted - Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -Ci-Cs alkoxy, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-C aryl, or - N(Re)2, and in which each Re is independently -H or -Ci-Cs alkyl;;
R2 and R3 are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-C aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OZ, -N(Z)2, -C(NH)N(Z)2, -OCH2OZ, -O(CH2)2OZ, -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z)2, -C(O)N(Z)2, -C(O)OZ, -SZ, -SOZ, -S(O)2Z, -NHC(O)Z, -NHS(O)2Z, -NHC(NH)N(Z)2, -NZC(NH)N(Z)2, -NHC(NCN)N(Z)2, -NZC(NCN)N(Z)2, or -PO(OZ)2; each Z is, independently, -H; optionally substituted -Ci-Cs alkyl; optionally substituted -C4-C12 alkcycloalkyl; optionally substituted -Cs-Cg alkheterocyclyl, in which the heterocycle is 3- to 9-membered; optionally substituted -C3-C12 cycloalkyl; optionally substituted -Ce-Cu aryl; optionally substituted -C7-C14 arylalkyl; optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle; optionally substituted -C2-C8 alkenyl; or optionally substituted -C2-C8 alkynyl; or two Z, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle;
A1 and A2 are each, independently, -H, -halo, -Ci-Cs alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C12 cycloalkyl, -Ce-Cu aryl, or -C7-C14 arylalkyl; and
A3 is a 3- to 9-membered aromatic or non-aromatic carbocycle or heterocycle.
E2. The compound of embodiment 1 , in which the compound is a compound of formula (I-2):
Figure imgf000048_0002
in which
V is O, S, NH, NZ, N-terminal linked amino acid, or CH2;
Figure imgf000048_0003
which Ra is -CH2NH- or -C(Rd)2O-, in which each Rd is independently -H, -Ci-Cs alkyl, -Ci-Cs cycloalkyl, -Ci-Cs aryl, or -Ci-Cs heteroaryl; Rb is H, OH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -Ci-Cs alkoxy, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-C aryl, or - N(Re)2, and in which each Re is independently -H or -Ci-Cs alkyl;
R2 and R3 are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-C aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OZ, -N(Z)2, -C(NH)N(Z)2, -OCH2OZ, -O(CH2)2OZ, -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z)2, -C(O)N(Z)2, -C(O)OZ, -SZ, -SOZ, -S(O)2Z, -NHC(O)Z, -NHS(O)2Z, -NHC(NH)N(Z)2, -NZC(NH)N(Z)2, -NHC(NCN)N(Z)2, -NZC(NCN)N(Z)2, or -PO(OZ)2;
R4, Rs, RB, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Z)2, -C(NH)N(Z)2I -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z)2, -C(O)N(Z)2, -C(O)OZ, -SZ, -S(O)Z, - S(O)2Z, -NHC(O)Z, -NHS(O)2Z, -NHC(NH)N(Z)2, -NYC(NH)N(Z)2, -NHC(NCN)N(Z)2, or -NZC(NCN)N(Z)2; each Z is, independently, -H; optionally substituted -Ci-Cs alkyl; optionally substituted -C4-C12 alkcycloalkyl; optionally substituted -Cs-Cg alkheterocyclyl, in which the heterocycle is 3- to 9-membered; optionally substituted -C3-C12 cycloalkyl; optionally substituted -CB-Cu aryl; optionally substituted optionally substituted -C7-C14 arylalkyl; optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle; optionally substituted -C2-C8 alkenyl; or optionally substituted -C2-C8 alkynyl; or two Z, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle; and
Q2, Q3, and Q4 are each, independently, N, N+-O-, or C, in which Q2, Q4, and QB are not simultaneously C.
E3. The compound of embodiment 2, in which the compound is a compound of formula (I-3):
Figure imgf000049_0001
or a pharmaceutically acceptable salt thereof, in which:
R4, Rs, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Cs-C aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OZ, -N(Z)2, -C(NH)N(Z)2, -O(CH2)nOZ, -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z)2, -C(O)N(Z)2, -C(O)OZ, -SZ, -S(O)Z, -S(O)2Z, -NHC(O)Z, -NHS(O)2Z, -NHC(NH)N(Z)2, -NYC(NH)N(Z)2, -NHC(NCN)N(Z)2, -NYC(NCN)N(Z)2, or - PO(OZ)2; and each Z is, independently, -H; optionally substituted -Ci-Cs alkyl; optionally substituted -C4-C12 alkcycloalkyl; optionally substituted -Cs-Cg alkheterocyclyl, in which the heterocycle is 3- to 9- membered; optionally substituted -C3-C12 cycloalkyl; optionally substituted -Ce-Cu aryl; optionally substituted -C7-C14 arylalkyl; 3- to 9-membered optionally substituted aromatic or non-aromatic heterocycle; optionally substituted -C2-C8 alkenyl; or optionally substituted -C2-C8 alkynyl; or two Z, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
E4. The compound of embodiment 3, in which R4 is -halo.
E5. The compound of embodiment 4, in which R4 is -Cl.
E6. The compound of any one of embodiments 3-5, in which Rs is -halo.
E7. The compound of embodiment 6, in which Rs is -Cl.
E8. The compound of any one of embodiments 3-5, in which Rs is Ci-Cs alkyl.
E9. The compound of embodiment 8, in which Rs is methyl.
E10. The compound of any one of embodiments 3-9, in which Rs is -H.
E11 . The compound of any one of embodiment 3-10, in which R7 is -H.
E12. The compound of embodiment 2, in which the compound is a compound of formula (I-4):
Figure imgf000050_0001
or a pharmaceutically acceptable salt thereof, in which:
R4, Rs, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-Cu aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OZ, -N(Z)2, -C(NH)N(Z)2, -O(CH2)nOZ, -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z)2, -C(O)N(Z)2, -C(O)OZ, -SZ, -S(O)Z, -S(O)2Z, -NHC(O)Z, -NHS(O)2Z, -NHC(NH)N(Z)2, -NYC(NH)N(Z)2, -NHC(NCN)N(Z)2, -NYC(NCN)N(Z)2, or - PO(OZ)2; and each Z is, independently, -H; optionally substituted -Ci-Cs alkyl; optionally substituted -C4-C12 alkcycloalkyl; optionally substituted -Cs-Cg alkheterocyclyl, in which the heterocycle is 3- to 9- membered; optionally substituted -C3-C12 cycloalkyl; optionally substituted -Ce-C aryl; optionally substituted -C7-C14 arylalkyl; 3- to 9-membered optionally substituted aromatic or non-aromatic heterocycle; optionally substituted -C2-C8 alkenyl; or optionally substituted -C2-C8 alkynyl; or two Z, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle. E13. The compound of embodiment 2, in which the compound is a compound of formula (I-5):
Figure imgf000051_0001
or a pharmaceutically acceptable salt thereof, in which:
R4, Rs, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-C aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OZ, -N(Z)2, -C(NH)N(Z)2, -O(CH2)nOZ, -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z)2, -C(O)N(Z)2, -C(O)OZ, -SZ, -S(O)Z, -S(O)2Z, -NHC(O)Z, -NHS(O)2Z, -NHC(NH)N(Z)2, -NYC(NH)N(Z)2, -NHC(NCN)N(Z)2, -NYC(NCN)N(Z)2, or -PO(OZ)2; and each Z is, independently, -H; optionally substituted -Ci-Cs alkyl; optionally substituted -C4-C12 alkcycloalkyl; optionally substituted -Cs-Cg alkheterocyclyl, in which the heterocycle is 3- to 9- membered; optionally substituted -C3-C12 cycloalkyl; optionally substituted -Ce-Cu aryl; optionally substituted -C7-C14 arylalkyl; 3- to 9-membered optionally substituted aromatic or non-aromatic heterocycle; optionally substituted -C2-C8 alkenyl; or optionally substituted -C2-C8 alkynyl; or two Z, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
E14. The compound of any one of embodiments 1-13, in which Rb is optionally substituted -Ci- Cs alkyl.
E15. The compound of embodiment 14, in which Rb is -(CH2)sCH3.
E16. The compound of embodiment 14, in which Rb is -CH3.
E17. The compound of embodiment 14, in which Rb is -C(CH3)3.
E18. The compound of embodiment 14, in which Rb is -CH(CH3)2.
E19. The compound of embodiment 14, in which Rb is carboxyl substituted -Ci-Cs alkyl.
E20. The compound of embodiment 19, in which Rb is -(CH2)4COOH.
E21 . The compound of embodiment 19, in which Rb is -CH2COOH.
Figure imgf000051_0002
E26. The compound of any one of embodiments 1-13, in which Rb is optionally substituted -Ci-
Cs alkoxy.
E27. The compound of embodiment 26, in which Rb is -OCH2CH3. E28. The compound of embodiment 26, in which
Figure imgf000052_0001
E29. The compound of any one of embodiments 1-13, in which Rb is -N(Re)2, in which each Re is independently -H or -Ci-Cs alkyl.
E30. The compound of embodiment 29, in which Rb is -NHCH2CH3.
E31 . The compound of any one of embodiments 1 -30, in which Ra is -CH2NH-.
E32. The compound of any one of embodiments 1-30, in which Ra is -C(Rd)2O-.
E33. The compound of embodiment 32, in which Rd is -CH2O-.
E34. The compound of embodiment 32, in which Rd is -CH(CH3)O-.
