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WO2020251870A1 - Steroids with altered pharmacokinetic properties and methods of use thereof - Google Patents

Steroids with altered pharmacokinetic properties and methods of use thereof Download PDF

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Publication number
WO2020251870A1
WO2020251870A1 PCT/US2020/036549 US2020036549W WO2020251870A1 WO 2020251870 A1 WO2020251870 A1 WO 2020251870A1 US 2020036549 W US2020036549 W US 2020036549W WO 2020251870 A1 WO2020251870 A1 WO 2020251870A1
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optionally substituted
disorder
nhc
group
alkyl
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French (fr)
Inventor
Andrew D. LEVIN
Neil Buckley
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Athenen Therapeutics Inc
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Athenen Therapeutics Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the invention generally relates to compositions containing steroids with altered pharmacokinetic properties and methods of using the same.
  • Neurological disorders affect up to one billion people worldwide.
  • Neurological disorders include a wide range of conditions, such as Alzheimer's disease, brain injuries, epilepsy, headache, infections, multiple sclerosis, and Parkinson's disease, and stroke.
  • Neuroactive steroids hold promise for treatment of a variety of neurological disorders. Such steroids alter neuronal excitability through interaction with ligand-gated ion channels and other cell surface receptors.
  • GABA neurotransmitter gamma-aminobutyric acid
  • steroids that target GABA receptors have been investigated for treatment of disorders associated with altered GABA signaling.
  • Steroids that target receptors for the neurotransmitter N-methyl-D-aspartate (NMDA) have also been examined as therapeutic candidates for central nervous system (CNS) conditions.
  • NMDA neurotransmitter N-methyl-D-aspartate
  • the invention provides compositions that contain neurosteroids having altered, e.g., improved, potency, bioavailability, and pharmacokinetic properties.
  • the invention recognizes that compounds having a steroid structural core and containing substituents at certain positions are effective at modulating various receptors that affect neuronal signaling. Consequently, the compositions of the invention are useful for treating a variety of neurological disorders.
  • the invention also provides methods of using such compositions to treat neurological disorders.
  • R 1A and R 1B are according to (i) or (ii) as follows:
  • R 4 is N(R 31 ) 2 or halogen
  • each instance of R 30 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; each instance of R 31 is independently hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl, heterocyclyl, aryl, heteroaryl, amine, nitrate, nitrite, thiol, thioether, thioester, sulfate, sulfite, disulfide, sulfoxide, phosphate, phosphate ester, thiophosphate, thiophosphate ester, phosphonate, phosphonate ester, thiophosphonate, thiophosphonate ester, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R 31
  • each instance of R 32 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and R 33 is absent or H.
  • R 4 is halogen
  • R 5 is not H; R 23 is not alkyl; and R 28 is not H. In certain embodiments, R 5 is not H. In certain embodiments, R 23 is not alkyl In certain embodiments, R 28 is not H. In certain embodiments, R 5 is not H and R 23 is not alkyl In certain embodiments, R 5 is not H and R 28 is not H. In certain embodiments, R 23 is not alkyl and R 28 is not H. In certain embodiments, R 5 is not H, R 23 is not alkyl, and R 28 is not H.
  • R 33 is H. In certain embodiments, R 33 is in an alpha
  • R 33 is H in an alpha stereochemical position.
  • R 23 is methyl. In certain embodiments, R 23 is H.
  • R 5 is methyl. In certain embodiments, R 5 is H.
  • R 28 is H. In certain embodiments, R 28 is an optionally substituted heteroaryl. In certain embodiments, R 28 is an optionally substituted pyrazole. In certain embodiments, R 28 is a heteroaryl substituted with–CN. In certain embodiments, R 28 has the following structure:
  • R 5 is not H, and R 28 is H.
  • the compound of formula (I) is represented by a structure of one of formulas (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (I-9), (I-10), (I-11), (I-12), (I-13), (I- 14), (I-15), (I-16), (I-17), (I-18), (I-19), (I-20), (I-21), (I-22), (I-23), (I-24), (I-25), (I-26), (I-27), (I-28), (I-29), (I-30), (I-31), and (I-32):
  • the compound of formula (I) is represented by a structure of one of formulas (I-1a), (I-2a), (I-3a), (I-4a), (I-5a), (I-6a), (I-7a), (I-8a), (I-9a), (I-10a), (I-11a), (I- 12a), (I-13a), (I-14a), (I-15a), (I-16a), (I-17a), (I-18a), (I-19a), (I-20a), (I-21a), (I-22a), (I-23a), (I-24a), (I-25a), (I-26a), (I-27a), (I-28a), (I-29a), (I-30a), (I-31a), and (I-32a):
  • the composition may modulate activity of a gamma-aminobutyric acid (GABA) receptor.
  • GABA gamma-aminobutyric acid
  • the composition may stimulate GABA receptor activity, or it may inhibit GABA receptor activity.
  • the composition may modulate, e.g., stimulate or inhibit, activity of a GABA A receptor.
  • the composition may modulate the activity of one or more subtypes of GABA receptors, such as a1b1g2, a1b2g2, a1b3g2, a2b1g2, a2b2g2, a2b3g2, a3b1g2, a3b2g2, a3b3g2, a4b1g2, a4b3d, a4b3g2, a5b1g2, a5b2g2, a5b3g2, a6b1g2, a6b2g2, and a6b3g2 GABA receptors.
  • GABA receptors such as a1b1g2, a1b2g2, a1b3g2, a2b1g2, a2b2g2, a2b3g2, a3b1g2, a3b2g2, a4b3d, a4b3g2, a5b1g2, a5b2g2, a5b3g2,
  • the composition may preferentially modulate the activity of one or more subtypes of GABA receptors, such as those described above, over one or more other subtypes of GABA receptors.
  • the composition may preferentially modulate the activity of a4b3d GABA receptors over a1b2g2 GABA receptors.
  • compositions may be effective for treating a condition, such as a central nervous system (CNS) condition, in a subject.
  • the composition may be effective for treating one or more of acute pain, an addictive disorder, Alzheimer’s disease, Angelman's syndrome, anti-social personality disorder, an anxiety disorder, attention deficit hyperactivity disorder (ADHD), an attention disorder, an auditory disorder, autism, an autism spectrum disorder, bipolar disorder, chronic pain, a cognitive disorder, a compulsive disorder, a convulsive disorder, dementia, depression, dysthymia, an epileptic disorder, essential tremor, epileptogenesis, fragile X syndrome, generalized anxiety disorder (GAD), Huntington’s disease, injury related pain syndrome, insomnia, ischemia, Lewis body type dementia, a memory disorder, migraines, a mood disorder, movement disorder, a neurodegenerative disease, neuropathic pain, an obsessive compulsive disorder, pain, a panic disorder, Parkinson’s disease, a personality disorder, posttraumatic stress disorder (PTSD), psychosis
  • the invention provides methods of treating a neurological condition in a subject by providing to the subject a compound of formula (I).
  • the composition may modulate activity of a gamma-aminobutyric acid (GABA) receptor.
  • GABA gamma-aminobutyric acid
  • the composition may increase GABA receptor activity, or it may inhibit GABA receptor activity.
  • the composition may modulate, e.g., increase or decrease, activity of a GABA A receptor.
  • the composition may modulate the activity of one or more subtypes of GABA receptors, such as a1b1g2, a1b2g2, a1b3g2, a2b1g2, a2b2g2, a2b3g2, a3b1g2, a3b2g2, a3b3g2, a4b1g2, a4b3d, a4b3g2, a5b1g2, a5b2g2, a5b3g2, a6b1g2, a6b2g2, and a6b3g2 GABA receptors.
  • GABA receptors such as a1b1g2, a1b2g2, a1b3g2, a2b1g2, a2b2g2, a2b3g2, a3b1g2, a3b2g2, a4b3d, a4b3g2, a5b1g2, a5b2g2, a5b3g2,
  • the composition may preferentially modulate the activity of one or more subtypes of GABA receptors, such as those described above, over one or more other subtypes of GABA receptors.
  • the composition may preferentially modulate the activity of a4b3d GABA receptors over a1b2g2 GABA receptors.
  • the neurological condition may be any condition, such as any of those described above.
  • the compound may have any of the structural elements described above.
  • the compound may be represented by any of the formulas described above. Brief Description of the Drawings
  • FIG.1 shows graphs of EC 50 dose response curves for compounds against GABA A a1b1g2.
  • FIG.2 shows graphs of IC 50 dose response curves for compounds against GABA A a1b1g2.
  • FIG.3 shows graphs of EC 50 dose response curves for compounds against GABA A a1b2g2.
  • FIG.4 shows graphs of IC 50 dose response curves for compounds against GABA A a1b2g2.
  • FIG.5 shows graphs of EC 50 dose response curves for compounds against GABA A a1b3g2.
  • FIG.6 shows graphs of IC 50 dose response curves for compounds against GABA A a1b3g2.
  • FIG.7 shows graphs of EC 50 dose response curves for compounds against GABA A a2b1g2.
  • FIG.8 shows graphs of IC 50 dose response curves for compounds against GABA A a2b1g2.
  • FIG.9 shows graphs of EC 50 dose response curves for compounds against GABA A a2b2g2.
  • FIG.10 shows graphs of IC 50 dose response curves for compounds against GABA A a2b2g2.
  • FIG.11 shows graphs of EC 50 dose response curves for compounds against GABA A a2b3g2.
  • FIG.12 shows graphs of IC 50 dose response curves for compounds against GABA A a2b3g2.
  • FIG.13 shows graphs of EC 50 dose response curves for compounds against GABA A a3b1g2.
  • FIG.14 shows graphs of IC 50 dose response curves for compounds against GABA A a3b1g2.
  • FIG.15 shows graphs of EC 50 dose response curves for compounds against GABA A a3b2g2.
  • FIG.16 shows graphs of IC 50 dose response curves for compounds against GABA A a3b2g2.
  • FIG.17 shows graphs of EC 50 dose response curves for compounds against GABA A a3b3g2..
  • FIG.18 shows graphs of IC 50 dose response curves for compounds against GABA A a3b3g2.
  • FIG.19 shows graphs of EC 50 dose response curves for compounds against GABA A a4b1g2.
  • FIG.20 shows graphs of IC 50 dose response curves for compounds against GABA A a4b1g2.
  • FIG.21 shows graphs of EC 50 dose response curves for compounds against GABA A a4b3d.
  • FIG.22 shows graphs of IC 50 dose response curves for compounds against GABA A a4b3d.
  • FIG.23 shows graphs of EC 50 dose response curves for compounds against GABA A a5b1g2.
  • FIG.24 shows graphs of IC 50 dose response curves for compounds against GABA A a5b1g2.
  • FIG.25 shows graphs of IC 50 dose response curves for compounds against GABA A a5b2g2.
  • FIG.26 shows graphs of EC 50 dose response curves for compounds against GABA A a5b3g2.
  • FIG.27 shows graphs of IC 50 dose response curves for compounds against GABA A a5b3g2.
  • FIG.28 shows graphs of EC 50 dose response curves for compounds against GABA A a6b1g2.
  • FIG.29 shows graphs of IC 50 dose response curves for compounds against GABA A a6b1g2.
  • FIG.30 shows graphs of IC 50 dose response curves for compounds against GABA A a6b2g2.
  • the invention provides neurosteroids that are effective GABA A receptor modulators and have different pharmacokinetic properties from previously described neurosteroids.
  • the neurosteroids of the invention are therefore useful for treating CNS disorders. Definitions
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC), supercritical fluid chromatography (SFC), and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
  • a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess).
  • an "S” form of the compound is substantially free from the "R” form of the compound and is, thus, in enantiomeric excess of the "R” form.
  • enantiomerically pure or “pure enantiomer” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer.
  • the weights are based upon total weight of all enantiomers or stereoisomers of the compound.
  • an enantiomerically pure compound can be present with other active or inactive ingredients.
  • a pharmaceutical composition comprising enantiomerically pure R-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R-compound.
  • the enantiomerically pure R- compound in such compositions can, for example, comprise, at least about 95% by weight R- compound and at most about 5% by weight S-compound, by total weight of the compound.
  • a pharmaceutical composition comprising enantiomerically pure S-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound.
  • the enantiomerically pure S compound in such compositions can, for example, comprise, at least about 95% by weight S compound and at most about 5% by weight R-compound, by total weight of the compound.
  • the active ingredient can be formulated with little or no excipient or carrier.
  • analogue means one analogue or more than one analogue.
  • C 1-6 alkyl is intended to encompass, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 alkyl.
  • Alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C 1-20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-12 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C 1-6 alkyl”, also referred to herein as "lower alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C 1-5 alkyl”).
  • an alkyl group has 1 to 4 carbon atoms ("C 1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C 1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2-6 alkyl”).
  • C 1-6 alkyl groups include methyl (C 1 ), ethyl (C 2 ), n- propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert-butyl (C 4 ), sec-butyl (C 4 ), isobutyl (C 4 ), n-pentyl (C 5 ), 3-pentanyl (C 5 ), amyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butanyl (C 5 ), tertiary amyl (C 5 ), and n-hexyl (C 6 ).
  • alkyl groups include n-heptyl (C 7 ), n-octyl (C 8 ) and the like.
  • each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • the alkyl group is unsubstituted C 1-10 alkyl (e.g., -CH 3 ).
  • the alkyl group is substituted C 1-10 alkyl.
  • Alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds ("C 2-20 alkenyl”). In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C 2-10 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2-8 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C 2-6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C 2-5 alkenyl”).
  • an alkenyl group has 2 to 4 carbon atoms ("C 2-4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C 2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms ("C 2 alkenyl”).
  • the one or more carbon-carbon double bonds can be internal (such as in 2- butenyl) or terminal (such as in 1-butenyl).
  • Examples of C 2-4 alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1- butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), and the like.
  • Examples of C 2-6 alkenyl groups include the aforementioned C 2-4 alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like.
  • Additional examples of alkenyl include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ), and the like.
  • each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkenyl") or substituted (a "substituted alkenyl") with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • the alkenyl group is unsubstituted C 2-10 alkenyl.
  • the alkenyl group is substituted C 2-10 alkenyl.
  • Alkynyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds, and optionally one or more double bonds ("C 2-20 alkynyl”).
  • an alkynyl group has 2 to 10 carbon atoms ("C 2-10 alkynyl”).
  • an alkynyl group has 2 to 8 carbon atoms ("C 2-8 alkynyl”).
  • an alkynyl group has 2 to 6 carbon atoms (“C 2-6 alkynyl”).
  • an alkynyl group has 2 to 5 carbon atoms (“C 2-5 alkynyl”).
  • an alkynyl group has 2 to 4 carbon atoms ("C 2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C 2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms ("C 2 alkynyl”).
  • the one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).
  • Examples of C 2-4 alkynyl groups include, without limitation, ethynyl (C 2 ), 1-propynyl (C 3 ), 2- propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), and the like.
  • Examples of C 2-6 alkenyl groups include the aforementioned C 2-4 alkynyl groups as well as pentynyl (C 5 ), hexynyl (C 6 ), and the like. Additional examples of alkynyl include heptynyl (C 7 ), octynyl (C 8 ), and the like.
  • each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkynyl") or substituted (a "substituted alkynyl") with on or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • the alkynyl group is unsubstituted C 2-10 alkynyl.
  • the alkynyl group is substituted C 2-10 alkynyl.
  • Aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6-1 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C 6-14 aryl").
  • an aryl group has six ring carbon atoms ("C 6 aryl”; e.g., phenyl).
  • an aryl group has ten ring carbon atoms ("C 10 aryl”; e.g., naphthyl such as 1- naphthyl and 2-naphthyl).
  • an aryl group has fourteen ring carbon atom ("C 14 aryl”; e.g., anthracyl).
  • Aryl also includes ring systems wherein the aryl ring, as define above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • Aryl groups include, but are not limited to, phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an
  • the aryl group is unsubstituted C 6-14 aryl. In certain embodiments, the aryl group is substituted C 6-14 aryl.
  • R 56 and R 57 may be hydrogen and at least one of R 56 and R 57 is each
  • SO 2 NR 58 R 59 S-alkyl, SOalkyl, SO 2 alkyl, Saryl, SOaryl, SO 2 aryl; or R 56 and R 57 may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O, or S.
