WO2023035913A1 - Methods of treating cns disorders - Google Patents

Methods of treating cns disorders Download PDF

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WO2023035913A1
WO2023035913A1 PCT/CN2022/113807 CN2022113807W WO2023035913A1 WO 2023035913 A1 WO2023035913 A1 WO 2023035913A1 CN 2022113807 W CN2022113807 W CN 2022113807W WO 2023035913 A1 WO2023035913 A1 WO 2023035913A1
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disorder
disease
group
alkyl
certain embodiments
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English (en)
French (fr)
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Congxin Liang
Wei Tang
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Hangzhou Highlightll Pharmaceutical Co Ltd
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Hangzhou Highlightll Pharmaceutical Co Ltd
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Priority to CN202280006751.7A priority Critical patent/CN116490180B/zh
Priority to CN202410217414.3A priority patent/CN118059096A/zh
Priority to US18/712,034 priority patent/US20250032465A1/en
Priority to JP2024532463A priority patent/JP2024543198A/ja
Priority to CA3239065A priority patent/CA3239065A1/en
Priority to EP22866386.0A priority patent/EP4419101A4/en
Priority to IL313097A priority patent/IL313097A/en
Priority to AU2022342095A priority patent/AU2022342095A1/en
Publication of WO2023035913A1 publication Critical patent/WO2023035913A1/en
Anticipated expiration legal-status Critical
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the central nervous system includes the brain and spinal cord.
  • the CNS is vulnerable to various disorders, which may be caused by various factors, including trauma, infections, degeneration, structural defects and/or damages, tumors, blood flow disruption, and autoimmune disorders. Symptoms of a CNS disorder would depend on the area of the nervous system that is involved and the cause of the disorder.
  • the protein kinases represent a large family of proteins that play a central role in the regulation of a wide variety of cellular processes and maintenance of cellular function.
  • a partial, non-limiting, list of these kinases include: non-receptor tyrosine kinases such as the Janus kinase family (JAK1, JAK2, JAK3 and TYK2) ; receptor tyrosine kinases such as platelet-derived growth factor receptor kinase (PDGFR) ; and serine/threonine kinases such as b-RAF.
  • non-receptor tyrosine kinases such as the Janus kinase family (JAK1, JAK2, JAK3 and TYK2)
  • receptor tyrosine kinases such as platelet-derived growth factor receptor kinase (PDGFR)
  • PDGFR platelet-derived growth factor receptor kinase
  • serine/threonine kinases such as
  • the compounds of this disclosure selectively inhibit the activity of one or more protein kinases over other related kinases, and are thus expected to be useful in the treatment of disorders mediated by the selectively inhibited kinase (s) while avoiding the undesirable side effects associated with the inhibition of the related kinase (s) .
  • the Janus kinase family comprises 4 known family members: JAK 1, 2, 3, and tyrosine kinase 2 (TYK2) .
  • JAK 1, 2, 3, and tyrosine kinase 2 TYK2
  • These cytoplasmic tyrosine kinases are associated with membrane cytokine receptors such as common gamma-chain receptors and the glycoprotein 130 (gp 130) trans-membrane proteins (Murray, J. Immunol. 178 (5) : 2623-2629, 2007) .
  • gp 130 glycoprotein 130
  • Almost 40 cytokine receptors signal through combinations of these 4 JAK family members and their 7 downstream substrates: the signal transduction activators of transcription (STAT) family members (Ghoreschi et al., Immunol Rev. 228 (1) : 273-287, 2009) .
  • STAT signal transduction activators of transcription
  • Cytokine binding to its receptor initiates JAK activation via trans-and auto-phosphorylation.
  • the JAK family kinases in turn phosphorylate cytokine receptor residues, creating binding sites for sarcoma homology 2 (SH2) containing proteins, such as the STAT factors and other regulators, which are subsequently activated by JAK phosphorylation.