E36. The compound of any one of embodiments 1-34, in which R2 is selected from -H, -halo, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C5 alkenyl, optionally substituted -C2-C5 alkynyl, optionally substituted -C7-C14 arylalkyl, and -CN.
E37. The compound of any one of embodiments 1-35, in which R3 is selected from -H, -halo, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C5 alkenyl, optionally substituted -C2-C5 alkynyl, optionally substituted -C7-C14 arylalkyl, and -CN.
E38. A compound of formula (II):
Figure imgf000052_0002
or a pharmaceutically acceptable salt thereof, in which:
Qi is -O-, -S-, -S(O)-, -S(O)2-, -CH2-, -CH2CH2-, -CH=CH-, -OCH2-, -SCH2-, -S(O)CH2-, or -S(O2)CH2-;
V is O, S, NH, NZ, or CH2;
Figure imgf000052_0003
which Ra’ is -H, -OH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, or optionally substituted -Ce-C aryl; and Ra is -CH2NH- or -C(Rd)2O-, in which each Rd is independently -H, -Ci-Cs alkyl, -Ci-Cs cycloalkyl, -Ci-Cs aryl, or -Ci-Cs heteroaryl; Rb is H, OH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -Ci-Cs alkoxy, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-Cu aryl, or -N(Re)2, in which each Re is independently -H or -Ci-Cs alkyl; and Rc is H, Ci-Cs alkyl, or C6-C14 aryl;
R2’ and R3’, together with the atoms to which each is attached, join to form a 5- to 6-membered aromatic or non-aromatic carbocycle or heterocycle;
Z is -H; optionally substituted -Ci-Cs alkyl; optionally substituted -C4-Ci2 alkcycloalkyl; optionally substituted -Cs-Cg alkheterocyclyl, in which the heterocycle is 3- to 9-membered; optionally substituted -C3-C12 cycloalkyl; optionally substituted -Ce-C aryl; optionally substituted optionally substituted -C7-C14 arylalkyl; optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle; optionally substituted -C2-C8 alkenyl; or optionally substituted -C2-C8 alkynyl;
A1 and A2 are each, independently, -H, -halo, -Ci-Cs alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C12 cycloalkyl, -Ce-Cu aryl, or -C7-C14 arylalkyl; and
A3 is a 3- to 9-membered aromatic or non-aromatic carbocycle or heterocycle.
E39. The compound of embodiment 38, in which the compound is a compound of formula (II- 2):
Figure imgf000053_0001
or a pharmaceutically acceptable salt thereof, in which:
V is O, S, NH, NZ, or CH2;
Figure imgf000053_0002
which Ra’ is -H, -OH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, or optionally substituted -Ce-Cu aryl; and Ra is -CH2NH-, or -C(Rd)2O-, in which each Rd is independently -H, -Ci-Cs alkyl, -Ci-Cs cycloalkyl, -Ci-Cs aryl, or -Ci-Cs heteroaryl; Rb is H, OH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -Ci-Cs alkoxy, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-C aryl, or -N(Re)2, in which each Re is independently -H or -Ci-Cs alkyl; and Rc is H, Ci-Cs alkyl, or Ce-Cu aryl;
R2’ and R3’, together with the atoms to which each is attached, join to form a 5- to 6-membered aromatic or non-aromatic carbocycle or heterocycle;
R4, Rs, RB, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Z)2, -C(NH)N(Z)2I -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z)2, -C(O)N(Z)2, -C(O)OZ, -SZ, -S(O)Z, -S(O)2Z, -NHC(O)Z, -NHS(O)2Z, -NHC(NH)N(Z)2, -NYC(NH)N(Z)2, -NHC(NCN)N(Z)2, or -NZC(NCN)N(Z)2; each Z is, independently, -H; optionally substituted -Ci-Cs alkyl; optionally substituted -C4-C12 alkcycloalkyl; optionally substituted -Cs-Cg alkheterocyclyl, in which the heterocycle is 3- to 9-membered; optionally substituted -C3-C12 cycloalkyl; optionally substituted -Ce-C aryl; optionally substituted optionally substituted -C7-C14 arylalkyl; optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle; optionally substituted -C2-C8 alkenyl; or optionally substituted -C2-C8 alkynyl; or two Z, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle; and Q2, Q3, and Q4 are each, independently, N, N+-O_, or C, in which Q2, Q4, and Gte are not simultaneously C.
E40. The compound of embodiment 39, in which the compound is a compound of formula (II- 3):
Figure imgf000054_0001
or a pharmaceutically acceptable salt thereof, in which:
R4, Rs, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-C aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OZ, -N(Z)2, -C(NH)N(Z)2, -O(CH2)nOZ, -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z)2, -C(O)N(Z)2, -C(O)OZ, -SZ, -S(O)Z, -S(O)2Z, -NHC(O)Z, -NHS(O)2Z, -NHC(NH)N(Z)2, -NYC(NH)N(Z)2, -NHC(NCN)N(Z)2, -NYC(NCN)N(Z)2, or -PO(OZ)2; and each Z is, independently, -H; optionally substituted -Ci-Cs alkyl; optionally substituted -C4-C12 alkcycloalkyl; optionally substituted -Cs-Cg alkheterocyclyl, in which the heterocycle is 3- to 9- membered; optionally substituted -C3-C12 cycloalkyl; optionally substituted -Ce-Cu aryl; optionally substituted -C7-C14 arylalkyl; 3- to 9-membered optionally substituted aromatic or non-aromatic heterocycle; optionally substituted -C2-C8 alkenyl; or optionally substituted -C2-C8 alkynyl; or two Z, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
E41 . The compound of embodiment 40, in which R4 is -halo.
E42. The compound of embodiment 41 , in which R4 is -Cl.
E43. The compound of any one of embodiments 41-42, in which Rs is -halo.
E44. The compound of embodiment 43, in which Rs is -Cl.
E45. The compound of any one of embodiments 41 -42, in which Rs is Ci-Cs alkyl.
E46. The compound of embodiment 45, in which Rs is methyl.
E47. The compound of any one of embodiments 40-46, in which Rs is -H.
E48. The compound of any one of embodiments 40-47, in which R7 is -H.
E49. The compound of embodiment 39, in which the compound is a compound of formula (II-
4):
Figure imgf000055_0001
or pharmaceutically acceptable salt thereof, in which:
R4, Rs, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-C aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OZ, -N(Z)2, -C(NH)N(Z)2, -O(CH2)nOZ, -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z)2, -C(O)N(Z)2, -C(O)OZ, -SZ, -S(O)Z, -S(O)2Z, -NHC(O)Z, -NHS(O)2Z, -NHC(NH)N(Z)2, -NYC(NH)N(Z)2, -NHC(NCN)N(Z)2, -NYC(NCN)N(Z)2, or -PO(OZ)2; and each Z is, independently, -H; optionally substituted -Ci-Cs alkyl; optionally substituted -C4-C12 alkcycloalkyl; optionally substituted -Cs-Cg alkheterocyclyl, in which the heterocycle is 3- to 9- membered; optionally substituted -C3-C12 cycloalkyl; optionally substituted -Ce-Cu aryl; optionally substituted -C7-C14 arylalkyl; 3- to 9-membered optionally substituted aromatic or non-aromatic heterocycle; optionally substituted -C2-C8 alkenyl; or optionally substituted -C2-C8 alkynyl; or two Z, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
E50. The compound of embodiment 39, in which the compound is a compound of formula (II- 5):
Figure imgf000055_0002
, or a pharmaceutically acceptable salt thereof, in which:
R4, Rs, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-Cu aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OZ, -N(Z)2, -C(NH)N(Z)2, -O(CH2)nOZ, -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z)2, -C(O)N(Z)2, -C(O)OZ, -SZ, -S(O)Z, -S(O)2Z, -NHC(O)Z, -NHS(O)2Z, -NHC(NH)N(Z)2, -NYC(NH)N(Z)2, -NHC(NCN)N(Z)2, -NYC(NCN)N(Z)2,or -PO(OZ)2; and each Z is, independently, -H; optionally substituted -Ci-Cs alkyl; optionally substituted -C4-C12 alkcycloalkyl; optionally substituted -Cs-Cg alkheterocyclyl, in which the heterocycle is 3- to 9- membered; optionally substituted -C3-C12 cycloalkyl; optionally substituted -Ce-C aryl; optionally substituted -C7-C14 arylalkyl; 3- to 9-membered optionally substituted aromatic or non-aromatic heterocycle; optionally substituted -C2-C8 alkenyl; or optionally substituted -C2-C8 alkynyl; or two Z, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle
E51 . The compound of any one of embodiments 37-50, in which R1’ is -C(O)Ra’.
E52. The compound of embodiment 51 , in which Ra’ is optionally substituted -Ci-Cs alkyl.
E53. The compound of embodiment 52, in which Ra’ is -CH2CH3.
E54. The compound of embodiment 52, in which
E55. The compound of embodiment 52, in which
E56. The compound of embodiment 52, in which
E57. The compound of embodiment 52, in which
E58. The compound of embodiment 52, in which
E59. The compound of embodiment 52, in which
Figure imgf000056_0001
E60. The compound of embodiment 52, in which Ra’
Figure imgf000056_0002
E61 The compound of any one of embodiments 37-50, in which Ri’ is
Figure imgf000056_0003
E62. The compound of embodiment 61 , in which Rb is optionally substituted -Ci-Cs alkyl.