  • R 60 and R61 are independently hydrogen, C 1 -C 8 alkyl, C 1 -C 4 haloalkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl, substituted C 6 -C 10 aryl, 5-10 membered heteroaryl, or substituted 5-10 membered heteroaryl.
  • aryl groups having a fused heterocyclyl group include the following:
  • each W is selected from C(R 66 ) 2 , NR 66 , O, and S; and each Y is selected from carbonyl, NR 66 , O and S; and R 66 is independently hydrogen, C 1 -C 8 alkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl, and 5-10 membered heteroaryl.
  • Halo or halogen independently or as part of another substituent, mean, unless otherwise stated, a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom.
  • halide by itself or as part of another substituent, refers to a fluoride, chloride, bromide, or iodide atom. In certain embodiments, the halo group is either fluorine or chlorine.
  • Haloalkyl and haloalkoxy can include alkyl and alkoxy structures that are substituted with one or more halo groups or with combinations thereof.
  • fluoroalkyl and fluoroalkoxy include haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine.
  • Heteroaryl refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl").
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heteroaryl includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system.
  • Heteroaryl also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system.
  • Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
  • the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
  • a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl").
  • a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl").
  • a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl").
  • the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted heteroaryl") or substituted (a "substituted heteroaryl") with one or more substituents.
  • the heteroaryl group is unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5-14 membered heteroaryl.
  • Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl.
  • Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containin three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5- membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl.
  • Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepi
  • Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl,
  • benzothiophenyl isobenzothiophenyl, benzofuranyl, benzoisofura benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
  • Exemplary 6,6-bicyclic hetero groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • each Y is selected from carbonyl, N, NR 65 , O, and S; and R 65 is independently hydrogen, C 1 -C 8 alkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl, and 5-10 membered heteroaryl.
  • Carbocyclyl or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms ("C 3-10 carbocyclyl") and zero heteroatoms in the non-aromatic ring system.
  • a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8 carbocyclyl”).
  • a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 carbocyclyl”).
  • a carbocyclyl group has 3 to 6 ring carbon atoms (“C 3-6 carbocyclyl”).
  • a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 carbocyclyl").
  • Exemplary C 3-6 carbocyclyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl C 6 ), cyclohexadienyl (C 6 ), and the like.
  • Exemplary C 3-6 carbocyclyl groups include, without limitation, the aforementioned C 3-6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ), and the like.
  • Exemplary C 3-10 carbocyclyl groups include, without limitation, the aforementioned C 3-8 carbocyclyl groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like.
  • the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) and can be saturated or can be partially unsaturated.
  • “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
  • each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl") with one or more substituents.
  • the carbocyclyl group is unsubstituted C 3- 10 carbocyclyl.
  • the carbocyclyl group is a substituted C 3-10 carbocyclyl.
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms ("C 3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5-6 , cycloalkyl").
  • a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5 10 cycloalkyl").
  • C 5-10 cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 5 ).
  • Examples of C 3-6 cycloalkyl groups include the aforementioned C 5-6 cycloalkyl groups as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ).
  • Examples of C 3-8 cycloalkyl groups include the aforementioned C 3-8 cycloalkyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 ).
  • each instance of a cycloalkyl group is independently unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl") with one or more substituents.
  • the cycloalkyl group is unsubstituted C 3-10 cycloalkyl.
  • the cycloalkyl group is substituted C 3-10 cycloalkyl.
  • Heterocyclyl or “heterocyclic” refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (" 3-10 membered heterocyclyl").
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic ("monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated.
  • Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.
  • each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an
  • heterocyclyl or substituted (a "substituted heterocyclyl") with one or more substituents.
  • the heterocyclyl group is unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3-10 membered heterocyclyl.
  • a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5-10 membered heterocyclyl").
  • a heterocyclyl group is a 5-8 membered non- aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl").
  • a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl").
  • the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl.
  • Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.
  • Exemplary 5- membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione.
  • Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one.
  • Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6- membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
  • Exemplary 5-membered heterocyclyl groups fused to a C 6 aryl ring include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.
  • Exemplary 6-membered heterocyclyl groups fused to an aryl ring include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
  • heterocyclyl groups are shown in the following illustrative examples:
  • each W is selected from CR 67 , C(R 67 ) 2 , NR 67 , O, and S; and each Y is selected from NR 67 , O, and S; and R 67 is independently hydrogen, C 1 -C 8 alkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl, and 5-10-membered heteroaryl.
  • heterocyclyl rings may be optionally substituted with one or more groups selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (e.g., amido), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, halogen, hydroxy, keto, nitro, thiol, -S-alkyl, -S aryl, -S(O)-alkyl, -S(O)-aryl, -S(O) 2 -alkyl, and -S(O) 2 -aryl.
  • Substituting groups include carbonyl or thiocarbonyl which provide, for example, lactam and urea derivatives.
  • Acyl refers to a radical-C(O)R 20 , where R 20 is hydrogen, substituted or unsubstitued alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstitued heteroaryl, as defined herein.
  • “Alkanoyl” is an acyl group wherein R 20 is a group other than hydrogen.
  • t is an integer from 0 to 4.
  • R 21 is C 1 -C 8 alkyl, substituted with halo or hydroxy; or C 3 -C 10 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxy.
  • Acylamino refers to a radical-NR 22 C(O)R 23 , where each instance of R 22 and R 23 is independently hydrogen, substituted or unsubstitued alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstitued heteroaryl,, as defined herein, or R 22 is an amino protecting group.
  • acylamino groups include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino and benzylcarbonylamino.
  • acylamino groups are -NR 24 C(O)-C 1 -C 8 alkyl, -NR 24 C(O)-(CH 2 ) t (C 6 -C 10 aryl), - NR 24 C(O)-(CH 2 ) t (5-10 membered heteroaryl), -NR 24 C(O)-(CH 2 ) t (C 3 -C 10 cycloalkyl), and - NR 24 C(O)-(CH 2 ) t (4-10 membered heterocyclyl), wherein t is an integer from 0 to 4, and each R 24 independently represents hydrogen or C 1 -C 8 alkyl.
  • R 25 is H, C 1 -C 8 alkyl, substituted with halo or hydroxy; C 3 -C 10 cycloalkyl, 4-10 membered heterocyclyl, C 6 - C 10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxy; and R 26 is H, C 1 -C 8 alkyl, substituted with halo or hydroxy; C 3 -C 10 cycloalkyl, 4-10- membered heterocyclyl, C 6 -C 10 aryl, arylalkyl
  • Acyloxy refers to a radical -OC(O)R 27 , where R 27 is hydrogen, substituted or unsubstitued alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstitued heteroaryl, as defined herein.
  • Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl,
  • R 28 is C 1 -C 8 alkyl, substituted with halo or hydroxy; C 3 -C 10 cycloalkyl, 4-10-membered heterocyclyl, C 6 -C 10 aryl, arylalkyl, 5-10-membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxy.
  • Alkoxy refers to the group -OR 29 where R 29 is substituted or unsubstituted alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstitued heteroaryl.
  • Particular alkoxy groups are methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2- dimethylbutoxy.
  • Particular alkoxy groups are lower alkoxy, i.e., with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.
  • R 29 is a group that has 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of amino, substituted amino, C 6 -C 10 aryl, aryloxy, carboxyl, cyano, C 3 - C 10 cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10 membered heteroaryl, hydroxy, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O) 2 - and aryl-S(O) 2 -
  • substituents for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of amino, substituted amino, C 6 -C 10 aryl, aryloxy, carboxyl, cyano, C 3 - C 10
  • Particular exemplary "substituted alkoxy" groups are -OCF 3 ,-OCH 2 CF 3 ,-OCH 2 Ph,-OCH 2 -cyclopropyl, -OCH 2 CH 2 OH, and - OCH 2 CH 2 Nme 2 .
  • Amino refers to the radical-NH 2 .
  • Substituted amino refers to an amino group of the formula-N(R 38 ) 2 wherein R 38 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstitued heteroaryl, or an amino protecting group, wherein at least one of R 38 is not a hydrogen.
  • each R 38 is independently selected from hydrogen, C 1 -C 8 alkyl, C 3 -C 8 alkenyl, C 3 -C 8 alkynyl, C 6 - C 10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, or C 3 -C 10 cycloalkyl; or C 1 -C 8 alkyl, substituted with halo or hydroxy; C 3 -C 8 alkenyl, substituted with halo or hydroxy; C 3 -C 8 alkynyl, substituted with halo or hydroxy, or -(CH 2 ) t (C 6 -C 10 aryl), -(CH 2 ) t (5-10 membered heteroaryl), -(CH 2 ) t (C 3 -C 10 cycloalkyl), or -(CH 2 ) t (4-10 membered heterocyclyl), wherein t is an integer between 0 and 8, each of which is substituted by
  • substituted amino groups include, but are not limited to, -NR 39 -C 1 -C 8 alkyl, -NR 39 -(CH 2) t (C 6 -C 10 aryl), -NR 39 -(CH 2 ) t (5-10 membered heteroaryl), -NR 39 - (CH 2 ) t (C 3 -C 10 cycloalkyl), and -NR 39 -(CH 2 ) t (4-10 membered heterocyclyl), wherein t is an integer from 0 to 4, for instance 1 or 2, each R 39 independently represents hydrogen or C 1 -C 8 alkyl; and any alkyl groups present, may themselves be substituted by halo, substituted or unsubstituted amino, or hydroxy; and any aryl, heteroaryl, cycloalkyl, or heterocyclyl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C
  • substituted amino includes the groups alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino as defined below.
  • Substituted amino encompasses both monosubstituted amino and disubstituted amino groups.
  • Carbamoyl or “amido” refers to the radical-C(O)NH 2 .
  • Substituted carbamoyl or “substituted amido” refers to the radical -C(O)N(R 62 ) 2 wherein each R 62 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued
  • R 62 is selected from H, C 1 -C 8 alkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl, and 5-10 membered heteroaryl; or C 1 -C 8 alkyl substituted with halo or hydroxy; or C 3 -C 10 cycloalkyl, 4-10 membered heterocyclyl, C 6 - C 10 aryl, or 5-10 membered heteroaryl, each of which is substituted by unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4
  • Carboxy refers to the radical -C(O)OH.
  • Haldroxy refers to the radical-OH.
  • Niro refers to the radical -NO 2 .
  • Ethylene refers to substituted or unsubstituted -(C-C)-.
  • Ethynyl refers to
  • Nonrogen-containing heterocyclyl means a 4- to 7- membered non-aromatic cyclic group containing at least one nitrogen atom, for example, but without limitation, morpholine, piperidine ⁇ e.g.2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g.2- pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2- pyrazoline, pyrazolidine, piperazine, and N-alkyl piperazines such as N-methyl piperazine. Particular examples include azetidine, piperidone and piperazone.
  • Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are optionally substituted, e.g., "substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, "substituted” or “unsubstituted” alkynyl, "substituted” or “unsubstituted” carbocyclyl, "substituted” or “unsubstituted” heterocyclyl, "substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group).
  • substituted means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • a "substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
  • substituted is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound.
  • the present invention contemplates any and all such combinations in order to arrive at a stable compound.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
  • Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, - NO 2 , -N 3 , -SO 2 H, -SO 3 H, -OH, -OR aa ,-ON(R bb ) 2 , -N(R bb ) +
  • each instance of is, independently, selected from C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, or two R aa groups are joined to form a 3-14 membered heterocyclyl or 5- 14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;
  • each instance of R cc is, independently, selected from hydrogen, C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, or two R cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;
  • each instance of R dd is, independently, selected from halogen, -CN, -NO 2 , -N 3 , -SO 2 H, - SO 3 H, -OH, -OR ee ,-ON(R ff ) 2 , -N(R ff ) 2 ,-N(R ff ) +
  • each instance of R ee is, independently, selected from C 1-3 , alkyl, C 1-3 , perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocyclyl, C 6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups; each instance of R ff is, independently, selected from hydrogen, C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, or two R ff groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered hetero
  • each instance of R gg is, independently, halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -OH, - OC 1-6 alkyl,-ON(C 1-6 alkyl) 2 , -N(C 1-6 alkyl) 2 , -N(C 1-6 alkyl) +
  • a "counterion” or “anionic counterion” is a negatively charged group associated with a cationic quaternary amino group in order to maintain electronic neutrality.
  • exemplary counterions include halide ions (e.g., F-, Cl-, Br-, I-), NO - 3 , ClO - 4 , OH-, HPO - 4 , HSO - 4 , sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10- camphor sulfonate, naphthalene-2-sulfonate, naphthalene-l-sulfonic acid-5-sulfonate, ethan-l- sulfonic acid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate, ethanoate, propan
  • Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms.
  • the substituent present on a nitrogen atom is an amino protecting group (also referred to herein as a nitrogen protecting group).
  • Amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • the substituent present on an oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group).
  • Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • oxygen protecting groups include, but are not limited to, methyl,
  • methoxylmethyl (MOM), 2-methoxyethoxymethyl (MEM), benzyl (Bn), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBDMS), t-butylmethoxyphenylsilyl (TBMPS), methanesulfonate
  • MOM methoxylmethyl
  • MEM 2-methoxyethoxymethyl
  • Bn benzyl
  • TIPS triisopropylsilyl
  • TDMS t-butyldimethylsilyl
  • TMPS t-butylmethoxyphenylsilyl
  • the substituent present on an sulfur atom is an sulfur protecting group (also referred to as a thiol protecting group).
  • Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • modulation refers to the inhibition or potentiation of GABA receptor function.
  • a “modulator” e.g., a modulator compound
  • “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts.
  • such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,
  • ethanesulfonic acid 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum i
  • Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • pharmaceutically acceptable cation refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like. See, e.g., Berge, el al., J. Pharm. Sci. (1977) 66(1): 1-79.
  • Solidvate refers to forms of the compound that are associated with a solvent or water (also referred to as "hydrate”), usually by a solvolysis reaction. This physical association includes hydrogen bonding.
  • solvents include water, ethanol, acetic acid, and the like.
  • the compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated.
  • Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • “Solvate” encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates.
  • isotopic variant refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound.
  • an “isotopic variant” of a compound can contain one or more non-radioactive isotopes, such as for example, deuterium ( 2 H or D), carbon-13 ( 13 C), nitrogen-15 ( 15 N), or the like.
  • non-radioactive isotopes such as for example, deuterium ( 2 H or D), carbon-13 ( 13 C), nitrogen-15 ( 15 N), or the like.
  • the following atoms, where present may vary, so that for example, any hydrogen may be 2 H/D, any carbon may be 13 C, or any nitrogen may be 15 N, and that the presence and placement of such atoms may be determined within the skill of the art.
  • the invention may include the preparation of isotopic variants with radioisotopes, in the instance for example, where the resulting compounds may be used for drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e., 3 H, and carbon-14, i.e., 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • compounds may be prepared that are substituted with positron emitting isotopes, such as 11 C, 18 F, 15 O, and 13 N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • Steps It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.”Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non superimposable mirror images of each other are termed “enantiomers.” When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)- isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".
  • Tautomers refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of n electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
  • a "subject" to which administration is contemplated includes, but is not limited to, a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or a non- human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs.
  • the subject is a human.
  • the subject is a non-human animal.
  • treatment contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition ("therapeutic treatment”), and also contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition ("prophylactic treatment").
  • the "effective amount" of a compound refers to an amount sufficient to elicit the desired biological response, e.g., to treat a CNS-related disorder, is sufficient to induce anesthesia or sedation.
  • the effective amount of a compound of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject.
  • An effective amount encompasses therapeutic and prophylactic treatment.
  • a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition.
  • a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition.
  • the term "therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.
  • a prophylactically effective amount of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent its recurrence.
  • a prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease, disorder or condition.
  • the term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
  • R 1A and R 1B are according to (i) or (ii) as follows:
  • R 1A is hydrogen and R 1B is -OR 30 , or
  • R 4 is N(R 31 ) 2 or halogen
  • each instance of R 30 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; each instance of R 31 is independently hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl, heterocyclyl, aryl, heteroaryl, amine, nitrate, nitrite, thiol, thioether, thioester, sulfate, sulfite, disulfide, sulfoxide, phosphate, phosphate ester, thiophosphate, thiophosphate ester, phosphonate, phosphonate ester, thiophosphonate, thiophosphonate ester, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R 31
  • each instance of R 32 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and R 33 is absent or H.