  • SH2 sarcoma homology 2
  • STATs enter the nucleus initiating expression of survival factors, cytokines, chemokines, and molecules that facilitate leukocyte cellular trafficking (Schindler et al., J. Biol. Chem. 282 (28) : 20059-20063, 2007) .
  • JAK activation also results in cell proliferation via phosphoinositide 3-kinase (PI3K) and protein kinase B-mediated pathways.
  • PI3K phosphoinositide 3-kinase
  • JAK3 and JAK1 are components of the common gamma-chain cytokine receptor complexes, and blockade of either inhibits signaling by inflammatory cytokines: interleukin (IL) -2, 4, 7, 9, 15, and 21 (Ghoreschi et al., Immunol. Rev. 228 (1) : 273-287, 2009) .
  • IL interleukin
  • other pathologically relevant cytokines such as IL-6
  • JAK1 blockade inhibits signaling of many pro-inflammatory cytokines (Guschin et al., EMBO J. 14 (7) : 1421-1429, 1995) .
  • JAK1 and JAK2 Humans deficient in JAK1 and JAK2 have not been described. Mice lacking JAK1 die perinatally (Schindler et al., J. Biol Chem. 282 (28) : 20059-20063, 2007) . JAK2 deficiency in mice is also lethal, with JAK2 -/- embryos dying between Day 12 and Day 13 after conception because of deficits in erythropoiesis (Neubauer et al., Cell 93 (3) : 397-409, 1998) . JAK3 deficiency has been described in humans and presents as severe combined immunodeficiency in the first few months of life, with symptoms such as failure to thrive, severe and recurrent infections, thrush, and diarrhea.
  • JAK1 and JAK2 Given the high degree of structural similarity between JAK1 and JAK2 (Williams et al., J. Mal. Biol. 387 (1) : 219-232, 2009) , the literature suggests that the majority of JAK1 inhibitors also inhibit JAK2 (lncyte Corp. press release, 10 Nov. 2010; Changelian et al., Science 302 (5646) : 875-878, 2003) . Recently, two JAK1 selective compounds, upadacitinib and abrocitinib, have been approved by the FDA. TYK2 selective inhibitor deucravacitinib is awaiting FDA approval.
  • AD Alzheimer’s disease
  • a ⁇ amyloid- ⁇
  • JAK1 inhibitors have been shown to reduce or prevent neuronal death, with potential applicability to treating amyotrophic lateral sclerosis (ALS) , frontotemporal dementia (FTD) , and Alzheimer’s disease (AD) (Rodriguez, S. et al. Nat Commun. 2021 Feb 15; 12 (1) : 1033; Rodriguez, S. et al. Sci. Transl. Med. 2021, 13, eaaz4699) .
  • Increased TYK2 and JAK1 activities have been implicated in AD pathophysiology (Wan et al., J. Neurosci. 2010, 30, 6873-81; Nevado-Holgado et al., Cells 2019, 8, 425) .
  • novel 1H-furo [3, 2-b] imidazo [4, 5-d] pyridine derivatives were described as selective dual TYK2/JAK1 inhibitors for systemic inflammatory diseases such as rheumatoid arthritis and psoriasis (WO 2018/067422 A1, WO 2020/244348 A1, WO 2020/244349 A1) .
  • this invention discloses selected compounds with very good brain penetration and anti-neuroinflammatory activities.
  • these compounds, and compositions comprising a compound of this disclosure are useful in treating disorders related to TYK2 and JAK1 activities such as CNS disorders, including multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, or amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) .
  • CNS disorders including multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, or amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) .
  • ALS/FTD amyotrophic lateral sclerosis/frontotemporal dementia
  • the present disclosure provides 1H-furo [3, 2-b] imidazo [4, 5-d] pyridine compounds, or salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof, as selective dual TYK2/JAK1 kinase inhibitors that have a good ability to penetrate the blood-brain barrier, and as such advantageous properties suited for use in addressing central nervous system (CNS) disorders.