E63. The compound of embodiment 62, in which Rb is -(CH2)sCH3.
E64. The compound of embodiment 62, in which Rb is -CH3.
E65. The compound of embodiment 62, in which Rb is -C(CH3)3.
E66. The compound of embodiment 62, in which Rb is -CH(CH3)2.
E67. The compound of embodiment 61 , in which Rb is carboxyl substituted -Ci-Cs alkyl.
E68. The compound of embodiment 67, in which Rb is -(CH2)4COOH.
E69. The compound of embodiment 67, in which Rb is -CH2COOH.
Figure imgf000056_0004
E74. The compound of embodiment 61 , in which Rb is optionally substituted -Ci-Cs alkoxy.
E75. The compound of embodiment 74, in which
E76. The compound of embodiment 74, in which
Figure imgf000057_0001
E77. The compound of embodiment 61 , in which Rb is -N(Re)2, in which each Re is independently -H or -Ci-Cs alkyl.
E78. The compound of embodiment 77, in which Rb is -NHCH2CH3.
E79. The compound of any one of embodiments 61-78, in which Ra is -CH2NH-.
E80. The compound of any one of embodiments 61-78, in which Ra is -C(Rd)2O-.
E81 . The compound of embodiment 80, in which Rd is -CH2O- or
E82. The compound of any one of embodiments 37-50, in which
Figure imgf000057_0002
E83. The compound of embodiment 82, in which both Rc are -H.
E84. The compound of embodiment 82, in which both Rc are -C(CH3)3.
E85. The compound of any one of embodiments 37-84, in which R2’ and R3’, together with the atoms to which each is attached, form optionally substituted cyclopentyl or optionally substituted cyclohexyl.
E86. The compound of embodiment 85, in which R2’ and R3’, together with the atoms to which each is attached, form cyclopentyl.
E87. The compound of any one of embodiments 1-86, in which V is O.
E88. The compound of any one of embodiments 1-86, in which V is S.
E89. The compound of any one of embodiments 1-86, in which V is NH.
E90. The compound of any one of embodiments 1 , 14-37, and 51-89, in which A3 is an aromatic heterocyclic ring selected from the group consisting of:
Rs R7
R7 Q6^ .
II5 T R6~~Q5 '^2 I
R6/Q4'QfQ2^R4 Q4-Q3
R5 (Fragment Fragment A-2), Rs Rz| (Fragment A-3), and
Figure imgf000057_0003
(Fragment A-4),
Q2, Q4, and Qe are each, independently, N, N+-O-, or C;
Q3 and Qs are each, independently, N, N+-O-, C, O, or S, in which only one of Q3 and Q4 can be O or S; in which Q2, Q3, Q4, Qs, and QB simultaneously are C only if R4 and Rs, Rs and Rs, RB and R7, or R7 and Rs, together with the atoms to which each is attached, join to form a 5- or 6-membered aromatic or non-aromatic heterocycle;
R4, Rs, RB, R7, and Rs are each, independently, absent, -H, -OH, -O', -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, optionally substituted -CB-Cu aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OY, N(Y)2, -C(NH)N(Y)2I -O(CH2)mOY, -C(O)Y, -OC(O)Y, -OC(O)OY, OC(O)N(Y)2, C(O)N(Y)2, -C(O)OY, -SY, -S(O)Y, -S(O)2Y, NHC(O)Y, -NHS(O)2Y, -NHC(NH)N(Y)2, -NZC(NH)N(Y)2, -NHC(NCN)N(Y)2, -NYC(NCN)N(Y)2, -PO(OY)2; or
R4 and Rs, Rs and RB, RB and R7, or R7 and Rs, together with the atoms to which each is attached, join to form an optionally substituted 5- or 6-membered aromatic or non-aromatic carbocycle or heterocycle.
Each Y is, independently, -H, -C1-C5 alkyl, -C3-C7 cycloalkyl, phenyl, -C7-C9 arylalkyl, 3- to 7- membered aromatic or non-aromatic heterocycle, -C2-C5 alkenyl, or -C2-Cs alkynyl; or two Y, together with the atom to which each is attached, join to form a 3- to 7-membered aromatic or non-aromatic heterocycle; and m is 0 or 1 .
E91 . The compound of embodiment 90, in which A3 is:
Figure imgf000058_0001
in which
R4, Rs, RB, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted - C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, - N(Y)2, -C(NH)N(Y)2I -C(O)Y, -OC(O)Y, -OC(O)OY, -OC(O)N(Y)2I -C(O)N(Y)2I
-C(O)OY, -SY, -S(O)Y, -S(O)2Y, -NHC(O)Y, -NHS(O)2Y, -NHC(NH)N(Y)2, -NYC(NH)N(Y)2, -NHC(NCN)N(Y)2, or -NZC(NCN)N(Y)2; or
R4 and Rs, Rs and RB, RB and R7, or R7 and Rs, together with the atoms to which each is attached, join to form an optionally substituted 5- or 6-membered aromatic or non-aromatic carbocycle or heterocycle; each Y is, independently, -H, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C7 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, optionally substituted -C2-C5 alkenyl, or optionally substituted -C2-C5 alkynyl; or two Y, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle; and Q2, Q4, and Qe are each, independently, N, N+-O_, or C, in which Q2, Q4, and Qe are not simultaneously C.
E92. The compound of embodiment 91 , in which A3 is:
Figure imgf000059_0001
in which
R4, Rs, Re, and R7 are each, independently, -H, -OH, -halo, -CN, NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Y)2, -C(NH)N(Y)2I -C(O)Y, -OC(O)Y, -OC(O)OY, -OC(O)N(Y)2I -C(O)N(Y)2I -C(O)OY, -SY, -S(O)Y, -S(O)2Y, -NHC(O)Y, -NHS(O)2Y, -NHC(NH)N(Y)2, -NYC(NH)N(Y)2, -NHC(NCN)N(Y)2, or -NYC(NCN)N(Y)2; or
R4 and Rs, Rs and Re, or Re and R7, together with the carbon atoms to which each is attached, join to form an optionally substituted 5- or 6-membered aromatic or non-aromatic carbocycle or heterocycle; and each Y is, independently, -H, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C7 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, optionally substituted -C2-C5 alkenyl, or optionally substituted -C2-C5 alkynyl; or two Y, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
E93. The compound of embodiment 91 , in which A3 is:
Figure imgf000059_0002
in which
R4, Rs, Re, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Y)2, -C(NH)N(Y)2I -C(O)Y, -OC(O)Y, -OC(O)OY, -OC(O)N(Y)2I -C(O)N(Y)2I -C(O)OY, -SY, -S(O)Y, -S(O)2Y, -NHC(O)Y, -NHS(O)2Y, -NHC(NH)N(Y)2, -NYC(NH)N(Y)2, -NHC(NCN)N(Y)2, or -NYC(NCN)N(Y)2; or
R4 and Rs or Rs and Re, together with the carbon atoms to which each is attached, join to form an optionally substituted 5- or 6-membered aromatic or non-aromatic carbocycle or heterocycle; and each Y is, independently, -H, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C7 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, optionally substituted -C2-C5 alkenyl, or optionally substituted -C2-C5 alkynyl; or two Y, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
E94. The compound of embodiment 91 , in which A3 is:
Figure imgf000060_0001
in which
R4, Rs, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Y)2, -C(NH)N(Y)2I -C(O)Y, -OC(O)Y, -OC(O)OY, -OC(O)N(Y)2I -C(O)N(Y)2I -C(O)OY, -SY, -S(O)Y, -S(O)2Y, -NHC(O)Y, -NHS(O)2Y, -NHC(NH)N(Y)2, -NYC(NH)N(Y)2, -NHC(NCN)N(Y)2, or -NYC(NCN)N(Y)2; or
R4 and Rs or R7 and Rs, together with the carbon atoms to which each is attached, join to form an optionally substituted 5- or 6-membered aromatic or non-aromatic carbocycle or heterocycle; and each Y is, independently, -H, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C7 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, optionally substituted -C2-C5 alkenyl, or optionally substituted -C2-C5 alkynyl; or two Y, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
E95. The compound of embodiment 94, in which each of R4 and Rs is -Cl, and each of Rs and R7 is -H.
E96. The compound of embodiment 94, in which each R4 is -Cl, and Rs is methyl, and each of
Rs and R7 is -H.
E97. The compound of embodiment 90, in which A3 is:
Figure imgf000060_0002
in which
R4, Rs, Re, and R7, are each, independently, -H, -OH, halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Y)2, -C(NH)N(Y)2I -C(O)Y, -OC(O)Y, -OC(O)OY, -OC(O)N(Y)2I -C(O)N(Y)2I -C(O)OY, -SY, -S(O)Y, -S(O)2Y, -NHC(O)Y, -NHS(O)2Y, -NHC(NH)N(Y)2, -NYC(NH)N(Y)2, -NHC(NCN)N(Y)2, or -NYC(NCN)N(Y)2; or
R4 and Rs, Rs and Re, or Re and R7, together with the atoms to which each is attached, join to form an optionally substituted 5- or 6-membered aromatic or non-aromatic carbocycle or heterocycle; each Y is, independently, -H, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C7 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, optionally substituted -C2-C5 alkenyl, or optionally substituted -C2-C5 alkynyl; or two Y, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle; and
Q3, Q4, Qs, and Qe are each, independently, N , N+-0-,or C.
E98. The compound of embodiment 97, in which A3 is:
Figure imgf000061_0001
in which