  • R 4 is halogen
  • R 5 is not H; R 23 is not alkyl; and R 28 is not H. In certain embodiments, R 5 is not H. In certain embodiments, R 23 is not alkyl In certain embodiments, R 28 is not H. In certain embodiments, R 5 is not H and R 23 is not alkyl In certain embodiments, R 5 is not H and R 28 is not H. In certain embodiments, R 23 is not alkyl and R 28 is not H. In certain embodiments, R 5 is not H, R 23 is not alkyl, and R 28 is not H.
  • R 33 is H. In certain embodiments, R 33 is in an alpha
  • R 33 is H in an alpha stereochemical position.
  • R 23 is methyl. In certain embodiments, R 23 is H.
  • R 5 is methyl. In certain embodiments, R 5 is H.
  • R 28 is H. In certain embodiments, R 28 is an optionally substituted heteroaryl. In certain embodiments, R 28 is an optionally substituted pyrazole. In certain embodiments, R 28 is a heteroaryl substituted with–CN. In certain embodiments, R 28 has the following structure:
  • R 5 is not H, and R 28 is H.
  • the compound of formula (I) is represented by a structure of one of formulas (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (I-9), (I-10), (I-11), (I-12), (I-13), (I- 14), (I-15), (I-16), (I-17), (I-18), (I-19), (I-20), (I-21), (I-22), (I-23), (I-24), (I-25), (I-26), (I-27), (I-28), (I-29), (I-30), (I-31), and (I-32):
  • the compound of formula (I) is represented by a structure of one of formulas (I-1a), (I-2a), (I-3a), (I-4a), (I-5a), (I-6a), (I-7a), (I-8a), (I-9a), (I-10a), (I-11a), (I- 12a), (I-13a), (I-14a), (I-15a), (I-16a), (I-17a), (I-18a), (I-19a), (I-20a), (I-21a), (I-22a), (I-23a), (I-24a), (I-25a), (I-26a), (I-27a), (I-28a), (I-29a), (I-30a), (I-31a), and (I-32a):
  • compositions may contain one or more compounds that modulate the activity of a receptor and/or ion channel on a cell, such as a neuron.
  • the compound may stimulate or inhibit activity of a receptor and/or ion channel on a neuron.
  • the target of the compound may be a GABA receptor, e.g., a GABA A receptor or GABA B receptor, a NMDA receptor, pregnane xenobiotic receptor (PXR), a serotonin receptor, a sigma-1 receptor, a transient receptor potential (TRP) channel, e.g., a TRPC channel, TRPV channel, TRPM channel, or TRPA channel, or a voltage-gated calcium channel (VGC), e.g., a L-type VGCC.
  • the compound may modulate, e.g., stimulate or inhibit, the activity of one or more subtypes of GABA receptors.
  • the composition may modulate the activity of one or more of a1b1g2, a1b2g2, a1b3g2, a2b1g2, a2b2g2, a2b3g2, a3b1g2, a3b2g2, a3b3g2, a4b1g2, a4b3d, a4b3g2, a5b1g2, a5b2g2, a5b3g2, a6b1g2, a6b2g2, and a6b3g2 GABA receptors.
  • the compound may preferentially modulate the activity of one or more subtypes of GABA receptors, such as those described above, over one or more other subtypes of GABA receptors.
  • the composition may preferentially modulate the activity of a4b3d GABA receptors over a1b2g2 GABA receptors.
  • composition may contain the compound in a therapeutically effective amount to modulate, e.g., stimulate or inhibit, the activity of any receptor or subtype of receptor described above.
  • funtumine has a structure encompassed by formula (I-1)
  • funtumidine has a structure encompassed by formula (I-2).
  • Funtumine, funtumidine, and related compounds are described in, for example, U.S.
  • compositions containing one or more of the compounds described above may be in a form suitable for oral use, for example, as tablets, troches, lozenges, fast-melts, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the compounds in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration in the stomach and absorption lower down in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in U.S. Patent Nos.4,256,108; 4,166,452; and 4,265,874, the contents of which are incorporated herein by reference, to form osmotic therapeutic tablets for control release. Preparation and administration of compounds is discussed in U.S. Patent No.6,214,841 and U.S. Pub. No.2003/0232877, the contents of which are incorporated herein by reference.
  • Formulations for oral use may also be presented as hard gelatin capsules in which the compounds are mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the compounds are mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example calcium carbonate, calcium phosphate or kaolin
  • an oil medium for example peanut oil, liquid paraffin or olive oil.
  • An alternative oral formulation where control of gastrointestinal tract hydrolysis of the compound is sought, can be achieved using a controlled-release formulation, where a compound of the invention is encapsulated in an enteric coating.
  • Aqueous suspensions may contain the compounds in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such a polyoxyethylene with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate.
  • suspending agents for example sodium carboxymethylcellulose, methylcellulose
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or n-propyl p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • flavoring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • sweetening agents such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the compounds in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the compounds in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent, suspending agent and one or more preservatives Suitable dispersing or wetting agents and suspending agents are exemplified, for example sweetening, flavoring and coloring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and agents for flavoring and/or coloring.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be in a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the formulation is not a sustained release formulation. In certain embodiments, the formulation is not injectable. In certain embodiments, the formulation does not contain particles having a D50 (volume weighted median diameter) of less than 10 microns. In certain embodiments, the formulation does not contain a polymer surface stabilizer. In certain embodiments, the formulation is not an aqueous suspension. Treatment of CNS disorders
  • compositions of the invention are useful for treating CNS disorders that are associated with, or can be ameliorated by, alteration of activity of a GABA A receptor.
  • GABA A receptors are responsible for most of the physiological activities of GABA in the central nervous system.
  • GABA A receptors are generally pentamers that include various combinations of a, b, and g subunits, but the minimal requirement to produce a GABA-gated ion channel is the inclusion of an a and a b subunit.
  • GABA A receptors may include other subunits as well, and the arrangement of subunits within the pentamer can vary. Moreover, there are multiple members of each subunit family, making a vast number of potential combinations to yield functional receptors.
  • GABA A receptors can vary between cell bodies and dendrites.
  • the structure and function of GABA A receptors are described in, for example, Sigel E., and Steinmann, M.E., Structure, Function, and Modulation of GABA A Receptors, J. Biol. Chem.287:48 pp.40224-402311 (2012), doi: 10.1074/jbc.R112.386664, the contents of which are incorporated herein by reference.
  • Modulation of GABA A receptor activity is useful for treatment of a variety of CNS diseases, disorders, and condition.
  • the CNS-related disease, disorder, or condition may be acute pain, an addictive disorder, Alzheimer’s disease, Angelman's syndrome, anti-social personality disorder, an anxiety disorder, attention deficit hyperactivity disorder (ADHD), an attention disorder, an auditory disorder, autism, an autism spectrum disorder, bipolar disorder, chronic pain, a cognitive disorder, a compulsive disorder, a convulsive disorder, dementia, depression, dysthymia, an epileptic disorder, essential tremor,
  • epileptogenesis fragile X syndrome, generalized anxiety disorder (GAD), Huntington’s disease, injury related pain syndrome, insomnia, ischemia, Lewis body type dementia, a memory disorder, migraines, a mood disorder, movement disorder, a neurodegenerative disease, neuropathic pain, an obsessive compulsive disorder, pain, a panic disorder, Parkinson’s disease, a personality disorder, posttraumatic stress disorder (PTSD), psychosis, Rett syndrome, a schizoaffective disorder, schizophrenia, a schizophrenia spectrum disorder, a seizure disorder, a sleep disorder, social anxiety disorder, status epilepticus, stress, stroke, tinnitus, traumatic brain injury (TBI), vascular disease, vascular malformation, vascular type dementia movement disorder, Wilson's disease, or withdrawal syndrome.
  • GAD generalized anxiety disorder
  • Huntington Huntington’s disease
  • injury related pain syndrome insomnia
  • insomnia ischemia
  • Lewis body type dementia a memory disorder, migraines
  • a mood disorder movement disorder
  • the methods of treating a subject having a CNS disease, disorder, or condition include providing a composition of the invention, as described above, to the subject.
  • Providing may include administering the composition to the subject.
  • the composition may be administered by any suitable means, such as orally, intravenously, enterally, parenterally, dermally, buccally, topically (including transdermally), by injection, nasally, pulmonarily, and with or on an implantable medical device (e.g., stent or drug-eluting stent or balloon equivalents).
  • an implantable medical device e.g., stent or drug-eluting stent or balloon equivalents.
  • the composition is provided orally.
  • the composition may be provided under any suitable dosing regimen.
  • the composition may be provided as a single dose or in multiple doses. Multiple doses may be provided in provided separated by intervals, such as 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, or more. Multiple doses may be provided within a period of time. For example, multiple doses may be provided over a period of 1 day, 2 days, 3 days, 4 days, 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, or more.
  • the compositions may be provided repeatedly for a specified duration. For example and without limitation, the compositions may be provided for 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 12 weeks, 3 months, 4 months, 5 months, 6 months, 8 months, 10 months, 12 months or more. Examples
  • Compounds of the invention were analyzed for activity as positive allosteric modulators and antagonists against the following human GABA A receptors.
  • Compounds were tested in fluorometric imaging plate reader (FLIPR) assays at seven concentrations against the following human GABA A receptors: a1b1g2, a1b2g2, a1b3g2, a2b1g2, a2b2g2, a2b3g2, a3b1g2, a3b2g2, a3b3g2, a4b1g2, a4b3d, a4b3g2, a5b1g2, a5b2g2, a5b3g2, a6b1g2, a6b2g2 and a6b3g2.
  • FLIPR fluorometric imaging plate reader
  • Human GABA cells were trypsinized, counted, and seeded in black, clear-bottomed 96 well plates at a density of 25,000 cells per well and incubated for 24 hours. After 24 hours cells were induced with 1 ⁇ g/ml tetracycline and incubated overnight. Next day, media was removed from cell plates before adding 70 ⁇ l assay buffer (25 mM HEPES: HBSS, pH 7.4). Red membrane potential dye solution (10 ⁇ l) was added to the wells and incubated at room temperature for 60 minutes. Dye solution was made up in assay buffer. Compound dilutions (including serial dilutions) were performed in 100% DMSO then transferred to intermediate dilutions for a very limited amount of time ( ⁇ 10 minutes) just before adding to the cell plate.
  • 70 ⁇ l assay buffer 25 mM HEPES: HBSS, pH 7.4
  • Red membrane potential dye solution (10 ⁇ l) was added to the wells and incubated at room temperature for 60 minutes
  • test compounds were added to the wells and incubated at room temperature for 10 minutes. Allopregnanolone was used as a reference compound. The plates were then placed in the FLIPR and fluorescence monitored every 1.52 seconds. After 20 seconds 10 ⁇ l of the GABA at approximately EC 20 was added and the fluorescence monitored for 5 minutes at ex/emm: 488 nm/510- 570 nm.
  • test compounds were added to the wells and incubated at room temperature for 10 minutes. Picrotoxin was use as a reference compound. The plates were then placed in the FLIPR and fluorescence monitored every 1.52 seconds. After 20 seconds 10 ⁇ l of the GABA at approximately EC 80 was added and the fluorescence monitored for 5 minutes at ex/emm: 488 nm/510- 570 nm.
  • the compounds were tested against GABA A a1b1g2, a1b2g2, a1b3g2, a2b1g2, a2b2g2, a2b3g2, a3b1g2, a3b2g2, a3b3g2, a4b1g2, a4b3d, a4b3g2, a5b1g2, a5b2g2, a5b3g2, a6b1g2, a6b2g2, and a6b3g2 in the FLIPR assay at 0.01, 0.03, 0.1, 0.3, 1.0, 3.0 and 10 ⁇ M in duplicate.
  • the no-compound data point was included on the graph at the concentration point of 3 nM.
  • FIG.1 shows graphs of EC 50 dose response curves for compounds against GABA A a1b1g2. Dose response curves and EC 50 values were generated by Prism software (GraphPad Inc.). R.F.U. denotes relative fluorescent units.
  • FIG.2 shows graphs of IC 50 dose response curves for compounds against GABA A a1b1g2. Dose response curves and EIC 50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
  • FIG.3 shows graphs of EC 50 dose response curves for compounds against GABA A a1b2g2. Dose response curves and EC 50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
  • FIG.4 shows graphs of IC 50 dose response curves for compounds against GABA A a1b2g2. Dose response curves and EIC 50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
  • FIG.5 shows graphs of EC 50 dose response curves for compounds against GABA A a1b3g2. Dose response curves and EC 50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
  • FIG.6 shows graphs of IC 50 dose response curves for compounds against GABA A a1b3g2. Dose response curves and EIC 50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
  • FIG.7 shows graphs of EC 50 dose response curves for compounds against GABA A a2b1g2. Dose response curves and EC 50 values were generated by Prism software. R.F.U. denotes relative fluorescent units. The datapoints at 10 ⁇ M and 1 ⁇ M for allopregnanolone were excluded from the final analysis as they were deemed to be outliers.
  • FIG.8 shows graphs of IC 50 dose response curves for compounds against GABA A a2b1g2. Dose response curves and EIC 50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
  • FIG.9 shows graphs of EC 50 dose response curves for compounds against GABA A a2b2g2. Dose response curves and EC 50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
  • FIG.10 shows graphs of IC 50 dose response curves for compounds against GABA A a2b2g2. Dose response curves and EIC 50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
  • FIG.11 shows graphs of EC 50 dose response curves for compounds against GABA A a2b3g2. Dose response curves and EC 50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
  • FIG.12 shows graphs of IC 50 dose response curves for compounds against GABA A a2b3g2. Dose response curves and EIC 50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
  • FIG.13 shows graphs of EC 50 dose response curves for compounds against GABA A a3b1g2. Dose response curves and EC 50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
  • FIG.14 shows graphs of IC 50 dose response curves for compounds against GABA A a3b1g2. Dose response curves and EIC 50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
  • FIG.15 shows graphs of EC 50 dose response curves for compounds against GABA A a3b2g2. Dose response curves and EC 50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
  • FIG.16 shows graphs of IC 50 dose response curves for compounds against GABA A a3b2g2. Dose response curves and EIC 50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
  • FIG.17 shows graphs of EC 50 dose response curves for compounds against GABA A a3b3g2. Dose response curves and EC 50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
  • FIG.18 shows graphs of IC 50 dose response curves for compounds against GABA A a3b3g2. Dose response curves and EIC 50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
  • FIG.19 shows graphs of EC 50 dose response curves for compounds against GABA A a4b1g2. Dose response curves and EC 50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
  • FIG.20 shows graphs of IC 50 dose response curves for compounds against GABA A a4b1g2. Dose response curves and EIC 50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
  • FIG.21 shows graphs of EC 50 dose response curves for compounds against GABA A a4b3d. Dose response curves and EC 50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
  • FIG.22 shows graphs of IC 50 dose response curves for compounds against GABA A a4b3d. Dose response curves and EIC 50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
  • FIG.23 shows graphs of EC 50 dose response curves for compounds against GABA A a5b1g2. Dose response curves and EC 50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
  • FIG.24 shows graphs of IC 50 dose response curves for compounds against GABA A a5b1g2. Dose response curves and EIC 50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
  • FIG.25 shows graphs of IC 50 dose response curves for compounds against GABA A a5b2g2. Dose response curves and EIC 50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
  • FIG.26 shows graphs of EC 50 dose response curves for compounds against GABA A a5b3g2. Dose response curves and EC 50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
  • FIG.27 shows graphs of IC 50 dose response curves for compounds against GABA A a5b3g2. Dose response curves and EIC 50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
  • FIG.28 shows graphs of EC 50 dose response curves for compounds against GABA A a6b1g2. Dose response curves and EC 50 values were generated by Prism software. R.F.U. denotes relative fluorescent units. The datapoint at 10 ⁇ M for allopregnanolone was excluded from the final analysis as it was deemed to be an outlier.