  • the present disclosure also provides compositions comprising a compound of this disclosure or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
  • the present disclosure further provides methods of use of such compounds, or salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof, or such compositions, for treating disorders associated with TYK2 and JAK1, including central nervous system (CNS) disorders such as multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, or amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) .
  • CNS central nervous system
  • Parkinson’s disease Parkinson’s disease
  • Alzheimer’s disease Alzheimer’s disease
  • ALS/FTD amyotrophic lateral sclerosis/frontotemporal dementia
  • the compounds of this invention, and compositions comprising them, are useful for treating or lessening the severity of TYK2 and JAK1 modulated diseases, disorders, or symptoms thereof.
  • one aspect of the present disclosure relates to a method for treating a CNS disorder, the method comprising administering to a subject in need thereof an effective amount of a compound of Formulae (I) - (III) herein, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, which may be formulated into a composition.
  • the composition may be a pharmaceutical composition, which may further comprise a pharmaceutically acceptable carrier.
  • the CNS disorder is neurotoxicity and/or neurotrauma, stroke, multiple sclerosis, spinal cord injury, epilepsy, a mental disorder, a sleep condition, a movement disorder, nausea and/or emesis, amyotrophic lateral sclerosis, Alzheimer’s disease and drug addiction.
  • the CNS disorder can be any of those modulated by TYK2 and JAK1.
  • the CNS disorder is Alzheimer’s Disease, Parkinson’s Disease, amyotrophic lateral sclerosis, dementia, frontotemporal dementia, mild cognitive impairment (MCI) , or neuroinflammation.
  • compositions for use in treating the target CNS disorders as described herein comprising a compound of Formulae (I) - (III) , or salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, and a pharmaceutically acceptable carrier; and (ii) uses of a compound of Formulae (I) - (III) , or salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, for manufacturing a medicament for use in treating any of the target CNS disorders.
  • FIG. 1 shows that a compound of Formula (II) reduced HT22 neuronal cell death induced by LPS activation of BV2 microglia (FIG. 1A) , but did not affect the viability of HT22 cells in the presence of LPS but without BV2 microglia (FIG. 1B) .
  • FIG. 2 shows that a compound of Formula (II) inhibited IL-6, TNF and MCP-1 production in LPS-stimulated BV2 cells.
  • FIG. 3 shows Disease Activity Index changes over time in each treatment group.
  • FIGs. 4A-4B show Disease Activity Index changes of individual mice that received vehicle treatment (FIG. 4A) or a compound of Formula (II) at 30 mg/kg BID (FIG. 4B) .
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric 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) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
  • HPLC high pressure liquid chromatography
  • the compounds herein may also contain linkages (e.g., carbon-carbon bonds) wherein bond rotation is restricted about that particular linkage, e.g., restriction resulting from the presence of a ring or double bond. Accordingly, all cis/trans and E/Z isomers are expressly included in the present disclosure.
  • the compounds herein may also be represented in multiple tautomeric forms; in such instances, the present disclosure expressly includes all tautomeric forms of the compounds described herein, even though only a single tautomeric form may be represented. All such isomeric forms of such compounds herein are expressly included in the present disclosure.
  • isomers is intended to include diastereoisomers, enantiomers, regioisomers, structural isomers, rotational isomers, tautomers, and the like.
  • the methods of the present disclosure may be carried out with an enantiomerically enriched compound, a racemate, or a mixture of diastereomers. All isomers of compounds delineated herein are expressly included in the present disclosure.
  • the bond is a single bond, the dashed line --- is a single bond or absent, and the bond is a single or double bond.
  • formulae and structures depicted herein include compounds that do not include isotopically enriched atoms, and also include compounds that include isotopically enriched atoms.
  • compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of 19 F with 18 F, or the replacement of a carbon by a 13 C-or 14 C-enriched carbon are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.