R4, Rs, Re, and R7, are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Y)2, -C(NH)N(Y)2I -C(O)Y, -OC(O)Y, -OC(O)OY, -OC(O)N(Y)2I -C(O)N(Y)2I -C(O)OY, -SY, -S(O)Y, -S(O)2Y, -NHC(O)Y, -NHS(O)2Y, -NHC(NH)N(Y)2, -NYC(NH)N(Y)2, -NHC(NCN)N(Y)2, or -NYC(NCN)N(Y)2; or
R4 and Rs, Rs and Re, or Re and R7, together with the atoms to which each is attached, join to form an optionally substituted 5- or 6-membered aromatic or non-aromatic carbocycle or heterocycle; each Y is, independently, -H, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C7 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, optionally substituted -C2-C5 alkenyl, or optionally substituted -C2-C5 alkynyl; or two Y, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle; and
Q3 and Qe are each, independently, N, N+-O-, or C.
E99. The compound of embodiment 98, in which A3 is:
Figure imgf000061_0002
E100. The compound of embodiment 98, in which A3 is:
Figure imgf000062_0001
E101 . The compound of embodiment 90, in which A3 is:
Figure imgf000062_0002
in which
Rs is -H, -OH, -CN, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7- membered aromatic or non-aromatic heterocycle, -N(Y)2, -C(NH)N(Y)2, -C(O)Y, -C(O)N(Y)2, -C(O)OY, -S(O)2Y, -NHC(O)Y, -NHS(O)2Y, -NHC(NH)N(Y)2, -NYC(NH)N(Y)2, -NHC(NCN)N(Y)2, or -NYC(NCN)N(Y)2;
Re and R7 are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OZ, -N(Y)2, -C(NH)N(Y)2, -C(O)Y, -OC(O)Y, -OC(O)OY, -OC(O)N(Y)2I -C(O)N(Y)2I -C(O)OY, -SY, -S(O)Y, -S(O)2Y, -NHC(O)Y, -NHS(O)2Y, -NHC(NH)N(Y)2, -NYC(NH)N(Y)2, -NHC(NCN)N(Y)2, -NYC(NCN)N(Y)2; or
Rs and Re or Re and R7, together with the atoms to which each is attached, join to form an optionally substituted 5- or 6-membered aromatic or non-aromatic carbocycle or heterocycle; and each Y is, independently, -H, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C7 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, optionally substituted -C2-C5 alkenyl, or optionally substituted -C2-C5 alkynyl; or two Y, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
E102. The compound of embodiment 90, in which A3 is:
Figure imgf000062_0003
in which
R4 is -H, -OH, -CN, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7- membered aromatic or non-aromatic heterocycle, -N(Y)2, -C(NH)N(Y)2, -C(O)Y, -C(O)N(Y)2, -C(O)OY, -S(O)2Y, -NHC(O)Y, -NHS(O)2Y, -NHC(NH)N(Y)2, -NYC(NH)N(Y)2, -NHC(NCN)N(Y)2, or -NZC(NCN)N(Y)2; Re and R7 are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Y)2, -C(NH)N(Y)2, -C(O)Y, -OC(O)Y, -OC(O)OY, -OC(O)N(Y)2I -C(O)N(Y)2I -C(O)OY, -SY, -S(O)Y, -S(O)2Y, -NHC(O)Y, -NHS(O)2Y, -NHC(NH)N(Y)2, -NYC(NH)N(Y)2, -NHC(NCN)N(Y)2, -NYC(NCN)N(Y)2; or
Re and R7, together with the carbon atoms to which each is attached, join to form an optionally substituted 5- or 6-membered aromatic or non-aromatic carbocycle or heterocycle; and each Y is, independently, -H, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C7 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, optionally substituted -C2-C5 alkenyl, or optionally substituted -C2-C5 alkynyl; or two Y, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
E102. The compound of embodiment 90, in which A3 is:
Figure imgf000063_0001
in which
R4 is -H, -OH, -CN, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7- membered aromatic or non-aromatic heterocycle, -N(Y)2, -C(NH)N(Y)2, -C(O)Y, -C(O)N(Y)2, -C(O)OY, -S(O)2Y, -NHC(O)Y, -NHS(O)2Y, -NHC(NH)N(Y)2, -NYC(NH)N(Y)2, -NHC(NCN)N(Y)2, or -NYC(NCN)N(Y)2;
Rs and R7 are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Y)2, -C(NH)N(Y)2, -C(O)Y, -OC(O)Y, -OC(O)OY, -OC(O)N(Y)2I -C(O)N(Y)2I -C(O)OY, -SY, -S(O)Y, -S(O)2Y, -NHC(O)Y, -NHS(O)2Y, -NHC(NH)N(Y)2, -NYC(NH)N(Y)2, -NHC(NCN)N(Y)2, -NYC(NCN)N(Y)2; or
R4 and Rs, together with the atoms to which each is attached, join to form an optionally substituted 5- or 6-membered aromatic or non-aromatic heterocycle; and each Y is, independently, -H, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C7 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, optionally substituted -C2-C5 alkenyl, or optionally substituted -C2-C5 alkynyl; or two Y, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
E103. The compound of embodiment 90, in which A3 is:
Figure imgf000064_0001
in which
R4 is -H, -OH, -CN, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7- membered aromatic or non-aromatic heterocycle, -N(Y)2, -C(NH)N(Y)2, -C(O)Y, -C(O)N(Y)2, -C(O)OY, -S(O)2Y, -NHC(O)Y, -NHS(O)2Y, -NHC(NH)N(Y)2, -NYC(NH)N(Y)2, -NHC(NCN)N(Y)2, or -NYC(NCN)N(Y)2;
Rs and Re are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Y)2, -C(NH)N(Y)2, -C(O)Y, -OC(O)Y, -OC(O)OY, -OC(O)N(Y)2I -C(O)N(Y)2I -C(O)OY, -SY, -S(O)Y, -S(O)2Y, -NHC(O)Y, -NHS(O)2Y, -NHC(NH)N(Y)2, -NYC(NH)N(Y)2, -NHC(NCN)N(Y)2, -NYC(NCN)N(Y)2; or
R4 and Rs or Rs and Re, together with the carbon atoms to which each is attached, join to form an optionally substituted 5- or 6-membered aromatic or non-aromatic carbocycle or heterocycle; and each Y is, independently, -H, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C7 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, optionally substituted -C2-C5 alkenyl, or optionally substituted -C2-C5 alkynyl; or two Y, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
E104. The compound of embodiment 90, in which A3 is:
Figure imgf000064_0002
in which
R4 is -H, -OH, -CN, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7- membered aromatic or non-aromatic heterocycle, -N(Y)2, -C(NH)N(Y)2, -C(O)Y, -C(O)N(Y)2, -C(O)OY, -S(O)2Y, -NHC(O)Y, -NHS(O)2Y, -NHC(NH)N(Y)2, -NYC(NH)N(Y)2, -NHC(NCN)N(Y)2, or -NYC(NCN)N(Y)2;
Rs, Re, and R7 are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Y)2, -C(NH)N(Y)2, -C(O)Y, -OC(O)Y, -OC(O)OY, -OC(O)N(Y)2I -C(O)N(Y)2I -C(O)OY, -SY, -S(O)Y, -S(O)2Y, -NHC(O)Y, -NHS(O)2Y, -NHC(NH)N(Y)2, -NYC(NH)N(Y)2, -NHC(NCN)N(Y)2, or -NYC(NCN)N(Y)2; or
Rs and Re or Re and R7, together with the carbon atoms to which each is attached, join to form an optionally substituted 5- or 6-membered aromatic or non-aromatic carbocycle or heterocycle; and each Y is, independently, -H, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C7 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, optionally substituted -C2-C5 alkenyl, or optionally substituted -C2-C5 alkynyl; or two Y, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
E105. The compound of embodiment 90, in which A3 is:
Figure imgf000065_0001
in which
Rs and Re are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Y)2, -C(NH)N(Y)2, -C(O)Y, -OC(O)Y, -OC(O)OY, -OC(O)N(Y)2I -C(O)N(Y)2I -C(O)OY, -SY, -S(O)Y, -S(O)2Y, -NHC(O)Y, -NHS(O)2Y, -NHC(NH)N(Y)2, -NYC(NH)N(Y)2, -NHC(NCN)N(Y)2, -NYC(NCN)N(Y)2; or
Rs and Re, together with the carbon atoms to which each is attached, join to form an optionally substituted 5- or 6-membered aromatic or non-aromatic carbocycle or heterocycle; and each Y is, independently, -H, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C7 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, optionally substituted -C2-C5 alkenyl, or optionally substituted -C2-C5 alkynyl; or two Y, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
E106. The compound of embodiment 90, in which A3 is:
Figure imgf000065_0002
in which
Rs and R7 are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Y)2, -C(NH)N(Y)2, -C(O)Y, -OC(O)Y, -OC(O)OY, -OC(O)N(Y)2I -C(O)N(Y)2I -C(O)OY, -SY, -S(O)Y, -S(O)2Y, -NHC(O)Y, -NHS(O)2Y, -NHC(NH)N(Y)2, -NYC(NH)N(Y)2, -NHC(NCN)N(Y)2, or -NYC(NCN)N(Y)2; and each Y is, independently, -H, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C7 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, optionally substituted -C2-C5 alkenyl, or optionally substituted -C2-C5 alkynyl; or two Y, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
E107. The compound of embodiment 90, in which A3 is:
Figure imgf000066_0001
in which
R4 and R7 are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Y)2, -C(NH)N(Y)2, -C(O)Y, -OC(O)Y, -OC(O)OY, -OC(O)N(Y)2I -C(O)N(Y)2I -C(O)OY, -SY, -S(O)Y, -S(O)2Y, -NHC(O)Y, -NHS(O)2Y, -NHC(NH)N(Y)2, -NYC(NH)N(Y)2, -NHC(NCN)N(Y)2, or -NYC(NCN)N(Y)2; and each Y is, independently, -H, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C7 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, optionally substituted -C2-C5 alkenyl, or optionally substituted -C2-C5 alkynyl; or two Y, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