  • FIG.29 shows graphs of IC 50 dose response curves for compounds against GABA A a6b1g2. Dose response curves and EIC 50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
  • FIG.30 shows graphs of IC 50 dose response curves for compounds against GABA A a6b2g2. Dose response curves and EIC 50 values were generated by Prism software. R.F.U. denotes relative fluorescent units. Conclusions

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Abstract

The invention provides steroid compounds with altered pharmacological properties and methods of using the compounds to treat a condition in a subject.

Description

STEROIDS WITH ALTERED PHARMACOKINETIC PROPERTIES
AND METHODS OF USE THEREOF Cross-Reference to Related Applications
This application claims the benefit of, and priority to, U.S. Provisional Patent Application No.62/860,910, filed June 13, 2019, and U.S. Provisional Patent Application No.62/866,890, filed June 26, 2019, the contents of each which are incorporated by reference. Field of the Invention
The invention generally relates to compositions containing steroids with altered pharmacokinetic properties and methods of using the same. Background
According the World Health Organization (WHO), neurological disorders affect up to one billion people worldwide. Neurological disorders include a wide range of conditions, such as Alzheimer's disease, brain injuries, epilepsy, headache, infections, multiple sclerosis, and Parkinson's disease, and stroke.
Neuroactive steroids hold promise for treatment of a variety of neurological disorders. Such steroids alter neuronal excitability through interaction with ligand-gated ion channels and other cell surface receptors. For example, several neuroactive steroids have been identified as either positive or negative modulators of receptors for the neurotransmitter gamma-aminobutyric acid (GABA). Accordingly, steroids that target GABA receptors have been investigated for treatment of disorders associated with altered GABA signaling. Steroids that target receptors for the neurotransmitter N-methyl-D-aspartate (NMDA) have also been examined as therapeutic candidates for central nervous system (CNS) conditions.
Nonetheless, the potential for using neuroactive steroids to treat neurological disorders remains largely untapped. One reason for the shortfall is that the large number of chemical variants that can be made from the steroid structural core makes it difficult to know whether compounds currently being investigated have superior pharmacological properties to other molecules that have not yet been made or analyzed. Another issue is that efforts to date have focused on compounds that modulate receptors for GABA or NMDA, while other targets have received less attention. Moreover, the targets for some endogenous neurosteroids are unknown. It is therefore likely that synthetic steroids with advantageous pharmacological properties remain to be identified. Consequently, millions of people continue to suffer from neurological conditions due to the limited arsenal of neuroactive steroids currently at our disposal. Summary
The invention provides compositions that contain neurosteroids having altered, e.g., improved, potency, bioavailability, and pharmacokinetic properties. The invention recognizes that compounds having a steroid structural core and containing substituents at certain positions are effective at modulating various receptors that affect neuronal signaling. Consequently, the compositions of the invention are useful for treating a variety of neurological disorders. The invention also provides methods of using such compositions to treat neurological disorders.
In an aspect, the invention provides compositions containing a compound of formula (I):
Figure imgf000003_0001
wherein:
R1A and R1B are according to (i) or (ii) as follows:
(i) R1A is hydrogen and R1B is -OR30, or (ii) R1A and R1B together are =O;
each of R2 and R3 is independently hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, - S(=O)R32, -SO2R32, -S(=O)2OR31, or R2 and R3 together are =NR31 or =S;
R4 is N(R31)2 or halogen;
R5 is hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, - N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, -S(=O)R32, -SO2R32, or -S(=O)2OR31;
each of R6, R7, R8, and R9, is independently hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, - S(=O)R32, -SO2R32, or -S(=O)2OR31;
each of R10 and R11 is independently hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, - S(=O)R32, -SO2R32, -S(=O)2OR31, or R10 and R11 together are =NR31 or =S;
each of R12 and R13 is independently hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, - S(=O)R32, -SO2R32, -S(=O)2OR31, or R12 and R13 together are =NR31 or =S;
each of R14 and R15 is independently absent, hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, - S(=O)R32, -SO2R32, -S(=O)2OR31, or R14 and R15 together are =NR31 or =S; each of R16 and R17 is independently absent, hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, - S(=O)R32, -SO2R32, -S(=O)2OR31, or R16 and R17 together are =NR31 or =S;
each of R18 and R19 is independently hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, - S(=O)R32, -SO2R32, -S(=O)2OR31, or R18 and R19 together are =NR31 or =S;
each of R20 and R21 is independently absent, hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, - S(=O)R32, -SO2R32, -S(=O)2OR31, or R14 and R15 together are =NR31 or =S;
R22 is absent, hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, - SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, -S(=O)R32, -SO2R32, or -S(=O)2OR31;
R23 is hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, - N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, -S(=O)R32, -SO2R32, or -S(=O)2OR31;
each of R24 and R25 is independently hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, - S(=O)R32, -SO2R32, or -S(=O)2OR31, or R24 and R25 together are =O;
each of R26 and R27 is independently hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, - S(=O)R32, -SO2R32, -S(=O)2OR31, or R20 and R21 together are =NR31 or =S;
R28 is hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, - N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, -S(=O)R32, -SO2R32, or -S(=O)2OR31;
each instance of R30 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; each instance of R31 is independently hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl, heterocyclyl, aryl, heteroaryl, amine, nitrate, nitrite, thiol, thioether, thioester, sulfate, sulfite, disulfide, sulfoxide, phosphate, phosphate ester, thiophosphate, thiophosphate ester, phosphonate, phosphonate ester, thiophosphonate, thiophosphonate ester, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R31 groups are joined to form an heterocyclic or heteroaryl ring;
each instance of R32 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and R33 is absent or H.
In certain embodiments, if R1A is hydrogen and R1B is -OR30, then R4 is halogen.
In certain embodiments, at least one of the following is true: R5 is not H; R23 is not alkyl; and R28 is not H. In certain embodiments, R5 is not H. In certain embodiments, R23 is not alkyl In certain embodiments, R28 is not H. In certain embodiments, R5 is not H and R23 is not alkyl In certain embodiments, R5 is not H and R28 is not H. In certain embodiments, R23 is not alkyl and R28 is not H. In certain embodiments, R5 is not H, R23 is not alkyl, and R28 is not H.
In certain embodiments, R33 is H. In certain embodiments, R33 is in an alpha
stereochemical position. In certain embodiments, R33 is H in an alpha stereochemical position.
In certain embodiments, R23 is methyl. In certain embodiments, R23 is H.
In certain embodiments, R5 is methyl. In certain embodiments, R5 is H.
In certain embodiments, R28 is H. In certain embodiments, R28 is an optionally substituted heteroaryl. In certain embodiments, R28 is an optionally substituted pyrazole. In certain embodiments, R28 is a heteroaryl substituted with–CN. In certain embodiments, R28 has the following structure:
Figure imgf000007_0001
. In certain embodiments, R5 is not H, and R28 is H.
In certain embodiments, the compound of formula (I) is represented by a structure of one of formulas (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (I-9), (I-10), (I-11), (I-12), (I-13), (I- 14), (I-15), (I-16), (I-17), (I-18), (I-19), (I-20), (I-21), (I-22), (I-23), (I-24), (I-25), (I-26), (I-27), (I-28), (I-29), (I-30), (I-31), and (I-32):
Figure imgf000007_0002
Figure imgf000008_0001
Figure imgf000009_0001
Figure imgf000010_0001
Figure imgf000011_0001
, In certain embodiments, the compound of formula (I) is represented by a structure of one of formulas (I-1a), (I-2a), (I-3a), (I-4a), (I-5a), (I-6a), (I-7a), (I-8a), (I-9a), (I-10a), (I-11a), (I- 12a), (I-13a), (I-14a), (I-15a), (I-16a), (I-17a), (I-18a), (I-19a), (I-20a), (I-21a), (I-22a), (I-23a), (I-24a), (I-25a), (I-26a), (I-27a), (I-28a), (I-29a), (I-30a), (I-31a), and (I-32a):
Figure imgf000011_0002
Figure imgf000012_0001
Figure imgf000013_0001
Figure imgf000014_0001
The composition may modulate activity of a gamma-aminobutyric acid (GABA) receptor. The composition may stimulate GABA receptor activity, or it may inhibit GABA receptor activity. The composition may modulate, e.g., stimulate or inhibit, activity of a GABAA receptor. The composition may modulate the activity of one or more subtypes of GABA receptors, such as a1b1g2, a1b2g2, a1b3g2, a2b1g2, a2b2g2, a2b3g2, a3b1g2, a3b2g2, a3b3g2, a4b1g2, a4b3d, a4b3g2, a5b1g2, a5b2g2, a5b3g2, a6b1g2, a6b2g2, and a6b3g2 GABA receptors. The composition may preferentially modulate the activity of one or more subtypes of GABA receptors, such as those described above, over one or more other subtypes of GABA receptors. The composition may preferentially modulate the activity of a4b3d GABA receptors over a1b2g2 GABA receptors.
The compositions may be effective for treating a condition, such as a central nervous system (CNS) condition, in a subject. The composition may be effective for treating one or more of acute pain, an addictive disorder, Alzheimer’s disease, Angelman's syndrome, anti-social personality disorder, an anxiety disorder, attention deficit hyperactivity disorder (ADHD), an attention disorder, an auditory disorder, autism, an autism spectrum disorder, bipolar disorder, chronic pain, a cognitive disorder, a compulsive disorder, a convulsive disorder, dementia, depression, dysthymia, an epileptic disorder, essential tremor, epileptogenesis, fragile X syndrome, generalized anxiety disorder (GAD), Huntington’s disease, injury related pain syndrome, insomnia, ischemia, Lewis body type dementia, a memory disorder, migraines, a mood disorder, movement disorder, a neurodegenerative disease, neuropathic pain, an obsessive compulsive disorder, pain, a panic disorder, Parkinson’s disease, a personality disorder, posttraumatic stress disorder (PTSD), psychosis, Rett syndrome, a schizoaffective disorder, schizophrenia, a schizophrenia spectrum disorder, a seizure disorder, a sleep disorder, social anxiety disorder, status epilepticus, stress, stroke, tinnitus, traumatic brain injury (TBI), vascular disease, vascular malformation, vascular type dementia movement disorder, Wilson's disease, and withdrawal syndrome.
In another aspect, the invention provides methods of treating a neurological condition in a subject by providing to the subject a compound of formula (I).
The composition may modulate activity of a gamma-aminobutyric acid (GABA) receptor. The composition may increase GABA receptor activity, or it may inhibit GABA receptor activity. The composition may modulate, e.g., increase or decrease, activity of a GABAA receptor. The composition may modulate the activity of one or more subtypes of GABA receptors, such as a1b1g2, a1b2g2, a1b3g2, a2b1g2, a2b2g2, a2b3g2, a3b1g2, a3b2g2, a3b3g2, a4b1g2, a4b3d, a4b3g2, a5b1g2, a5b2g2, a5b3g2, a6b1g2, a6b2g2, and a6b3g2 GABA receptors. The composition may preferentially modulate the activity of one or more subtypes of GABA receptors, such as those described above, over one or more other subtypes of GABA receptors. For example, the composition may preferentially modulate the activity of a4b3d GABA receptors over a1b2g2 GABA receptors.
The neurological condition may be any condition, such as any of those described above. The compound may have any of the structural elements described above. The compound may be represented by any of the formulas described above. Brief Description of the Drawings
FIG.1 shows graphs of EC50 dose response curves for compounds against GABAA a1b1g2.
FIG.2 shows graphs of IC50 dose response curves for compounds against GABAA a1b1g2.
FIG.3 shows graphs of EC50 dose response curves for compounds against GABAA a1b2g2.
FIG.4 shows graphs of IC50 dose response curves for compounds against GABAA a1b2g2.
FIG.5 shows graphs of EC50 dose response curves for compounds against GABAA a1b3g2.
FIG.6 shows graphs of IC50 dose response curves for compounds against GABAA a1b3g2.
FIG.7 shows graphs of EC50 dose response curves for compounds against GABAA a2b1g2.
FIG.8 shows graphs of IC50 dose response curves for compounds against GABAA a2b1g2.
FIG.9 shows graphs of EC50 dose response curves for compounds against GABAA a2b2g2.
FIG.10 shows graphs of IC50 dose response curves for compounds against GABAA a2b2g2. FIG.11 shows graphs of EC50 dose response curves for compounds against GABAA a2b3g2.
FIG.12 shows graphs of IC50 dose response curves for compounds against GABAA a2b3g2.
FIG.13 shows graphs of EC50 dose response curves for compounds against GABAA a3b1g2.
FIG.14 shows graphs of IC50 dose response curves for compounds against GABAA a3b1g2.
FIG.15 shows graphs of EC50 dose response curves for compounds against GABAA a3b2g2.
FIG.16 shows graphs of IC50 dose response curves for compounds against GABAA a3b2g2.
FIG.17 shows graphs of EC50 dose response curves for compounds against GABAA a3b3g2..
FIG.18 shows graphs of IC50 dose response curves for compounds against GABAA a3b3g2.
FIG.19 shows graphs of EC50 dose response curves for compounds against GABAA a4b1g2.
FIG.20 shows graphs of IC50 dose response curves for compounds against GABAA a4b1g2.
FIG.21 shows graphs of EC50 dose response curves for compounds against GABAA a4b3d.
FIG.22 shows graphs of IC50 dose response curves for compounds against GABAA a4b3d.
FIG.23 shows graphs of EC50 dose response curves for compounds against GABAA a5b1g2.
FIG.24 shows graphs of IC50 dose response curves for compounds against GABAA a5b1g2.
FIG.25 shows graphs of IC50 dose response curves for compounds against GABAA a5b2g2. FIG.26 shows graphs of EC50 dose response curves for compounds against GABAA a5b3g2.
FIG.27 shows graphs of IC50 dose response curves for compounds against GABAA a5b3g2.
FIG.28 shows graphs of EC50 dose response curves for compounds against GABAA a6b1g2.
FIG.29 shows graphs of IC50 dose response curves for compounds against GABAA a6b1g2.
FIG.30 shows graphs of IC50 dose response curves for compounds against GABAA a6b2g2. Detailed Description
The invention provides neurosteroids that are effective GABAA receptor modulators and have different pharmacokinetic properties from previously described neurosteroids. The neurosteroids of the invention are therefore useful for treating CNS disorders. Definitions
Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’ s Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition,
Cambridge University Press, Cambridge, 1987.
Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC), supercritical fluid chromatography (SFC), and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The invention additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.
As used herein a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an "S" form of the compound is substantially free from the "R" form of the compound and is, thus, in enantiomeric excess of the "R" form. The term "enantiomerically pure" or "pure enantiomer" denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound.
In the compositions provided herein, an enantiomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure R-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R-compound. In certain embodiments, the enantiomerically pure R- compound in such compositions can, for example, comprise, at least about 95% by weight R- compound and at most about 5% by weight S-compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure S-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound. In certain embodiments, the enantiomerically pure S compound in such compositions can, for example, comprise, at least about 95% by weight S compound and at most about 5% by weight R-compound, by total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier.
Compounds described herein may also comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including 1H, 2H (D or deuterium), and 3H (T or tritium); C may be in any isotopic form, including 12C, 13C, and 14C; N may be any isotopic form, including 14N and 15N; O may be in any isotopic form, including 16O and 18O; and the like.
The articles "a" and "an" may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example "an analogue" means one analogue or more than one analogue.
When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example "C1-6 alkyl" is intended to encompass, C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.
The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention.
"Alkyl" refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms ("C1-20 alkyl"). In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C1-12 alkyl"). In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C1-8 alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C1-6 alkyl", also referred to herein as "lower alkyl"). In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C1-5 alkyl"). In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C1-4 alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C1-3 alkyl"). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C1-2 alkyl"). In some embodiments, an alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C2-6 alkyl"). Examples of C1-6 alkyl groups include methyl (C1), ethyl (C2), n- propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8) and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is unsubstituted C1-10 alkyl (e.g., -CH3). In certain embodiments, the alkyl group is substituted C1-10 alkyl. Common alkyl abbreviations include Me (-CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (- CH2CH2CH3), n-Bu (- CH2CH2CH2CH3), or i-Bu (-CH2CH(CH3)2).
"Alkenyl" refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds ("C2-20 alkenyl"). In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C2-10 alkenyl"). In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C2-8 alkenyl"). In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C2-6 alkenyl"). In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C2-5 alkenyl"). In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C2-4 alkenyl"). In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C2-3 alkenyl"). In some embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as in 2- butenyl) or terminal (such as in 1-butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1- butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkenyl") or substituted (a "substituted alkenyl") with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkenyl group is unsubstituted C2-10 alkenyl. In certain embodiments, the alkenyl group is substituted C2-10 alkenyl.
"Alkynyl" refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds, and optionally one or more double bonds ("C2-20 alkynyl"). In some embodiments, an alkynyl group has 2 to 10 carbon atoms ("C2-10 alkynyl"). In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C2-8 alkynyl"). In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C2-6 alkynyl"). In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C2-5 alkynyl"). In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C2-4 alkynyl"). In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C2-3 alkynyl"). In some embodiments, an alkynyl group has 2 carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2- propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkynyl") or substituted (a "substituted alkynyl") with on or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkynyl group is unsubstituted C2-10 alkynyl. In certain embodiments, the alkynyl group is substituted C2-10 alkynyl.
"Aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6-1 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C6-14 aryl"). In some embodiments, an aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C10 aryl"; e.g., naphthyl such as 1- naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atom ("C14 aryl"; e.g., anthracyl). "Aryl" also includes ring systems wherein the aryl ring, as define above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Aryl groups include, but are not limited to, phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an
"unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents. In certain embodiments, the aryl group is unsubstituted C6-14 aryl. In certain embodiments, the aryl group is substituted C6-14 aryl.
In certain embodiments, an aryl group substituted with one or more of groups selected from halo, C1-C8 alkyl, C1-C8 haloalkyl, cyano, hydroxy, C1-C8 alkoxy, and amino.
Examples of representative substituted aryls include the following:
Figure imgf000023_0001
wherein one of R56 and R57 may be hydrogen and at least one of R56 and R57 is each
independently selected from C1-C8 alkyl, C1-C8 haloalkyl, 4-10 membered heterocyclyl, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR58COR59, NR58SOR59 NR58SO2R59, COOalkyl, COOaryl, CONR58R59, CONR58OR59, NR58R59,
SO2NR58R59, S-alkyl, SOalkyl, SO2alkyl, Saryl, SOaryl, SO2aryl; or R56 and R57 may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O, or S. R60 and R61 are independently hydrogen, C1-C8 alkyl, C1-C4 haloalkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6-C10 aryl, substituted C6-C10 aryl, 5-10 membered heteroaryl, or substituted 5-10 membered heteroaryl.
Other representative aryl groups having a fused heterocyclyl group include the following:
Figure imgf000023_0002
wherein each W is selected from C(R66)2, NR66, O, and S; and each Y is selected from carbonyl, NR66, O and S; and R66 is independently hydrogen, C1-C8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6-C10 aryl, and 5-10 membered heteroaryl.
"Halo" or "halogen," independently or as part of another substituent, mean, unless otherwise stated, a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom. The term "halide" by itself or as part of another substituent, refers to a fluoride, chloride, bromide, or iodide atom. In certain embodiments, the halo group is either fluorine or chlorine.
"Haloalkyl" and "haloalkoxy" can include alkyl and alkoxy structures that are substituted with one or more halo groups or with combinations thereof. For example, the terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine. "Heteroaryl" refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted heteroaryl") or substituted (a "substituted heteroaryl") with one or more substituents. In certain embodiments, the heteroaryl group is unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5-14 membered heteroaryl.
Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containin three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5- membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepi Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl,
benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofura benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic hetero groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
Examples of representative heteroaryls include the following formulae:
Figure imgf000026_0001
wherein each Y is selected from carbonyl, N, NR65, O, and S; and R65 is independently hydrogen, C1-C8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6-C10 aryl, and 5-10 membered heteroaryl.
"Carbocyclyl" or "carbocyclic" refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms ("C3-10 carbocyclyl") and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C3-8 carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C3-6 carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C3-6 carbocyclyl"). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C5-10 carbocyclyl"). Exemplary C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl C6), cyclohexadienyl (C6), and the like. Exemplary C3-6 carbocyclyl groups include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-10 carbocyclyl groups include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or contain a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic carbocyclyl") and can be saturated or can be partially unsaturated. "Carbocyclyl" also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl") with one or more substituents. In certain embodiments, the carbocyclyl group is unsubstituted C3- 10 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-10 carbocyclyl.
In some embodiments, "carbocyclyl" is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms ("C3-10 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C3-8 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C3-6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C5-6, cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C5 10 cycloalkyl"). Examples of C5-6, cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-8 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl") with one or more substituents. In certain embodiments, the cycloalkyl group is unsubstituted C3-10 cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C3-10 cycloalkyl.
"Heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3-10 membered heterocyclyl"). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic ("monocyclic heterocyclyl") or a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic heterocyclyl"), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an
"unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents. In certain embodiments, the heterocyclyl group is unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3-10 membered heterocyclyl.
In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5-10 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-8 membered non- aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.
Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5- membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6- membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
Particular examples of heterocyclyl groups are shown in the following illustrative examples:
Figure imgf000029_0001
wherein each W is selected from CR67, C(R67)2, NR67, O, and S; and each Y is selected from NR67, O, and S; and R67 is independently hydrogen, C1-C8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6-C10 aryl, and 5-10-membered heteroaryl. These heterocyclyl rings may be optionally substituted with one or more groups selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (e.g., amido), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, halogen, hydroxy, keto, nitro, thiol, -S-alkyl, -S aryl, -S(O)-alkyl, -S(O)-aryl, -S(O)2-alkyl, and -S(O)2-aryl. Substituting groups include carbonyl or thiocarbonyl which provide, for example, lactam and urea derivatives.
"Acyl" refers to a radical-C(O)R20, where R20 is hydrogen, substituted or unsubstitued alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstitued heteroaryl, as defined herein. "Alkanoyl" is an acyl group wherein R20 is a group other than hydrogen. Representative acyl groups include, but are not limited to, formyl (-CHO), acetyl (-C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH2Ph),— C(O)-C1-C8 alkyl, -C(O)-(CH2)t(C6-C10 aryl), -C(O)-(CH2)t(5-10 membered heteroaryl), -C(O)- (CH2)t(C3-C10 cycloalkyl), and -C(O)- (CH2)t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4. In certain
embodiments, R21 is C1-C8 alkyl, substituted with halo or hydroxy; or C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6-C10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
"Acylamino" refers to a radical-NR22C(O)R23, where each instance of R22 and R23 is independently hydrogen, substituted or unsubstitued alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstitued heteroaryl,, as defined herein, or R22 is an amino protecting group. Exemplary "acylamino" groups include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino and benzylcarbonylamino. Particular exemplary "acylamino" groups are -NR24C(O)-C1-C8 alkyl, -NR24C(O)-(CH2)t(C6-C10 aryl), - NR24C(O)-(CH2)t(5-10 membered heteroaryl), -NR24C(O)-(CH2)t(C3-C10 cycloalkyl), and - NR24C(O)-(CH2)t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4, and each R24 independently represents hydrogen or C1-C8 alkyl. In certain embodiments, R25 is H, C1-C8 alkyl, substituted with halo or hydroxy; C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6- C10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; and R26 is H, C1-C8 alkyl, substituted with halo or hydroxy; C3-C10 cycloalkyl, 4-10- membered heterocyclyl, C6-C10 aryl, arylalkyl, 5-10-membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; provided at least one of R25 and R26 is other than H.
"Acyloxy" refers to a radical -OC(O)R27, where R27 is hydrogen, substituted or unsubstitued alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstitued heteroaryl, as defined herein. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl,
cyclohexylmethylcarbonyl, benzoyl, and benzylcarbonyl. In certain embodiments, R28 is C1-C8 alkyl, substituted with halo or hydroxy; C3-C10 cycloalkyl, 4-10-membered heterocyclyl, C6-C10 aryl, arylalkyl, 5-10-membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
"Alkoxy" refers to the group -OR29 where R29 is substituted or unsubstituted alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstitued heteroaryl. Particular alkoxy groups are methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2- dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e., with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.
In certain embodiments, R29 is a group that has 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of amino, substituted amino, C6-C10 aryl, aryloxy, carboxyl, cyano, C3- C10 cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10 membered heteroaryl, hydroxy, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2- and aryl-S(O)2- Exemplary "substituted alkoxy" groups include, but are not limited to, -O-(CH2)t(C6-C10 aryl), -O-(CH2)t(5- 10 memberedheteroaryl),-O-(CH2)t(C3-C10 cycloalkyl),and-O-(CH2)t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocyclyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. Particular exemplary "substituted alkoxy" groups are -OCF3,-OCH2CF3,-OCH2Ph,-OCH2-cyclopropyl, -OCH2CH2OH, and - OCH2CH2Nme2.
"Amino" refers to the radical-NH2.
"Substituted amino" refers to an amino group of the formula-N(R38)2 wherein R38 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstitued heteroaryl, or an amino protecting group, wherein at least one of R38 is not a hydrogen. In certain embodiments, each R38 is independently selected from hydrogen, C1-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C6- C10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, or C3-C10 cycloalkyl; or C1-C8 alkyl, substituted with halo or hydroxy; C3-C8 alkenyl, substituted with halo or hydroxy; C3-C8 alkynyl, substituted with halo or hydroxy, or -(CH2)t(C6-C10 aryl), -(CH2)t(5-10 membered heteroaryl), -(CH2)t(C3-C10 cycloalkyl), or -(CH2)t(4-10 membered heterocyclyl), wherein t is an integer between 0 and 8, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; or both R38 groups are joined to form an alkylene group.
Exemplary "substituted amino" groups include, but are not limited to, -NR39-C1-C8 alkyl, -NR39-(CH 2)t(C6-C10 aryl), -NR39-(CH2)t(5-10 membered heteroaryl), -NR39- (CH2)t(C3-C10 cycloalkyl), and -NR39-(CH2)t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4, for instance 1 or 2, each R39 independently represents hydrogen or C1-C8 alkyl; and any alkyl groups present, may themselves be substituted by halo, substituted or unsubstituted amino, or hydroxy; and any aryl, heteroaryl, cycloalkyl, or heterocyclyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. For the avoidance of doubt the term‘substituted amino’ includes the groups alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino as defined below. Substituted amino encompasses both monosubstituted amino and disubstituted amino groups.
"Azido" refers to the radical-N3.
"Carbamoyl" or "amido" refers to the radical-C(O)NH2.
"Substituted carbamoyl" or "substituted amido" refers to the radical -C(O)N(R62)2 wherein each R62 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstitued heteroaryl, or an amino protecting group, wherein at least one of R62 is not a hydrogen. In certain embodiments, R62 is selected from H, C1-C8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6-C10 aryl, and 5-10 membered heteroaryl; or C1-C8 alkyl substituted with halo or hydroxy; or C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6- C10 aryl, or 5-10 membered heteroaryl, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4
hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; provided that at least one R62 is other than H.
"Carboxy" refers to the radical -C(O)OH.
"Cyano" refers to the radical-CN.
"Hydroxy" refers to the radical-OH.
"Nitro" refers to the radical -NO2.
"Ethenyl" refers to substituted or unsubstituted-(C=C)-. "Ethylene" refers to substituted or unsubstituted -(C-C)-. "Ethynyl" refers to
Figure imgf000033_0001
"Nitrogen-containing heterocyclyl" group means a 4- to 7- membered non-aromatic cyclic group containing at least one nitrogen atom, for example, but without limitation, morpholine, piperidine {e.g.2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g.2- pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2- pyrazoline, pyrazolidine, piperazine, and N-alkyl piperazines such as N-methyl piperazine. Particular examples include azetidine, piperidone and piperazone.
Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are optionally substituted, e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl or "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted", whether preceded by the term "optionally" or not, means that at least one hydrogen present on a group ( e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term "substituted" is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound. The present invention contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, - NO2, -N3, -SO2H, -SO3H, -OH, -ORaa,-ON(Rbb)2, -N(Rbb) +
2,-N(Rbb)3 X-,-N(ORcc)Rbb, - SH, -SRaa, - SSRcc,-C(=O)Raa,-CO2H, -CHO, -C(ORcc)2, -CO2Raa, -OC(=O)Raa,-OCO2Raa, -C(=O)N(Rbb)2,- OC(=O)N(Rbb)2,-NRbbC(=O)Raa,-NRbbCO2Raa,-NRbbC(=O)N(Rbb)2,- C(=NRbb)Raa, - C(=NRbb)ORaa, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, - OC(=NRbb)N(Rbb)2, - NRbbC(=NRbb)N(Rbb)2,-C(=O)NRbbSO2Raa, -NRbbSO2Raa, -SO2N(Rbb)2, -SO2Raa,-SO2ORaa,- OSO2Raa,-S(=O)Raa,-OS(=O)Raa,-Si(Raa)3,-Osi(Raa)3-C(=S)N(Rbb)2, -C(=O)SRaa,-C(=S)SRaa,- SC(=S)SRaa,-SC(=O)SRaa,-OC(=O)SRaa,-SC(=O)ORaa,- SC(=O)Raa, -P(=O)2Raa,-OP(=O)2Raa,- P(=O)(Raa)2, -OP(=O)(Raa)2,-OP(=O)(ORcc)2,- P(=O)2N(Rbb)2,-OP(=O)2N(Rbb)2,-P(=O)(NRbb)2,- OP(=O)(NRbb)2, -NRbbP(=O)(ORcc)2,- NRbbP(=O)(NRbb)2, -P(Rcc)2, -P(Rcc)3, -OP(Rcc)2, - OP(Rcc)3, -B(Raa)2, -B(ORcc)2, - BRaa(ORcc), C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3- 14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups;
each instance of is, independently, selected from C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Raa groups are joined to form a 3-14 membered heterocyclyl or 5- 14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups;
each instance of Rbb is, independently, selected from hydrogen, -OH, -ORaa, -N(Rcc)2,- CN, -C(=O)Raa,-C(=O)N(Rcc)2, -CO2Raa, -SO2Raa,-C(=NRcc)ORaa,-C(=NRcc)N(Rcc)2,- SO2N(Rcc)2, -SO2Rcc,-SO2ORcc,-SORaa, -C(=S)N(Rcc)2, -C(=O)SRcc, -C(=S)SRcc, - P(=O)2Raa,- P(=O)(Raa)2,-P(=O)2N(Rcc)2, -P(=O)(NRcc)2, CHO alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rbb groups are joined to form a 3-14 membered heterocyclyl or 5- 14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups;
each instance of Rcc is, independently, selected from hydrogen, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rcc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups;
each instance of Rdd is, independently, selected from halogen, -CN, -NO2, -N3, -SO2H, - SO3H, -OH, -ORee,-ON(Rff)2, -N(Rff)2,-N(Rff) +
3 X-,-N(ORee)Rff,-SH, -SRee,-SSRee, - C(=O)Ree,- CO2H, -CO2Ree, -OC(=O)Ree, -OCO2Ree,-C(=O)N(Rff)2, -OC(=O)N(Rff)2, - NRffC(=O)Ree, - NRffCO2Ree, -NRffC(=O)N(Rff)2, -C(=NRff)ORee, -OC(=NRff)Ree, - OC(=NRff)ORee, - C(=NRff)N(Rff)2,-OC(=NRff)N(Rff)2, -NRffC(=NRff)N(Rff)2,-NRffSO2Ree,- SO2N(Rff)2,-SO2Ree,- SO2ORee, -OSO2Ree,-S(=O)Ree,-Si(Ree)3,-Osi(Ree)3, -C(=S)N(Rff)2,- C(=O)SRee, -C(=S)SRee, - SC(=S)SRee, -P(=O)2Ree, -P(=O)(Ree)2,-OP(=O)(Ree)2, - OP(=O)(ORee)2, C1-3, alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups;
each instance of Ree is, independently, selected from C1-3, alkyl, C1-3, perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups; each instance of Rff is, independently, selected from hydrogen, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl and 5-10 membered heteroaryl, or two Rff groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups; and
each instance of Rgg is, independently, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, - OC1-6 alkyl,-ON(C1-6 alkyl)2, -N(C1-6 alkyl)2, -N(C1-6 alkyl) +
3 X-,-NH(C1-6 alkyl) +
2 X-,- NH2(C1-6 alkyl) +X-, -NH +
3 X-, -N(OC1-6 alkyl)(C1-6 alkyl), -N (OH)(C1-6 alkyl), -NH(OH), - SH, -4SC1-6 alkyl, -SS(C1-6 alkyl), -C(=O)(C1-6 alkyl), -CO2H, -CO2(C1-6 alkyl), -OC(=O)(C1-6 alkyl), - OCO2(C1-6 alkyl), -C(=O)NH2, -C(=O)N(C1-6 alkyl)2, -OC(=O)NH(C1-6 alkyl), - NHC(=O)( C1-6 alkyl), -N(C1-6 alkyl)C(=O)( C1-6 alkyl), -NHCO2(C1-6 alkyl), -NHC(=O)N(C1-6 alkyl)2,- NHC(=O)NH(C1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C1-6 alkyl),-OC(=NH)(C1-6 alkyl), - OC(=NH)OC1-6 alkyl, -C(=NH)N (C1-6 alkyl)2, -C(=NH)NH(C1-6 alkyl), -C(=NH)NH2, - OC(=NH)N(C1-6 alkyl)2,-OC(NH)NH(C1-6 alkyl),-OC(NH)NH2,-NHC(NH)N(C1-6 alkyl)2,- NHC(=NH)NH2, -NHSO2(C1-6 alkyl), -SO2N(C1-6 alkyl)2, -SO2NH(C1-6 alkyl), -SO2NH2,- SO2C1-6 alkyl, -SO2OC1-6 alkyl, -OSO2C1-6 alkyl, -SOC1-6 alkyl, -Si(C1-6 alkyl)3, -Osi(C1-6 alkyl)3 -C(=S)N(C1-6 alkyl)2, C(=S)NH(C1-6 alkyl), C(=S)NH2, -C(=O)S(C1-6 alkyl), - C(=S)SC1-6 alkyl, -SC(=S)SC1-6 alkyl, -P(=O)2(C1-6 alkyl), -P(=O)(C1-6 alkyl)2, -OP(=O)(C1-6 alkyl)2, - OP(=O)(OC1-6 alkyl)2, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; wherein X- is a counterion.