E108. The compound of embodiment 90, in which A3 is:
Figure imgf000066_0002
in which
Re and R7 are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Y)2, -C(NH)N(Y)2, -C(O)Y, -OC(O)Y, -OC(O)OY, -OC(O)N(Y)2I -C(O)N(Y)2I -C(O)OY, -SY, -S(O)Y, -S(O)2Y, -NHC(O)Y, -NHS(O)2Y, -NHC(NH)N(Y)2, -NYC(NH)N(Y)2, -NHC(NCN)N(Y)2, -NYC(NCN)N(Y)2; or
Re and R7, together with the carbon atoms to which each is attached, join to form an optionally substituted 5- or 6-membered aromatic or non-aromatic carbocycle or heterocycle; and each Y is, independently, -H, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C7 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, optionally substituted -C2-C5 alkenyl, or optionally substituted -C2-C5 alkynyl; or two Y, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle. E109. The compound of embodiment 90, in which A3 is:
Figure imgf000067_0001
in which
Rs and Re are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Y)2, -C(NH)N(Y)2, -C(O)Y, -OC(O)Y, -OC(O)OY, -OC(O)N(Y)2I -C(O)N(Y)2I -C(O)OY, -SY, -S(O)Y, -S(O)2Y, NHC(O)Y, -NHS(O)2Y, -NHC(NH)N(Y)2, -NYC(NH)N(Y)2, -NHC(NCN)N(Y)2, -NYC(NCN)N(Y)2; or
Rs and Re, together with the carbon atoms to which each is attached, join to form an optionally substituted 5- or 6-membered aromatic or non-aromatic carbocycle or heterocycle; and each Y is, independently, -H, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C7 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, optionally substituted -C2-C5 alkenyl, or optionally substituted -C2-C5 alkynyl; or two Y, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
E110. The compound of embodiment 90, in which A3 is:
Figure imgf000067_0002
in which
Rs and R7 are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Y)2, -C(NH)N(Y)2, -C(O)Y, -OC(O)Y, -OC(O)OY, -OC(O)N(Y)2I -C(O)N(Y)2I -C(O)OY, -SY, -S(O)Y, -S(O)2Y, -NHC(O)Y, -NHS(O)2Y, -NHC(NH)N(Y)2, -NYC(NH)N(Y)2, -NHC(NCN)N(Y)2, or -NYC(NCN)N(Y)2; and each Y is, independently, -H, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C7 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, optionally substituted -C2-C5 alkenyl, or optionally substituted -C2-C5 alkynyl; or two Y, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle. E111 . The compound of embodiment 90, in which A3 is:
Figure imgf000068_0001
in which
R4, Rs, and R7 are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Y)2, -C(NH)N(Y)2, -C(O)Y, -OC(O)Y, -OC(O)OY, -OC(O)N(Y)2I -C(O)N(Y)2I -C(O)OY, -SY, -S(O)Y, -S(O)2Y, -NHC(O)Y, -NHS(O)2Y, -NHC(NH)N(Y)2, -NYC(NH)N(Y)2, -NHC(NCN)N(Y)2, -NYC(NCN)N(Y)2; or
R4 and Rs, together with the carbon atoms to which each is attached, join to form an optionally substituted 5- or 6-membered aromatic or non-aromatic carbocycle or heterocycle; and each Y is, independently, -H, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C7 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, optionally substituted -C2-C5 alkenyl, or optionally substituted -C2-C5 alkynyl; or two Y, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
E112. The compound of embodiment 90, in which A3 is:
Figure imgf000068_0002
in which
R4 and Rs, or Rs and Rs, or Rs and R7, or R7 and Rs, together with the carbon atoms to which each is attached, join to form an optionally substituted 5- or 6-membered aromatic or non-aromatic heterocycle; and each Y is, independently, -H; optionally substituted -Ci-Cs alkyl; optionally substituted -C4-C12 alkcycloalkyl; optionally substituted -Cs-Cg alkheterocyclyl, in which the heterocycle is 3- to 9- membered; optionally substituted -C3-C12 cycloalkyl; optionally substituted -Ce-C aryl; optionally substituted -C7-C14 arylalkyl; 3- to 9-membered optionally substituted aromatic or non-aromatic heterocycle; optionally substituted -C2-C8 alkenyl; or optionally substituted -C2-C8 alkynyl; or two Y, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
E113. The compound of any one of embodiments 1 , 14-37, and 51-89, in which A3 is optionally substituted phenyl. E114. The compound of embodiment 113, in which A3 is:
Figure imgf000069_0001
in which
R4, Rs, Re, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-C aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OY, -N(Y)2, -C(NH)N(Y)2I -O(CH2)nOY, -C(O)Y, -OC(O)Y, -OC(O)OY, -OC(O)N(Y)2, -C(O)N(Y)2, -C(O)OY, -SY, -S(O)Y, -S(O)2Y, -NHC(O)Y, -NHS(O)2Y, -NHC(NH)N(Y)2, -NYC(NH)N(Y)2, -NHC(NCN)N(Y)2, -NYC(NCN)N(Y)2, or -PO(OY)2; and each Y is, independently, -H; optionally substituted -Ci-Cs alkyl; optionally substituted -C4-C12 alkcycloalkyl; optionally substituted -Cs-Cg alkheterocyclyl, in which the heterocycle is 3- to 9- membered; optionally substituted -C3-C12 cycloalkyl; optionally substituted -Ce-Cu aryl; optionally substituted -C7-C14 arylalkyl; 3- to 9-membered optionally substituted aromatic or non-aromatic heterocycle; optionally substituted -C2-C8 alkenyl; or optionally substituted -C2-C8 alkynyl; or two Y, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
E115. The compound of any one of embodiments 1 , 14-37, and 51-114, in which A1 is -H.
E116. The compound of any one of embodiments 1 , 14-37, and 51-114, in which A1 is -halo.
E117. The compound of embodiment 116, in which A1 is -F.
E118. The compound of any one of embodiments 1 , 14-37, and 51-117, in which A2 is -H.
E119. The compound of any one of embodiments 1 , 14-37, and 51-117, in which A2 is -halo.
E120. The compound of embodiment 119, in which A2 is -F.
E121 . The compound of any one of embodiments 1 , 14-37, and 51-120, in which Qi is -S-.
E122. The compound of any one of embodiments 1 , 14-37, and 51-120, in which Qi is -S(O)-.
E123. The compound of any one of embodiments 1 , 14-37, and 51-120, in which Qi is -S(O)2-.
E124. A compound of structure:
Figure imgf000069_0002
Figure imgf000070_0001
Figure imgf000071_0001
or a pharmaceutically acceptable salt thereof.
E125. A pharmaceutically composition including a compound of any one of embodiments 1-124 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
E126. A method for treating a neurological disorder, including administering to a subject in need thereof a therapeutically effective amount of a compound of any one of embodiments 1 -124 or a pharmaceutically acceptable salt thereof.
E127. The method of embodiment 126, in which the neurological disorder is a neurotraumatic disorder, a neurodevelopmental disorder, or an affective disorder.
E128. The method of embodiment 127, in which the neurological disorder is a neurotraumatic disorder.
E129. The method of embodiment 128, in which the neurotraumatic disorder is selected from the group consisting of spinal cord injury, traumatic brain injury, stroke, peripheral nerve injury, multiple sclerosis, ischemia, amyotrophic lateral sclerosis, Parkinson’s disease, Alzheimer’s disease, myelopathy, hypoxic-ischemic encephalopathy, tumor-associated epilepsy, spasticity, and peripheral neuropathy.
E130. The method of embodiment 127, in which the neurological disorder is a neurodevelopmental disorder.
E131 . The method of embodiment 130, in which the neurodevelopmental disorder is selected from an autism spectrum disorder, Rett syndrome, Fragile X syndrome, Angelman syndrome, Tuberous Sclerosis Complex (TSC), cerebral palsy, Down syndrome, pain, Dravet syndrome, epilepsy, and sudden unexpected death in epilepsy.
E132. The method of embodiment 131 , in which the pain is selected from neuropathic pain, inflammation, inflammatory pain, arthritic pain, diabetic pain, and neuralgia.
E133. The method of embodiment 131 , in which the epilepsy is selected from temporal lobe epilepsy, refractory epilepsy, neurotrauma associated epilepsy, status epilepticus, tumor associated epilepsy, and hypoxic-ischemic encephalopathy. E134. The method of embodiment 127, in which the neurological disorder is an affective disorder.
E135. The method of embodiment 132, in which the affective disorder is disorder is schizophrenia, bipolar disorder, anxiety disorder, or major depressive disorder. Other Embodiments
While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the disclosure and including such departures from the invention that come within known or customary practice within the art to which the disclosure pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims. Other embodiments are within the claims.