Additional substituents are described in, for example, International Publication Nos. WO 2013/036835, WO 2013/056181, WO 2013/112605, WO 2013/188792, WO 2014/031792, WO 2014/100228, WO 2014/160441, WO 2014/160480, WO 2014/169831, WO 2014/169832, WO 2014/169833, WO 2014/169836, WO 2015/010054, WO 2015/027227, WO 2015/180679, WO 2015/195962, WO 2015/195967, WO 2016/040322, WO 2016/057713, WO 2016/061527, WO 2016/061537, WO 2016/082789, WO 2016/123056, WO 2016/134301, WO 2016/164763, WO 2016/205721, WO 2017/007832, WO 2017/007836, WO 2017/007840, WO 2017/087864, WO 2017/156103, WO 2017/173358, WO 2017/193046, WO 2018/009867, WO 2018/013613, WO 2018/013615, WO 2018/039378, WO 2018/064649, WO 2018/075698, WO 2018/075699, WO 2019/051264, WO 2019/051477, and WO 2019/055764; U.S. Patent Nos.9365611, 9512165, 9630986, 9676812, 9725481, 10023606, 10172871, 10201550, and 10227375; and U.S. Patent Publication Nos.20140057885, 20140235600, 20150018327, 20150158903, 20150175651, 20150291654, 20150315230, 20160022701, 20160031930, 20160083417, 20160083418, 20160108080, 20160152658, 20160229887, 20170152282, 20170190732, 20170232006, 20170233432, 20170233433, 20170240589, 20170246191, 20170247405, 20170247406, 20170304321, 20170305960, 20170319695, 20170342102, 20170342103, 20170348326, 20170348327, 20180037602, 20180051052, 20180141971, 20180179247, 20180194797, 20180200267, 20180201643, 20180215779, 20180237470, 20180311258, 20180311262, 20180362573, 20190008873, and 20190038639, the contents of each of which are incorporated herein by reference. The compounds described herein may contain any of the substituents described in any of the aforementioned patents and patent publications.
A "counterion" or "anionic counterion" is a negatively charged group associated with a cationic quaternary amino group in order to maintain electronic neutrality. Exemplary counterions include halide ions (e.g., F-, Cl-, Br-, I-), NO - 3 , ClO - 4 , OH-, HPO - 4 , HSO - 4 , sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10- camphor sulfonate, naphthalene-2-sulfonate, naphthalene-l-sulfonic acid-5-sulfonate, ethan-l- sulfonic acid-2-sulfonate, and the like), and carboxylate ions ( e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, and the like).
Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -ORaa, -N(Rcc)2,-CN, -C(=O)Raa, - C(=O)N(Rcc)2,-CO2Raa,-SO2Raa,-C(=NRbb)Raa,-C(=NRcc)ORaa,-C(=NRcc)N(Rcc)2,- SO2N(Rcc)2, - SO2Rcc,-SO2ORcc,-SORaa, -C(=S)N(Rcc)2, -C(=O)SRcc, -C(=S)SRcc, - P(=O)2Raa,-P(=O)(Raa)2,- P(=O)2N(Rcc)2, -P(=O)(NRcc)2, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14- membered heteroaryl, or two Rcc groups attached to a nitrogen atom are joined to form a 3-14- membered heterocyclyl or 5-14- membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups, and wherein Raa, Rbb, Rcc and Rdd are as defined above.
In certain embodiments, the substituent present on a nitrogen atom is an amino protecting group (also referred to herein as a nitrogen protecting group). Amino protecting groups include, but are not limited to, -OH, -ORaa, -N(Rcc)2,-C(=O)Raa,-C(=O)ORaa,- C(=O)N(Rcc)2, -S(=O)2Raa,- C(=NRcc)Raa,-C(=NRcc)ORaa,-C(=NRcc)N(Rcc)2,-SO2N(Rcc)2, - SO2Rcc, -SO2ORcc,-SORaa,- C(=S)N(Rcc)2, -C(=O)SRcc,-C(=S)SRcc, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14-membered heterocyclyl, C6-14 aryl, and 5-14- membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups, and wherein Raa, Rbb, Rcc and Rdd are as defined herein. Amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
Exemplary amino protecting groups include, but are not limited to amide groups (e.g., - C(=O)Raa), which include, but are not limited to, formamide and acetamide; carbamate groups ( e.g., -C(=O)ORaa), which include, but are not limited to, 9-fluorenylmethyl carbamate (Fmoc), t- butyl carbamate (BOC), and benzyl carbamate (Cbz); sulfonamide groups (e.g.,-S(=O)2Raa), which include, but are not limited to, p-toluenesulfonamide (Ts), methanesulfonamide (Ms), and N-[2-(trimethylsilyl)ethoxy]methylamine (SEM).
In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Oxygen protecting groups include, but are not limited to, -Raa,-N(Rbb)2, -C(=O)SRaa, -C(=O)Raa, -CO2Raa,- C(=O)N(Rbb)2, - C(=NRbb)Raa, -C(=NRbb)ORaa,-C(=NRbb)N(Rbb)2, -S(=O)Raa, -SO2Raa,- Si(Raa)3 -P(Rcc)2,-P(Rcc)3, -P(=O)2Raa, -P(=O)(Raa)2,-P(=O)(ORcc)2,-P(=O)2N(Rbb)2, and - P(=O)(NRbb)2, wherein Raa, Rbb, and Rcc are as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
Exemplary oxygen protecting groups include, but are not limited to, methyl,
methoxylmethyl (MOM), 2-methoxyethoxymethyl (MEM), benzyl (Bn), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBDMS), t-butylmethoxyphenylsilyl (TBMPS), methanesulfonate
(mesylate), and tosylate (Ts).
In certain embodiments, the substituent present on an sulfur atom is an sulfur protecting group (also referred to as a thiol protecting group). Sulfur protecting groups include, but are not limited to, -Raa,-N(Rbb)2, -C(=O)SRaa,-C(=O)Raa,-CO2Raa,-C(=O)N(Rbb)2,-C(=NRbb)Raa,- C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2,-S(=O)Raa, -SO2Raa,-Si(Raa)3,-P(Rcc)2, -P(Rcc)3, - P(=O)2Raa,- P(=O)(Raa)2,-P(=O)(ORcc)2, -P(=O)2N(Rbb)2, and -P(=O)(NRbb)2, wherein Raa, Rbb, and Rcc are as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
As used herein, the term "modulation" refers to the inhibition or potentiation of GABA receptor function. A "modulator" (e.g., a modulator compound) may be, for example, an agonist, partial agonist, antagonist, or partial antagonist of the GABA receptor.
"Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
"Pharmaceutically acceptable salt" refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,
ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like. See, e.g., Berge, el al., J. Pharm. Sci. (1977) 66(1): 1-79.
"Solvate" refers to forms of the compound that are associated with a solvent or water (also referred to as "hydrate"), usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, ethanol, acetic acid, and the like. The compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates.
As used herein, the term "isotopic variant" refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound. For example, an "isotopic variant" of a compound can contain one or more non-radioactive isotopes, such as for example, deuterium (2H or D), carbon-13 (13C), nitrogen-15 (15N), or the like. It will be understood that, in a compound where such isotopic substitution is made, the following atoms, where present, may vary, so that for example, any hydrogen may be 2H/D, any carbon may be 13C, or any nitrogen may be 15N, and that the presence and placement of such atoms may be determined within the skill of the art. Likewise, the invention may include the preparation of isotopic variants with radioisotopes, in the instance for example, where the resulting compounds may be used for drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e., 3H, and carbon-14, i.e., 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Further, compounds may be prepared that are substituted with positron emitting isotopes, such as 11C, 18F,15O, and 13N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. All isotopic variants of the compounds provided herein, radioactive or not, are intended to be encompassed within the scope of the invention. "Stereoisomers" : It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers."Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers." Stereoisomers that are not mirror images of one another are termed "diastereomers" and those that are non superimposable mirror images of each other are termed "enantiomers." When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)- isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".
"Tautomers" refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of n electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
A "subject" to which administration is contemplated includes, but is not limited to, a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or a non- human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal.
Disease, disorder, and condition are used interchangeably herein.
As used herein, and unless otherwise specified, the terms "treat," "treating" and
"treatment" contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition ("therapeutic treatment"), and also contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition ("prophylactic treatment").
In general, the "effective amount" of a compound refers to an amount sufficient to elicit the desired biological response, e.g., to treat a CNS-related disorder, is sufficient to induce anesthesia or sedation. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject. An effective amount encompasses therapeutic and prophylactic treatment.
As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.
As used herein, and unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease, disorder or condition. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. Compositions
In an aspect, the invention provides compositions containing a compound of formula (I):
Figure imgf000043_0001
, wherein:
R1A and R1B are according to (i) or (ii) as follows:
(i) R1A is hydrogen and R1B is -OR30, or
(ii) R1A and R1B together are =O;
each of R2 and R3 is independently hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, - S(=O)R32, -SO2R32, -S(=O)2OR31, or R2 and R3 together are =NR31 or =S;
R4 is N(R31)2 or halogen;
R5 is hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, - N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, -S(=O)R32, -SO2R32, or -S(=O)2OR31;
each of R6, R7, R8, and R9, is independently hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, - S(=O)R32, -SO2R32, or -S(=O)2OR31;
each of R10 and R11 is independently hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, - S(=O)R32, -SO2R32, -S(=O)2OR31, or R10 and R11 together are =NR31 or =S;
each of R12 and R13 is independently hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, - S(=O)R32, -SO2R32, -S(=O)2OR31, or R12 and R13 together are =NR31 or =S;
each of R14 and R15 is independently absent, hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, - S(=O)R32, -SO2R32, -S(=O)2OR31, or R14 and R15 together are =NR31 or =S;
each of R16 and R17 is independently absent, hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, - S(=O)R32, -SO2R32, -S(=O)2OR31, or R16 and R17 together are =NR31 or =S;
each of R18 and R19 is independently hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, - S(=O)R32, -SO2R32, -S(=O)2OR31, or R18 and R19 together are =NR31 or =S;
each of R20 and R21 is independently absent, hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, - S(=O)R32, -SO2R32, -S(=O)2OR31, or R14 and R15 together are =NR31 or =S;
R22 is absent, hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, - SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, -S(=O)R32, -SO2R32, or -S(=O)2OR31;
R23 is hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, - N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, -S(=O)R32, -SO2R32, or -S(=O)2OR31;
each of R24 and R25 is independently hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, - S(=O)R32, -SO2R32, or -S(=O)2OR31, or R24 and R25 together are =O;
each of R26 and R27 is independently hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, - S(=O)R32, -SO2R32, -S(=O)2OR31, or R20 and R21 together are =NR31 or =S;
R28 is hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, - N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, -S(=O)R32, -SO2R32, or -S(=O)2OR31;
each instance of R30 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; each instance of R31 is independently hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl, heterocyclyl, aryl, heteroaryl, amine, nitrate, nitrite, thiol, thioether, thioester, sulfate, sulfite, disulfide, sulfoxide, phosphate, phosphate ester, thiophosphate, thiophosphate ester, phosphonate, phosphonate ester, thiophosphonate, thiophosphonate ester, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R31 groups are joined to form an heterocyclic or heteroaryl ring;
each instance of R32 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and R33 is absent or H.
In certain embodiments, if R1A is hydrogen and R1B is -OR30, then R4 is halogen.
In certain embodiments, at least one of the following is true: R5 is not H; R23 is not alkyl; and R28 is not H. In certain embodiments, R5 is not H. In certain embodiments, R23 is not alkyl In certain embodiments, R28 is not H. In certain embodiments, R5 is not H and R23 is not alkyl In certain embodiments, R5 is not H and R28 is not H. In certain embodiments, R23 is not alkyl and R28 is not H. In certain embodiments, R5 is not H, R23 is not alkyl, and R28 is not H.
In certain embodiments, R33 is H. In certain embodiments, R33 is in an alpha
stereochemical position. In certain embodiments, R33 is H in an alpha stereochemical position.
In certain embodiments, R23 is methyl. In certain embodiments, R23 is H.
In certain embodiments, R5 is methyl. In certain embodiments, R5 is H.
In certain embodiments, R28 is H. In certain embodiments, R28 is an optionally substituted heteroaryl. In certain embodiments, R28 is an optionally substituted pyrazole. In certain embodiments, R28 is a heteroaryl substituted with–CN. In certain embodiments, R28 has the following structure:
Figure imgf000046_0001
. In certain embodiments, R5 is not H, and R28 is H.
In certain embodiments, the compound of formula (I) is represented by a structure of one of formulas (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (I-9), (I-10), (I-11), (I-12), (I-13), (I- 14), (I-15), (I-16), (I-17), (I-18), (I-19), (I-20), (I-21), (I-22), (I-23), (I-24), (I-25), (I-26), (I-27), (I-28), (I-29), (I-30), (I-31), and (I-32):
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
In certain embodiments, the compound of formula (I) is represented by a structure of one of formulas (I-1a), (I-2a), (I-3a), (I-4a), (I-5a), (I-6a), (I-7a), (I-8a), (I-9a), (I-10a), (I-11a), (I- 12a), (I-13a), (I-14a), (I-15a), (I-16a), (I-17a), (I-18a), (I-19a), (I-20a), (I-21a), (I-22a), (I-23a), (I-24a), (I-25a), (I-26a), (I-27a), (I-28a), (I-29a), (I-30a), (I-31a), and (I-32a):
Figure imgf000050_0002
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Without wishing to be bound by theory, the compositions may contain one or more compounds that modulate the activity of a receptor and/or ion channel on a cell, such as a neuron. For example, the compound may stimulate or inhibit activity of a receptor and/or ion channel on a neuron. For example and without limitation, the target of the compound may be a GABA receptor, e.g., a GABAA receptor or GABAB receptor, a NMDA receptor, pregnane xenobiotic receptor (PXR), a serotonin receptor, a sigma-1 receptor, a transient receptor potential (TRP) channel, e.g., a TRPC channel, TRPV channel, TRPM channel, or TRPA channel, or a voltage-gated calcium channel (VGC), e.g., a L-type VGCC. The compound may modulate, e.g., stimulate or inhibit, the activity of one or more subtypes of GABA receptors. For example, the composition may modulate the activity of one or more of a1b1g2, a1b2g2, a1b3g2, a2b1g2, a2b2g2, a2b3g2, a3b1g2, a3b2g2, a3b3g2, a4b1g2, a4b3d, a4b3g2, a5b1g2, a5b2g2, a5b3g2, a6b1g2, a6b2g2, and a6b3g2 GABA receptors. The compound may preferentially modulate the activity of one or more subtypes of GABA receptors, such as those described above, over one or more other subtypes of GABA receptors. For example, the composition may preferentially modulate the activity of a4b3d GABA receptors over a1b2g2 GABA receptors. The
composition may contain the compound in a therapeutically effective amount to modulate, e.g., stimulate or inhibit, the activity of any receptor or subtype of receptor described above.
Certain compounds of formula (I) are known in the art. For example, funtumine has a structure encompassed by formula (I-1), and funtumidine has a structure encompassed by formula (I-2). Funtumine, funtumidine, and related compounds are described in, for example, U.S. Patent Nos.3,053,861; 3,092,643; 3,098,082; 3,098,859; 3,102,895; 3,119,817; 3,196,168; 3,196,169; 3,206,456; 3,251,867; 3,264,326; 3,382,257; 3,424,747; 3,515,784; and 4,376,734; and Slavikovo, et al., Suppressing aggressive behavior with analogs of allopregnanolone (epalon), Steroids.2001 Feb;66(2):99-105., 10.1016/S0039-128X(00)00215-4; and Matyas, et al., Effects of 3a-Amino-5a-pregnan-20-one on GABAA Receptor: Synthesis, Activity and Cytotoxicity, Collection of Czechoslovak Chemical Communications 69(7), July 2004,
10.1135/cccc20041506, the contents of each of which are incorporated herein by reference. Formulations
The invention provides pharmaceutical compositions containing one or more of the compounds described above. A pharmaceutical composition containing the compounds may be in a form suitable for oral use, for example, as tablets, troches, lozenges, fast-melts, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the compounds in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration in the stomach and absorption lower down in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in U.S. Patent Nos.4,256,108; 4,166,452; and 4,265,874, the contents of which are incorporated herein by reference, to form osmotic therapeutic tablets for control release. Preparation and administration of compounds is discussed in U.S. Patent No.6,214,841 and U.S. Pub. No.2003/0232877, the contents of which are incorporated herein by reference.
Formulations for oral use may also be presented as hard gelatin capsules in which the compounds are mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the compounds are mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
An alternative oral formulation, where control of gastrointestinal tract hydrolysis of the compound is sought, can be achieved using a controlled-release formulation, where a compound of the invention is encapsulated in an enteric coating.
Aqueous suspensions may contain the compounds in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such a polyoxyethylene with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the compounds in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the compounds in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified, for example sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and agents for flavoring and/or coloring. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be in a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
In certain embodiments, the formulation is not a sustained release formulation. In certain embodiments, the formulation is not injectable. In certain embodiments, the formulation does not contain particles having a D50 (volume weighted median diameter) of less than 10 microns. In certain embodiments, the formulation does not contain a polymer surface stabilizer. In certain embodiments, the formulation is not an aqueous suspension. Treatment of CNS disorders
The compositions of the invention are useful for treating CNS disorders that are associated with, or can be ameliorated by, alteration of activity of a GABAA receptor. GABAA receptors are responsible for most of the physiological activities of GABA in the central nervous system. GABAA receptors are generally pentamers that include various combinations of a, b, and g subunits, but the minimal requirement to produce a GABA-gated ion channel is the inclusion of an a and a b subunit. GABAA receptors may include other subunits as well, and the arrangement of subunits within the pentamer can vary. Moreover, there are multiple members of each subunit family, making a vast number of potential combinations to yield functional receptors. Within neurons, the type and density of GABAA receptors can vary between cell bodies and dendrites. The structure and function of GABAA receptors are described in, for example, Sigel E., and Steinmann, M.E., Structure, Function, and Modulation of GABAA Receptors, J. Biol. Chem.287:48 pp.40224-402311 (2012), doi: 10.1074/jbc.R112.386664, the contents of which are incorporated herein by reference.
Modulation of GABAA receptor activity is useful for treatment of a variety of CNS diseases, disorders, and condition. For example and without limitation, the CNS-related disease, disorder, or condition may be acute pain, an addictive disorder, Alzheimer’s disease, Angelman's syndrome, anti-social personality disorder, an anxiety disorder, attention deficit hyperactivity disorder (ADHD), an attention disorder, an auditory disorder, autism, an autism spectrum disorder, bipolar disorder, chronic pain, a cognitive disorder, a compulsive disorder, a convulsive disorder, dementia, depression, dysthymia, an epileptic disorder, essential tremor,
epileptogenesis, fragile X syndrome, generalized anxiety disorder (GAD), Huntington’s disease, injury related pain syndrome, insomnia, ischemia, Lewis body type dementia, a memory disorder, migraines, a mood disorder, movement disorder, a neurodegenerative disease, neuropathic pain, an obsessive compulsive disorder, pain, a panic disorder, Parkinson’s disease, a personality disorder, posttraumatic stress disorder (PTSD), psychosis, Rett syndrome, a schizoaffective disorder, schizophrenia, a schizophrenia spectrum disorder, a seizure disorder, a sleep disorder, social anxiety disorder, status epilepticus, stress, stroke, tinnitus, traumatic brain injury (TBI), vascular disease, vascular malformation, vascular type dementia movement disorder, Wilson's disease, or withdrawal syndrome.
The methods of treating a subject having a CNS disease, disorder, or condition include providing a composition of the invention, as described above, to the subject. Providing may include administering the composition to the subject. The composition may be administered by any suitable means, such as orally, intravenously, enterally, parenterally, dermally, buccally, topically (including transdermally), by injection, nasally, pulmonarily, and with or on an implantable medical device (e.g., stent or drug-eluting stent or balloon equivalents). Preferably, the composition is provided orally.
The composition may be provided under any suitable dosing regimen. For example, the composition may be provided as a single dose or in multiple doses. Multiple doses may be provided in provided separated by intervals, such as 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, or more. Multiple doses may be provided within a period of time. For example, multiple doses may be provided over a period of 1 day, 2 days, 3 days, 4 days, 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, or more. The compositions may be provided repeatedly for a specified duration. For example and without limitation, the compositions may be provided for 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 12 weeks, 3 months, 4 months, 5 months, 6 months, 8 months, 10 months, 12 months or more. Examples
Example 1
Compounds of the invention were analyzed for activity as positive allosteric modulators and antagonists against the following human GABAA receptors. Compounds were tested in fluorometric imaging plate reader (FLIPR) assays at seven concentrations against the following human GABAA receptors: a1b1g2, a1b2g2, a1b3g2, a2b1g2, a2b2g2, a2b3g2, a3b1g2, a3b2g2, a3b3g2, a4b1g2, a4b3d, a4b3g2, a5b1g2, a5b2g2, a5b3g2, a6b1g2, a6b2g2 and a6b3g2. The following compounds were tested: CV-10264:
Figure imgf000060_0001
, ,
CV-10266:
Figure imgf000060_0002
, . Assay summary
Human GABA cells were trypsinized, counted, and seeded in black, clear-bottomed 96 well plates at a density of 25,000 cells per well and incubated for 24 hours. After 24 hours cells were induced with 1 µg/ml tetracycline and incubated overnight. Next day, media was removed from cell plates before adding 70 µl assay buffer (25 mM HEPES: HBSS, pH 7.4). Red membrane potential dye solution (10 µl) was added to the wells and incubated at room temperature for 60 minutes. Dye solution was made up in assay buffer. Compound dilutions (including serial dilutions) were performed in 100% DMSO then transferred to intermediate dilutions for a very limited amount of time (<10 minutes) just before adding to the cell plate.
For positive allosteric modulator testing, the test compounds were added to the wells and incubated at room temperature for 10 minutes. Allopregnanolone was used as a reference compound. The plates were then placed in the FLIPR and fluorescence monitored every 1.52 seconds. After 20 seconds 10 µl of the GABA at approximately EC20 was added and the fluorescence monitored for 5 minutes at ex/emm: 488 nm/510- 570 nm.
For antagonist testing, the test compounds were added to the wells and incubated at room temperature for 10 minutes. Picrotoxin was use as a reference compound. The plates were then placed in the FLIPR and fluorescence monitored every 1.52 seconds. After 20 seconds 10 µl of the GABA at approximately EC80 was added and the fluorescence monitored for 5 minutes at ex/emm: 488 nm/510- 570 nm. The compounds were tested against GABAA a1b1g2, a1b2g2, a1b3g2, a2b1g2, a2b2g2, a2b3g2, a3b1g2, a3b2g2, a3b3g2, a4b1g2, a4b3d, a4b3g2, a5b1g2, a5b2g2, a5b3g2, a6b1g2, a6b2g2, and a6b3g2 in the FLIPR assay at 0.01, 0.03, 0.1, 0.3, 1.0, 3.0 and 10 µM in duplicate. The no-compound data point was included on the graph at the concentration point of 3 nM.
The EC50 or IC50 values of the compounds and standard activators or inhibitors were determined where possible. The compounds and all controls were tested in a final DMSO concentration of 0.5%. Results
EC50 values of compounds against GABA receptor panel are shown in Table 1. Table 1
Figure imgf000061_0001
Figure imgf000062_0001
All values are in molar
--: not analyzed
*: value generated by extrapolation IC50 Values of Compounds against GABA Panel are shown in Table 2. Table 2
Figure imgf000062_0002
All values are in molar
--: not analyzed
*: value generated by extrapolation FIG.1 shows graphs of EC50 dose response curves for compounds against GABAA a1b1g2. Dose response curves and EC50 values were generated by Prism software (GraphPad Inc.). R.F.U. denotes relative fluorescent units.
FIG.2 shows graphs of IC50 dose response curves for compounds against GABAA a1b1g2. Dose response curves and EIC50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
FIG.3 shows graphs of EC50 dose response curves for compounds against GABAA a1b2g2. Dose response curves and EC50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
FIG.4 shows graphs of IC50 dose response curves for compounds against GABAA a1b2g2. Dose response curves and EIC50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
FIG.5 shows graphs of EC50 dose response curves for compounds against GABAA a1b3g2. Dose response curves and EC50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
FIG.6 shows graphs of IC50 dose response curves for compounds against GABAA a1b3g2. Dose response curves and EIC50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
FIG.7 shows graphs of EC50 dose response curves for compounds against GABAA a2b1g2. Dose response curves and EC50 values were generated by Prism software. R.F.U. denotes relative fluorescent units. The datapoints at 10 µM and 1 µM for allopregnanolone were excluded from the final analysis as they were deemed to be outliers.
FIG.8 shows graphs of IC50 dose response curves for compounds against GABAA a2b1g2. Dose response curves and EIC50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
FIG.9 shows graphs of EC50 dose response curves for compounds against GABAA a2b2g2. Dose response curves and EC50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
FIG.10 shows graphs of IC50 dose response curves for compounds against GABAA a2b2g2. Dose response curves and EIC50 values were generated by Prism software. R.F.U. denotes relative fluorescent units. FIG.11 shows graphs of EC50 dose response curves for compounds against GABAA a2b3g2. Dose response curves and EC50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
FIG.12 shows graphs of IC50 dose response curves for compounds against GABAA a2b3g2. Dose response curves and EIC50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
FIG.13 shows graphs of EC50 dose response curves for compounds against GABAA a3b1g2. Dose response curves and EC50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
FIG.14 shows graphs of IC50 dose response curves for compounds against GABAA a3b1g2. Dose response curves and EIC50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
FIG.15 shows graphs of EC50 dose response curves for compounds against GABAA a3b2g2. Dose response curves and EC50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
FIG.16 shows graphs of IC50 dose response curves for compounds against GABAA a3b2g2. Dose response curves and EIC50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
FIG.17 shows graphs of EC50 dose response curves for compounds against GABAA a3b3g2. Dose response curves and EC50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
FIG.18 shows graphs of IC50 dose response curves for compounds against GABAA a3b3g2. Dose response curves and EIC50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
FIG.19 shows graphs of EC50 dose response curves for compounds against GABAA a4b1g2. Dose response curves and EC50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
FIG.20 shows graphs of IC50 dose response curves for compounds against GABAA a4b1g2. Dose response curves and EIC50 values were generated by Prism software. R.F.U. denotes relative fluorescent units. FIG.21 shows graphs of EC50 dose response curves for compounds against GABAA a4b3d. Dose response curves and EC50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
FIG.22 shows graphs of IC50 dose response curves for compounds against GABAA a4b3d. Dose response curves and EIC50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
FIG.23 shows graphs of EC50 dose response curves for compounds against GABAA a5b1g2. Dose response curves and EC50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
FIG.24 shows graphs of IC50 dose response curves for compounds against GABAA a5b1g2. Dose response curves and EIC50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
FIG.25 shows graphs of IC50 dose response curves for compounds against GABAA a5b2g2. Dose response curves and EIC50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
FIG.26 shows graphs of EC50 dose response curves for compounds against GABAA a5b3g2. Dose response curves and EC50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
FIG.27 shows graphs of IC50 dose response curves for compounds against GABAA a5b3g2. Dose response curves and EIC50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
FIG.28 shows graphs of EC50 dose response curves for compounds against GABAA a6b1g2. Dose response curves and EC50 values were generated by Prism software. R.F.U. denotes relative fluorescent units. The datapoint at 10 µM for allopregnanolone was excluded from the final analysis as it was deemed to be an outlier.
FIG.29 shows graphs of IC50 dose response curves for compounds against GABAA a6b1g2. Dose response curves and EIC50 values were generated by Prism software. R.F.U. denotes relative fluorescent units.
FIG.30 shows graphs of IC50 dose response curves for compounds against GABAA a6b2g2. Dose response curves and EIC50 values were generated by Prism software. R.F.U. denotes relative fluorescent units. Conclusions
The results show that compounds of the invention are effective at modulating the activity of GABAA receptors. In addition, certain compounds preferentially modulate a4b3d GABA receptors over a1b2g2 GABA receptors. Incorporation by Reference
References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, have been made throughout this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes. Equivalents
Various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including references to the scientific and patent literature cited herein. The subject matter herein contains important information, exemplification, and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.

Claims

Claims
What is claimed is: 1. A method of treating a neurological condition, the method comprising providing to a subject having a neurological condition a composition comprising a compound of formula (I):
Figure imgf000067_0001
wherein:
R1A and R1B are according to (i) or (ii) as follows:
(i) R1A is hydrogen and R1B is -OR30, or
(ii) R1A and R1B together are =O;
each of R2 and R3 is independently hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, - S(=O)R32, -SO2R32, -S(=O)2OR31, or R2 and R3 together are =NR31 or =S;
R4 is N(R31)2 or halogen; R5 is hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, - N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, -S(=O)R32, -SO2R32, or -S(=O)2OR31;
each of R6, R7, R8, and R9, is independently hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, - S(=O)R32, -SO2R32, or -S(=O)2OR31;
each of R10 and R11 is independently hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, - S(=O)R32, -SO2R32, -S(=O)2OR31, or R10 and R11 together are =NR31 or =S;
each of R12 and R13 is independently hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, - S(=O)R32, -SO2R32, -S(=O)2OR31, or R12 and R13 together are =NR31 or =S;
each of R14 and R15 is independently absent, hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, - S(=O)R32, -SO2R32, -S(=O)2OR31, or R14 and R15 together are =NR31 or =S;
each of R16 and R17 is independently absent, hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, - S(=O)R32, -SO2R32, -S(=O)2OR31, or R16 and R17 together are =NR31 or =S;
each of R18 and R19 is independently hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, - S(=O)R32, -SO2R32, -S(=O)2OR31, or R18 and R19 together are =NR31 or =S;
each of R20 and R21 is independently absent, hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, - S(=O)R32, -SO2R32, -S(=O)2OR31, or R14 and R15 together are =NR31 or =S;
R22 is absent, hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, - SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, -S(=O)R32, -SO2R32, or -S(=O)2OR31;
R23 is hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, - N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, -S(=O)R32, -SO2R32, or -S(=O)2OR31;
each of R24 and R25 is independently hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, - S(=O)R32, -SO2R32, or -S(=O)2OR31, or R24 and R25 together are =O;
each of R26 and R27 is independently hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, - S(=O)R32, -SO2R32, -S(=O)2OR31, or R20 and R21 together are =NR31 or =S;
R28 is hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, - N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, -S(=O)R32, -SO2R32, or -S(=O)2OR31; each instance of R30 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; each instance of R31 is independently hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl, heterocyclyl, aryl, heteroaryl, amine, nitrate, nitrite, thiol, thioether, thioester, sulfate, sulfite, disulfide, sulfoxide, phosphate, phosphate ester, thiophosphate, thiophosphate ester, phosphonate, phosphonate ester, thiophosphonate, thiophosphonate ester, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R31 groups are joined to form an heterocyclic or heteroaryl ring;
each instance of R32 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and R33 is absent or H.