Claims

What is claimed is: CLAIMS
1 . A compound of formula (I-2):
Figure imgf000073_0001
or a pharmaceutically acceptable salt thereof, wherein
V is O, S, NH, NZ, N-terminal linked amino acid, or CH2;
Figure imgf000073_0002
wherein Ra is -CH2NH- or -C(Rd)2O-, wherein each Rd is independently -H, -Ci-Cs alkyl, -Ci-Cs cycloalkyl, -Ci-Cs aryl, or -Ci-Cs heteroaryl; Rb is H, OH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -Ci-Cs alkoxy, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-C aryl, or - N(Re)2, and wherein each Re is independently -H or -Ci-Cs alkyl;
R2 and R3 are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-C aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OZ, -N(Z)2, -C(NH)N(Z)2, -OCH2OZ, -O(CH2)2OZ, -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z)2, -C(O)N(Z)2, -C(O)OZ, -SZ, -SOZ, -S(O)2Z, -NHC(O)Z, -NHS(O)2Z, -NHC(NH)N(Z)2, -NZC(NH)N(Z)2, -NHC(NCN)N(Z)2, -NZC(NCN)N(Z)2, or -PO(OZ)2;
R4, Rs, RB, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Z)2, -C(NH)N(Z)2I -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z)2, -C(O)N(Z)2, -C(O)OZ, -SZ, -S(O)Z, -S(O)2Z, -NHC(O)Z, -NHS(O)2Z, -NHC(NH)N(Z)2, -NYC(NH)N(Z)2, -NHC(NCN)N(Z)2, or -NZC(NCN)N(Z)2; each Z is, independently, -H; optionally substituted -Ci-Cs alkyl; optionally substituted -C4-C12 alkcycloalkyl; optionally substituted -Cs-Cg alkheterocyclyl, wherein the heterocycle is 3- to 9-membered; optionally substituted -C3-C12 cycloalkyl; optionally substituted -CB-Cu aryl; optionally substituted -C7-C14 arylalkyl; optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle; optionally substituted -C2-C8 alkenyl; or optionally substituted -C2-C8 alkynyl; or two Z, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle; and Q2, Q3, and Q4 are each, independently, N, N+-O-, or C, wherein Q2, Q4, and Qs are not simultaneously C.
2. The compound of claim 1 , wherein the compound is a compound of formula (I-3):
Figure imgf000074_0001
or a pharmaceutically acceptable salt thereof, wherein:
R4, Rs, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-C aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OZ, -N(Z)2, -C(NH)N(Z)2, -O(CH2)nOZ, -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z)2, -C(O)N(Z)2, -C(O)OZ, -SZ, -S(O)Z, -S(O)2Z, -NHC(O)Z, -NHS(O)2Z, -NHC(NH)N(Z)2, -NYC(NH)N(Z)2, -NHC(NCN)N(Z)2, -NYC(NCN)N(Z)2, or - PO(OZ)2; and each Z is, independently, -H; optionally substituted -Ci-Cs alkyl; optionally substituted -C4-C12 alkcycloalkyl; optionally substituted -Cs-Cg alkheterocyclyl, wherein the heterocycle is 3- to 9- membered; optionally substituted -C3-C12 cycloalkyl; optionally substituted -Ce-Cu aryl; optionally substituted -C7-C14 arylalkyl; 3- to 9-membered optionally substituted aromatic or non-aromatic heterocycle; optionally substituted -C2-C8 alkenyl; or optionally substituted -C2-C8 alkynyl; or two Z, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
3. The compound of claim 2, wherein R4 is -halo.
4. The compound of claim 3, wherein R4 is -Cl.
5. The compound of any one of claims 2-4, wherein Rs is -halo.
6. The compound of claim 5, wherein Rs is -Cl.
7. The compound of any one of claims 2-4, wherein Rs is Ci - Cs alkyl.
8. The compound of claim 7, wherein Rs is methyl.
9. The compound of any one of claims 2-8, wherein Rs is -H.
10. The compound of any one of claims 2-9, wherein R7 is -H.
11. The compound of claim 1 , wherein the compound is a compound of formula (I-4):
Figure imgf000075_0001
or a pharmaceutically acceptable salt thereof, wherein:
R4, Rs, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-C aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OZ, -N(Z)2, -C(NH)N(Z)2, -O(CH2)nOZ, -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z)2, -C(O)N(Z)2, -C(O)OZ, -SZ, -S(O)Z, -S(O)2Z, -NHC(O)Z, -NHS(O)2Z, -NHC(NH)N(Z)2, -NYC(NH)N(Z)2, -NHC(NCN)N(Z)2, -NYC(NCN)N(Z)2, or -PO(OZ)2; and each Z is, independently, -H; optionally substituted -Ci-Cs alkyl; optionally substituted -C4-C12 alkcycloalkyl; optionally substituted -Cs-Cg alkheterocyclyl, wherein the heterocycle is 3- to 9- membered; optionally substituted -C3-C12 cycloalkyl; optionally substituted -Ce-Cu aryl; optionally substituted -C7-C14 arylalkyl; 3- to 9-membered optionally substituted aromatic or non-aromatic heterocycle; optionally substituted -C2-C8 alkenyl; or optionally substituted -C2-C8 alkynyl; or two Z, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
12. The compound of claim 1 , wherein the compound is a compound of formula (I-5):
Figure imgf000075_0002
or a pharmaceutically acceptable salt thereof, wherein:
R4, Rs, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-Cu aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OZ, -N(Z)2, -C(NH)N(Z)2, -O(CH2)nOZ, -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z)2, -C(O)N(Z)2, -C(O)OZ, -SZ, -S(O)Z, -S(O)2Z, -NHC(O)Z, -NHS(O)2Z, -NHC(NH)N(Z)2, -NYC(NH)N(Z)2, -NHC(NCN)N(Z)2, -NYC(NCN)N(Z)2, or -PO(OZ)2; and each Z is, independently, -H; optionally substituted -Ci-Cs alkyl; optionally substituted -C4-C12 alkcycloalkyl; optionally substituted -Cs-Cg alkheterocyclyl, wherein the heterocycle is 3- to 9- membered; optionally substituted -C3-C12 cycloalkyl; optionally substituted -Ce-C aryl; optionally substituted -C7-C14 arylalkyl; 3- to 9-membered optionally substituted aromatic or non-aromatic heterocycle; optionally substituted -C2-C8 alkenyl; or optionally substituted -C2-C8 alkynyl; or two Z, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
13. The compound of any one of claims 1-12, wherein Rb is optionally substituted -Ci-Cs alkyl.
14. The compound of claim 13, wherein Rb is -(CH2)sCH3, -CH3, -C(CH3)3, or -CH(CH3)2.
15. The compound of any one of claims 1-12, wherein Rb is carboxyl substituted -Ci-Cs alkyl.
16. The compound of claim 15, wherein Rb is -(CH2)4COOH, -CH2COOH, -(CH2)2COOH,
Figure imgf000076_0001
17. The compound of any one of claims 1-12, wherein Rb is optionally substituted -Ci-Cs alkoxy.
18. The compound of claim 17, wherein
Figure imgf000076_0002
19. The compound of any one of claims 1-12, wherein Rb is -N(Re)2, in which each Re is independently -H or -Ci-Cs alkyl.
20. The compound of claim 19, wherein Rb is -NHCH2CH3.
21 . The compound of any one of claims 1 -20, wherein Ra is -CH2NH-.
22. The compound of any one of claims 1 -20, wherein Ra is -C(Rd)2O-.
23. The compound of claim 22, wherein Rd is -CH2O- or -CH(CH3)O-.
24. The compound of any one of claims 1-23, wherein R2 is selected from -H, -halo, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C5 alkenyl, optionally substituted -C2-C5 alkynyl, optionally substituted -C7-C14 arylalkyl, and -CN.
25. The compound of any one of claims 1-24, wherein R3 is selected from -H, -halo, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C5 alkenyl, optionally substituted -C2-C5 alkynyl, optionally substituted -C7-C14 arylalkyl, and -CN.
26. A compound of formula (11-2):
Figure imgf000077_0001
or a pharmaceutically acceptable salt thereof, wherein:
V is O, S, NH, NZ, or CH2;
Figure imgf000077_0002
optionally substituted
-Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, or optionally substituted -Ce-C aryl; and Ra is -CH2NH- or -C(Rd)20-, wherein each Rd is independently -H, -Ci-Cs alkyl, -Ci-Cs cycloalkyl, -Ci-Cs aryl, or -Ci-Cs heteroaryl; Rb is H, OH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -Ci-Cs alkoxy, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-Cu aryl, or -N(Re)2, wherein each Re is independently -H or -Ci-Cs alkyl; and Rc is H, Ci- Cs alkyl, or Ce-C aryl;
R2’ and R3’, together with the atoms to which each is attached, join to form a 5- to 6-membered aromatic or non-aromatic carbocycle or heterocycle;
R4, Rs, RB, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, optionally substituted -C1-C5 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted -C7-C9 arylalkyl, optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle, -OY, -N(Z)2, -C(NH)N(Z)2I -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z)2, -C(O)N(Z)2, -C(O)OZ, -SZ, -S(O)Z, -S(O)2Z, -NHC(O)Z, -NHS(O)2Z, -NHC(NH)N(Z)2, -NYC(NH)N(Z)2, -NHC(NCN)N(Z)2, or -NZC(NCN)N(Z)2; each Z is, independently, -H; optionally substituted -Ci-Cs alkyl; optionally substituted -C4-C12 alkcycloalkyl; optionally substituted -Cs-Cg alkheterocyclyl, wherein the heterocycle is 3- to 9-membered; optionally substituted -C3-C12 cycloalkyl; optionally substituted -CB-Cu aryl; optionally substituted -C7-C14 arylalkyl; optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle; optionally substituted -C2-C8 alkenyl; or optionally substituted -C2-C8 alkynyl; or two Z, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle; and
Q2, Q3, and Q4 are each, independently, N, N+-O_, or C, wherein Q2, Q4, and QB are not simultaneously C.
27. The compound of claim 26, wherein the compound is a compound of formula (11-3):
Figure imgf000078_0001
or a pharmaceutically acceptable salt thereof, wherein:
R4, Rs, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-C aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OZ, -N(Z)2, -C(NH)N(Z)2, -O(CH2)nOZ, -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z)2, -C(O)N(Z)2, -C(O)OZ, -SZ, -S(O)Z, -S(O)2Z, - NHC(O)Z, -NHS(O)2Z, -NHC(NH)N(Z)2, -NYC(NH)N(Z)2, -NHC(NCN)N(Z)2, -NYC(NCN)N(Z)2, or - PO(OZ)2; and each Z is, independently, -H; optionally substituted -Ci-Cs alkyl; optionally substituted -C4-C12 alkcycloalkyl; optionally substituted -Cs-Cg alkheterocyclyl, wherein the heterocycle is 3- to 9- membered; optionally substituted -C3-C12 cycloalkyl; optionally substituted -Ce-Cu aryl; optionally substituted -C7-C14 arylalkyl; 3- to 9-membered optionally substituted aromatic or non-aromatic heterocycle; optionally substituted -C2-C8 alkenyl; or optionally substituted -C2-C8 alkynyl; or two Z, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
28. The compound of claim 26 or 27, wherein R4 is -halo.
29. The compound of claim 28, wherein R4 is -Cl.
30. The compound of any one of claims 26-29, wherein Rs is -halo.
31 . The compound of claim 30, wherein Rs is -Cl.
32. The compound of any one of claims 26-29, wherein Rs is Ci-Cs alkyl.
33. The compound of claim 32, wherein Rs is methyl.
34. The compound of any one of claims 26-33, wherein Rs is -H.
35. The compound of any one of claims 26-34, wherein R7 is -H.
36. The compound of claim 26, wherein the compound is a compound of formula (11-4):
Figure imgf000079_0001
or a pharmaceutically acceptable salt thereof, wherein:
R4, Rs, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-C aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OZ, -N(Z)2, -C(NH)N(Z)2, -O(CH2)nOZ, -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z)2, -C(O)N(Z)2, -C(O)OZ, -SZ, -S(O)Z, -S(O)2Z, -NHC(O)Z, -NHS(O)2Z, -NHC(NH)N(Z)2, -NYC(NH)N(Z)2, -NHC(NCN)N(Z)2, -NYC(NCN)N(Z)2, or - PO(OZ)2; and each Z is, independently, -H; optionally substituted -Ci-Cs alkyl; optionally substituted -C4-C12 alkcycloalkyl; optionally substituted -Cs-Cg alkheterocyclyl, wherein the heterocycle is 3- to 9- membered; optionally substituted -C3-C12 cycloalkyl; optionally substituted -Ce-Cu aryl; optionally substituted -C7-C14 arylalkyl; 3- to 9-membered optionally substituted aromatic or non-aromatic heterocycle; optionally substituted -C2-C8 alkenyl; or optionally substituted -C2-C8 alkynyl; or two Z, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
37. The compound of claim 26, wherein the compound is a compound of formula (II-5):
Figure imgf000079_0002
or a pharmaceutically acceptable salt thereof, wherein:
R4, Rs, R7, and Rs are each, independently, -H, -OH, -halo, -CN, -NO2, -SH, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C12 cycloalkyl, optionally substituted -Ce-Cu aryl, optionally substituted -C7-C14 arylalkyl, optionally substituted 3- to 9-membered aromatic or non-aromatic heterocycle, -OZ, -N(Z)2, -C(NH)N(Z)2, -O(CH2)nOZ, -C(O)Z, -OC(O)Z, -OC(O)OZ, -OC(O)N(Z)2, -C(O)N(Z)2, -C(O)OZ, -SZ, -S(O)Z, -S(O)2Z, - NHC(O)Z, -NHS(O)2Z, -NHC(NH)N(Z)2, -NYC(NH)N(Z)2, -NHC(NCN)N(Z)2, -NYC(NCN)N(Z)2, or -PO(OZ)2; and each Z is, independently, -H; optionally substituted -Ci-Cs alkyl; optionally substituted -C4-Ci2 alkcycloalkyl; optionally substituted -C3-Cg alkheterocyclyl, wherein the heterocycle is 3- to 9- membered; optionally substituted -C3-Ci2 cycloalkyl; optionally substituted -Ce-C aryl; optionally substituted -C7-C14 arylalkyl; 3- to 9-membered optionally substituted aromatic or non-aromatic heterocycle; optionally substituted -C2-Cs alkenyl; or optionally substituted -C2-Cs alkynyl; or two Z, together with the atom to which each is attached, join to form an optionally substituted 3- to 7-membered aromatic or non-aromatic heterocycle.
38. The compound of any one of claims 26-37, wherein R1’ is -C(O)Ra’.
39. The compound of claim 38, wherein Ra’ is optionally substituted -Ci-Cs alkyl.
40. The compound of claim 39, wherein Ra’ is -CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2N(CH3)2,
Figure imgf000080_0001
41. The compound of any one of claims 26-37, wherein Ri’ is
Figure imgf000080_0002
42. The compound of claim 41 , wherein Rb is optionally substituted -Ci-Cs alkyl.
43. The compound of claim 42, wherein Rb is -(CH2)sCH3, -CH3, -C(CH3)3, or -CH(CH3)2.
44. The compound of claim 41 , wherein Rb is carboxyl substituted -Ci-Cs alkyl.
45. The compound of claim 44, wherein Rb is -(CH2)4COOH, -CH2COOH, -(CH2)2COOH, -
Figure imgf000080_0003
46. The compound of claim 41 , wherein Rb is optionally substituted -Ci-Cs alkoxy.
47. The compound of claim 46, wherein
Figure imgf000080_0004
48. The compound of claim 41 , wherein Rb is -N(Re)2, in which each Re is independently -H or
-Ci-Cs alkyl.
49. The compound of claim 48, wherein Rb is -NHCH2CH3.
50. The compound of any one of claims 26-37, wherein
Figure imgf000081_0001
51 . The compound of claim 50, wherein each Rc is independently -H or -C(CH3)3.
52. The compound of any one of claims 41-51 , wherein Ra is -CH2NH-.
53. The compound of any one of claims 41-51 , wherein Ra is -C(Rd)2O-.
54. The compound of claim 53, wherein Rd is -CH2O- or -CH(CH3)O-.
55. The compound of any one of claims 26-54, wherein R2’ and R3’, together with the atoms to which each is attached, form optionally substituted cyclopentyl or optionally substituted cyclohexyl.
56. The compound of claim 55, wherein R2’ and R3’, together with the atom to which each is attached, join to form cyclopentyl.
57. The compound of any one of claims 1-56, wherein V is O, S, or NH.
Figure imgf000081_0002
Figure imgf000082_0001
Figure imgf000083_0001
59. A pharmaceutical composition comprising a compound of any one of claims 1-58 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
60. A method for treating a neurological disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 -58 or a pharmaceutically acceptable salt thereof.
61 . The method of claim 60, wherein the neurological disorder is a neurotraumatic disorder, a neurodevelopmental disorder, or an affective disorder.
62. The method of claim 61 , wherein the neurological disorder is a neurotraumatic disorder.
63. The method of claim 62, wherein the neurotraumatic disorder is selected from the group consisting of spinal cord injury, traumatic brain injury, stroke, peripheral nerve injury, multiple sclerosis, ischemia, amyotrophic lateral sclerosis, Parkinson’s disease, Alzheimer’s disease, myelopathy, hypoxic- ischemic encephalopathy, tumor-associated epilepsy, status epilepticus, spasticity, and peripheral neuropathy.
64. The method of claim 61 , wherein the neurological disorder is a neurodevelopmental disorder.
65. The method of claim 64, wherein the neurodevelopmental disorder is selected from an autism spectrum disorder, Rett syndrome, Tuberous Sclerosis Complex (TSC), Fragile X syndrome, Angelman syndrome, cerebral palsy, Down syndrome, pain, Dravet syndrome, epilepsy, and sudden unexpected death in epilepsy.
66. The method of claim 64, wherein the pain is neuropathic pain, inflammation, inflammatory pain, arthritic pain, diabetic pain, or neuralgia.
67. The method of claim 64, wherein the epilepsy is temporal lobe epilepsy, refractory epilepsy, neurotrauma associated epilepsy, status epilepticus, tumor associated epilepsy, hypoxic- ischemic encephalopathy and sudden unexpected death in epilepsy.
68. The method of claim 61 , wherein the neurological disorder is an affective disorder.
69. The method of claim 66, wherein the affective disorder is disorder is schizophrenia, bipolar disorder, anxiety disorder, or major depressive disorder.
PCT/US2023/017917 2022-04-08 2023-04-07 Methods and compounds for treating neurological disorders WO2023196614A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202263329207P 2022-04-08 2022-04-08
US63/329,207 2022-04-08