2. The method of claim 1, wherein the composition modulates activity of a gamma- aminobutyric acid (GABA) receptor.
3. The method of claim 2, wherein the composition modulates activity of a GABAA receptor.
4. The method of claim 1, wherein the condition is selected from the group consisting of acute pain, an addictive disorder, Alzheimer’s disease, Angelman's syndrome, anti-social personality disorder, an anxiety disorder, attention deficit hyperactivity disorder (ADHD), an attention disorder, an auditory disorder, autism, an autism spectrum disorder, bipolar disorder, chronic pain, a cognitive disorder, a compulsive disorder, a convulsive disorder, dementia, depression, dysthymia, an epileptic disorder, essential tremor, epileptogenesis, fragile X syndrome, generalized anxiety disorder (GAD), Huntington’s disease, injury related pain syndrome, insomnia, ischemia, Lewis body type dementia, a memory disorder, migraines, a mood disorder, movement disorder, a neurodegenerative disease, neuropathic pain, an obsessive compulsive disorder, pain, a panic disorder, Parkinson’s disease, a personality disorder, posttraumatic stress disorder (PTSD), psychosis, Rett syndrome, a schizoaffective disorder, schizophrenia, a schizophrenia spectrum disorder, a seizure disorder, a sleep disorder, social anxiety disorder, status epilepticus, stress, stroke, tinnitus, traumatic brain injury (TBI), vascular disease, vascular malformation, vascular type dementia movement disorder, Wilson's disease, and withdrawal syndrome.
5. The method of claim 4, wherein the condition is depression.
6. The method of claim 1, wherein R33 is H in an alpha stereochemical position.
7. The method of claim 1, wherein R23 is methyl.
8. The method of claim 7, wherein R28 is H.
9. The method of claim 8, wherein R5 is H.
10. The method of claim 9, wherein the compound of formula (I) is represented by a structure selected from the group consisting of (I-1), (I-2), (I-3), and (I-4):
Figure imgf000071_0001
11. The method of claim 9, wherein the compound of formula (I) is represented by a structure selected from the group consisting of (I-1a), (I-2a), (I-3a), and (I-4a):
Figure imgf000072_0001
12. The method of claim 8, wherein R5 is methyl. 13. The method of claim 12, wherein the compound of formula (I) is represented by a structure selected from the group consisting of (I-5), (I-6), (I-7), and (I-8):
Figure imgf000072_0002
Figure imgf000073_0002
14. The method of claim 12, wherein the compound of formula (I) is represented by a structure selected from the group consisting of (I-5a), (I-6a), (I-7a), and (I-8a):
Figure imgf000073_0001
15. The method of claim 7, wherein R28 is an optionally substituted heteroaryl.
16. The method of claim 15, wherein R5 is H.
17. The method of claim 16, wherein the compound of formula (I) is represented by a structure selected from the group consisting of (I-9), (I-10), (I-11), and (I-12):
Figure imgf000074_0001
18. The method of claim 16, wherein the compound of formula (I) is represented by a structure selected from the group consisting of (I-9a), (I-10a), (I-11a), and (I-12a):
Figure imgf000074_0002
19. The method of claim 15, wherein R5 is methyl. 20. The method of claim 19, wherein the compound of formula (I) is represented by a structure selected from the group consisting of (I-13), (I-14), (I-15), and (I-16):
Figure imgf000075_0001
21. The method of claim 19, wherein the compound of formula (I) is represented by a structure selected from the group consisting of (I-13a), (I-14a), (I-15a), and (I-16a):
Figure imgf000075_0002
Figure imgf000076_0001
,
22. The method of claim 1, wherein R23 is H.
23. The method of claim 22, wherein R28 is H.
24. The method of claim 23, wherein R5 is H.
25. The method of claim 24, wherein the compound of formula (I) is represented by a structure selected from the group consisting of (I-17), (I-18), (I-19), and (I-20):
Figure imgf000076_0002
26. The method of claim 24, wherein the compound of formula (I) is represented by a structure selected from the group consisting of (I-17a), (I-18a), (I-19a), and (I-20a):
Figure imgf000077_0001
27. The method of claim 23, wherein R5 is methyl.
28. The method of claim 27, wherein the compound of formula (I) is represented by a structure selected from the group consisting of (I-21), (I-22), (I-23), and (I-24):
Figure imgf000077_0002
29. The method of claim 27, wherein the compound of formula (I) is represented by a structure selected from the group consisting of (I-21a), (I-22a), (I-23a), and (I-24a):
Figure imgf000078_0001
30. The method of claim 22, wherein R28 is an optionally substituted heteroaryl. 31. The method of claim 30, wherein R5 is H. 32. The method of claim 31, wherein the compound of formula (I) is represented by a structure selected from the group consisting of (I-25), (I-26), (I-27), and (I-28):
Figure imgf000078_0002
Figure imgf000079_0002
33. The method of claim 31, wherein the compound of formula (I) is represented by a structure selected from the group consisting of (I-25a), (I-26a), (I-27a), and (I-28a):
Figure imgf000079_0001
34. The method of claim 30, wherein R5 is methyl.
35. The method of claim 34, wherein the compound of formula (I) is represented by a structure selected from the group consisting of (I-29), (I-30), (I-31), and (I-32):
Figure imgf000080_0002
36. The method of claim 34, wherein the compound of formula (I) is represented by a structure selected from the group consisting of (I-29a), (I-30a), (I-31a), and (I-32a):
Figure imgf000080_0001
37. A method of treating a neurological condition, the method comprising providing to a subject having a neurological condition a composition comprising a compound of formula (I):
Figure imgf000081_0001
, wherein:
R1A and R1B are according to (i) or (ii) as follows:
(i) R1A is hydrogen and R1B is -OR30, or
(ii) R1A and R1B together are =O;
each of R2 and R3 is independently hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, - S(=O)R32, -SO2R32, -S(=O)2OR31, or R2 and R3 together are =NR31 or =S;
R4 is N(R31)2 or halogen;
R5 is hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, - N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, -S(=O)R32, -SO2R32, or -S(=O)2OR31; each of R6, R7, R8, and R9, is independently hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, - S(=O)R32, -SO2R32, or -S(=O)2OR31;
each of R10 and R11 is independently hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, - S(=O)R32, -SO2R32, -S(=O)2OR31, or R10 and R11 together are =NR31 or =S;
each of R12 and R13 is independently hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, - S(=O)R32, -SO2R32, -S(=O)2OR31, or R12 and R13 together are =NR31 or =S;
each of R14 and R15 is independently absent, hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, - S(=O)R32, -SO2R32, -S(=O)2OR31, or R14 and R15 together are =NR31 or =S;
each of R16 and R17 is independently absent, hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, - S(=O)R32, -SO2R32, -S(=O)2OR31, or R16 and R17 together are =NR31 or =S;
each of R18 and R19 is independently hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, - S(=O)R32, -SO2R32, -S(=O)2OR31, or R18 and R19 together are =NR31 or =S; each of R20 and R21 is independently absent, hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, - S(=O)R32, -SO2R32, -S(=O)2OR31, or R14 and R15 together are =NR31 or =S;
R22 is absent, hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, - SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, -S(=O)R32, -SO2R32, or -S(=O)2OR31;
R23 is hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, - N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, -S(=O)R32, -SO2R32, or -S(=O)2OR31;
each of R24 and R25 is independently hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, - S(=O)R32, -SO2R32, or -S(=O)2OR31, or R24 and R25 together are =O;
each of R26 and R27 is independently hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, -N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, - S(=O)R32, -SO2R32, -S(=O)2OR31, or R20 and R21 together are =NR31 or =S;
R28 is hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR31, -SR31, - N(R31)2,-NHC(=O)R31, -NHC(=O)OR31, -S(=O)R32, -SO2R32, or -S(=O)2OR31;
each instance of R30 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; each instance of R31 is independently hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl, heterocyclyl, aryl, heteroaryl, amine, nitrate, nitrite, thiol, thioether, thioester, sulfate, sulfite, disulfide, sulfoxide, phosphate, phosphate ester, thiophosphate, thiophosphate ester, phosphonate, phosphonate ester, thiophosphonate, thiophosphonate ester, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R31 groups are joined to form an heterocyclic or heteroaryl ring;
each instance of R32 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and R33 is absent or H,
wherein the composition is provided in a therapeutically effective amount to preferentially modulate a4b3d gamma-aminobutyric acid (GABA) receptors over a1b2g2 GABA receptors.
38. The method of claim 37, wherein the condition is selected from the group consisting of acute pain, an addictive disorder, Alzheimer’s disease, Angelman's syndrome, anti-social personality disorder, an anxiety disorder, attention deficit hyperactivity disorder (ADHD), an attention disorder, an auditory disorder, autism, an autism spectrum disorder, bipolar disorder, chronic pain, a cognitive disorder, a compulsive disorder, a convulsive disorder, dementia, depression, dysthymia, an epileptic disorder, essential tremor, epileptogenesis, fragile X syndrome, generalized anxiety disorder (GAD), Huntington’s disease, injury related pain syndrome, insomnia, ischemia, Lewis body type dementia, a memory disorder, migraines, a mood disorder, movement disorder, a neurodegenerative disease, neuropathic pain, an obsessive compulsive disorder, pain, a panic disorder, Parkinson’s disease, a personality disorder, posttraumatic stress disorder (PTSD), psychosis, Rett syndrome, a schizoaffective disorder, schizophrenia, a schizophrenia spectrum disorder, a seizure disorder, a sleep disorder, social anxiety disorder, status epilepticus, stress, stroke, tinnitus, traumatic brain injury (TBI), vascular disease, vascular malformation, vascular type dementia movement disorder, Wilson's disease, and withdrawal syndrome.
39. The method of claim 38, wherein the condition is depression.
40. The method of claim 37, wherein R33 is H in an alpha stereochemical position.
41. The method of claim 37, wherein R23 is methyl.
42. The method of claim 41, wherein R28 is H.
43. The method of claim 42, wherein R5 is H.
44. The method of claim 43, wherein the compound of formula (I) is represented by a structure selected from the group consisting of (I-1), (I-2), (I-3), and (I-4):
Figure imgf000085_0001
45. The method of claim 43, wherein the compound of formula (I) is represented by a structure selected from the group consisting of (I-1a), (I-2a), (I-3a), and (I-4a):
Figure imgf000085_0002
Figure imgf000086_0003
46. The method of claim 42, wherein R5 is methyl.
47. The method of claim 46, wherein the compound of formula (I) is represented by a structure selected from the group consisting of (I-5), (I-6), (I-7), and (I-8):
Figure imgf000086_0001
48. The method of claim 46, wherein the compound of formula (I) is represented by a structure selected from the group consisting of (I-5a), (I-6a), (I-7a), and (I-8a):
Figure imgf000086_0002
Figure imgf000087_0001
,
49. The method of claim 41, wherein R28 is an optionally substituted heteroaryl.
50. The method of claim 49, wherein R5 is H.
51. The method of claim 50, wherein the compound of formula (I) is represented by a structure selected from the group consisting of (I-9), (I-10), (I-11), and (I-12):
Figure imgf000087_0002
52. The method of claim 50, wherein the compound of formula (I) is represented by a structure selected from the group consisting of (I-9a), (I-10a), (I-11a), and (I-12a):
Figure imgf000088_0002
53. The method of claim 49, wherein R5 is methyl. 54. The method of claim 53, wherein the compound of formula (I) is represented by a structure selected from the group consisting of (I-13), (I-14), (I-15), and (I-16):
Figure imgf000088_0001
Figure imgf000089_0002
55. The method of claim 53, wherein the compound of formula (I) is represented by a structure selected from the group consisting of (I-13a), (I-14a), (I-15a), and (I-16a):
Figure imgf000089_0001
56. The method of claim 37, wherein R23 is H.
57. The method of claim 56, wherein R28 is H.
58. The method of claim 57, wherein R5 is H.
59. The method of claim 58, wherein the compound of formula (I) is represented by a structure selected from the group consisting of (I-17), (I-18), (I-19), and (I-20):
Figure imgf000090_0001
60. The method of claim 58, wherein the compound of formula (I) is represented by a structure selected from the group consisting of (I-17a), (I-18a), (I-19a), and (I-20a):
Figure imgf000090_0002
61. The method of claim 57, wherein R5 is methyl.
62. The method of claim 61, wherein the compound of formula (I) is represented by a structure selected from the group consisting of (I-21), (I-22), (I-23), and (I-24):
Figure imgf000091_0001
63. The method of claim 61, wherein the compound of formula (I) is represented by a structure selected from the group consisting of (I-21a), (I-22a), (I-23a), and (I-24a):
Figure imgf000091_0002
64. The method of claim 56, wherein R28 is an optionally substituted heteroaryl.
65. The method of claim 64, wherein R5 is H.
66. The method of claim 65, wherein the compound of formula (I) is represented by a structure selected from the group consisting of (I-25), (I-26), (I-27), and (I-28):
Figure imgf000092_0001
67. The method of claim 65, wherein the compound of formula (I) is represented by a structure selected from the group consisting of (I-25a), (I-26a), (I-27a), and (I-28a):
Figure imgf000092_0002
Figure imgf000093_0002
68. The method of claim 64, wherein R5 is methyl. 69. The method of claim 68, wherein the compound of formula (I) is represented by a structure selected from the group consisting of (I-29), (I-30), (I-31), and (I-32):
Figure imgf000093_0001
70. The method of claim 68, wherein the compound of formula (I) is represented by a structure selected from the group consisting of (I-29a), (I-30a), (I-31a), and (I-32a):
Figure imgf000094_0001
, 71. A method of treating a neurological condition, the method comprising providing to a subject having a neurological condition a composition comprising a compound of formula (I-11a):
Figure imgf000094_0002
72. The method of claim 71, wherein the composition is provided in a therapeutically effective amount to preferentially modulate a4b3d gamma-aminobutyric acid (GABA) receptors over a1b2g2 GABA receptors. 73. The method of claim 71, wherein the condition is selected from the group consisting of acute pain, an addictive disorder, Alzheimer’s disease, Angelman's syndrome, anti-social personality disorder, an anxiety disorder, attention deficit hyperactivity disorder (ADHD), an attention disorder, an auditory disorder, autism, an autism spectrum disorder, bipolar disorder, chronic pain, a cognitive disorder, a compulsive disorder, a convulsive disorder, dementia, depression, dysthymia, an epileptic disorder, essential tremor, epileptogenesis, fragile X syndrome, generalized anxiety disorder (GAD), Huntington’s disease, injury related pain syndrome, insomnia, ischemia, Lewis body type dementia, a memory disorder, migraines, a mood disorder, movement disorder, a neurodegenerative disease, neuropathic pain, an obsessive compulsive disorder, pain, a panic disorder, Parkinson’s disease, a personality disorder, posttraumatic stress disorder (PTSD), psychosis, Rett syndrome, a schizoaffective disorder, schizophrenia, a schizophrenia spectrum disorder, a seizure disorder, a sleep disorder, social anxiety disorder, status epilepticus, stress, stroke, tinnitus, traumatic brain injury (TBI), vascular disease, vascular malformation, vascular type dementia movement disorder, Wilson's disease, and withdrawal syndrome. 74. The method of claim 73, wherein the condition is depression.
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Citations (1)

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Publication number Priority date Publication date Assignee Title
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US3102895A (en) * 1957-09-27 1963-09-03 Oletta Sa 3alpha-amino-allopregnanes

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Title
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