Publications (1)

Publication Number Publication Date
WO2023196614A1 true WO2023196614A1 (en) 2023-10-12

Family

ID=88243564

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2023/017917 WO2023196614A1 (en) 2022-04-08 2023-04-07 Methods and compounds for treating neurological disorders

Country Status (1)

Country Link
WO (1) WO2023196614A1 (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010132999A1 (en) * 2009-05-21 2010-11-25 Chlorion Pharma, Inc. Methyl sulfanyl pyrmidmes useful as antiinflammatories, analgesics, and antiepileptics
US20190151263A1 (en) * 2009-01-22 2019-05-23 Neuropro Therapeutics, Inc. Bumetanide analgos, compositions, and methods of use
US20200276337A1 (en) * 2017-09-26 2020-09-03 INSERM (Institut National de la Santé et de la Recherche Médicale) Radiolabeled darapladib and analogs thereof and their use as imaging compounds
US20210022978A1 (en) * 2018-04-06 2021-01-28 Zilentin AG Bumetanide derivatives for the therapy of hyperhidrosis

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190151263A1 (en) * 2009-01-22 2019-05-23 Neuropro Therapeutics, Inc. Bumetanide analgos, compositions, and methods of use
WO2010132999A1 (en) * 2009-05-21 2010-11-25 Chlorion Pharma, Inc. Methyl sulfanyl pyrmidmes useful as antiinflammatories, analgesics, and antiepileptics
US20200276337A1 (en) * 2017-09-26 2020-09-03 INSERM (Institut National de la Santé et de la Recherche Médicale) Radiolabeled darapladib and analogs thereof and their use as imaging compounds
US20210022978A1 (en) * 2018-04-06 2021-01-28 Zilentin AG Bumetanide derivatives for the therapy of hyperhidrosis

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DELPIRE ERIC: "Advances in the development of novel compounds targeting cation-chloride cotransporter physiology", AMERICAN JOURNAL OF PHYSIOLOGY CELL PHYSIOLOGY, AMERICAN PHYSIOLOGICAL SOCIETY, US, vol. 320, no. 3, 1 March 2021 (2021-03-01), US , pages C324 - C340, XP093101021, ISSN: 0363-6143, DOI: 10.1152/ajpcell.00566.2020 *

Similar Documents

Publication Publication Date Title
JP6523251B2 (en) C-linked heterocycloalkyl substituted pyrimidines and their uses
KR20230028543A (en) tryptamine prodrug
US20150329525A1 (en) Pyrrolidine-2, 5-dione derivatives, pharmaceutical compositions and methods for use as ido1 inhibitors
US20170189386A1 (en) Tetrahydrocarboline derivative
US9422300B2 (en) Bisulfate of janus kinase (JAK) inhibitor and preparation method therefor
TW202342454A (en) Multifunctional compound, preparation method therefor, and application thereof in pharmaceuticals
KR20150128891A (en) Inhibitors of indoleamine 2,3-dioxygenase (ido)
US10925876B2 (en) Methods for using triazolo-pyrazinyl soluble guanylate cyclase activators in fibrotic disorders
US8889715B2 (en) Substituted pyridoxine-lactam carboxylate salts
KR20020073589A (en) Fused Imidazolium Derivatives
WO2018019222A1 (en) Heterocyclic compound as jak inhibitor, and salts and therapeutic use thereof
US12084451B2 (en) Compositions and methods for reducing tactile dysfunction, anxiety, and social impairment
ES2971319T3 (en) Compounds and compositions to induce chondrogenesis
JP2009527467A (en) Amino acid derivatives
WO2023196614A1 (en) Methods and compounds for treating neurological disorders
US10494360B2 (en) Inhibitors of indoleamine 2,3-dioxygenase
EP3634963A1 (en) 1-(2-azaspiro[3.3]heptan-6-yl)-5,6-dihydro-4h-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine derivatives as v1a receptor antagonists for treating neuropsychological disorders
CA3222404A1 (en) Heterocyclic jak inhibitor
CN113666938A (en) Tetrahydroisoquinoline derivatives
WO2024211686A1 (en) Kcc2 potentiators and uses thereof
WO2020007698A1 (en) Novel amino-imidazopyrimidine derivatives as janus kinase inhibitors and pharmaceutical use thereof
US8741893B2 (en) 6,7-dihydro-[1,3,4]thiadiazolo-[3,2-a][1,3]diazepin derivatives and pharmaceutical compositions containing the same as hypnotic or anesthetic agent and method for their preparation
US11053230B2 (en) 3-hydroxy-imidazolidin-4-one compounds as inhibitors of indoleamine 2,3-dioxygenase
WO2024125551A1 (en) Cyclin k degrader and use thereof
KR20190040340A (en) Hydroxynorketamine derivatives for the treatment of disorders

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23785458

Country of ref document: EP

Kind code of ref document: A1