  • isotopes refers to variants of a particular chemical element such that, while all isotopes of a given element share the same number of protons in each atom of the element, those isotopes differ in the number of neutrons.
  • C 1-6 alkyl encompasses, 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.
  • aliphatic refers to alkyl, alkenyl, alkynyl, and carbocyclic groups.
  • heteroaliphatic refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.
  • 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 ( “C 1–12 alkyl” ) . In some embodiments, an alkyl group has 1 to 10 carbon atoms ( “C 1–10 alkyl” ) . In some embodiments, an alkyl group has 1 to 9 carbon atoms ( “C 1–9 alkyl” ) . In some embodiments, an alkyl group has 1 to 8 carbon atoms ( “C 1–8 alkyl” ) .
  • an alkyl group has 1 to 7 carbon atoms ( “C 1–7 alkyl” ) . In some embodiments, an alkyl group has 1 to 6 carbon atoms ( “C 1–6 alkyl” ) . In some embodiments, an alkyl group has 1 to 5 carbon atoms ( “C 1–5 alkyl” ) . In some embodiments, 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” ) .
  • 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” ) .
  • Examples of C 1–6 alkyl groups include methyl (C 1 ) , ethyl (C 2 ) , propyl (C 3 ) (e.g., n-propyl, isopropyl) , butyl (C 4 ) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl) , pentyl (C 5 ) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tert-amyl) , and hexyl (C 6 ) (e.g., n-hexyl) .
  • alkyl groups include n-heptyl (C 7 ) , n-octyl (C 8 ) , n-dodecyl (C 12 ) , and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl” ) or substituted (a “substituted alkyl” ) with one or more substituents (e.g., halogen, such as F) .
  • substituents e.g., halogen, such as F
  • the alkyl group is an unsubstituted C 1–12 alkyl (such as unsubstituted C 1–6 alkyl, e.g., -CH 3 (Me) , unsubstituted ethyl (Et) , unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr) , unsubstituted isopropyl (i-Pr) ) , unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu) , unsubstituted tert-butyl (tert-Bu or t-Bu) , unsubstituted sec-butyl (sec-Bu or s-Bu) , unsubstituted isobutyl (i-Bu) ) .
  • C 1–12 alkyl such as unsubstituted C
  • the alkyl group is a substituted C 1–12 alkyl (such as substituted C 1–6 alkyl, e.g., –CH 2 F, –CHF 2 , –CF 3 , –CH 2 CH 2 F, –CH 2 CHF 2 , –CH 2 CF 3 , or benzyl (Bn) ) .
  • substituted C 1–6 alkyl e.g., –CH 2 F, –CHF 2 , –CF 3 , –CH 2 CH 2 F, –CH 2 CHF 2 , –CH 2 CF 3 , or benzyl (Bn)
  • haloalkyl is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo.
  • Perhaloalkyl is a subset of haloalkyl and refers to an alkyl group wherein all of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo.
  • the haloalkyl moiety has 1 to 20 carbon atoms ( “C 1–20 haloalkyl” ) .
  • the haloalkyl moiety has 1 to 10 carbon atoms ( “C 1–10 haloalkyl” ) . In some embodiments, the haloalkyl moiety has 1 to 9 carbon atoms ( “C 1–9 haloalkyl” ) . In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms ( “C 1–8 haloalkyl” ) . In some embodiments, the haloalkyl moiety has 1 to 7 carbon atoms ( “C 1–7 haloalkyl” ) .
  • the haloalkyl moiety has 1 to 6 carbon atoms ( “C 1–6 haloalkyl” ) . In some embodiments, the haloalkyl moiety has 1 to 5 carbon atoms ( “C 1–5 haloalkyl” ) . In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms ( “C 1–4 haloalkyl” ) . In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms ( “C 1–3 haloalkyl” ) .
  • the haloalkyl moiety has 1 to 2 carbon atoms ( “C 1–2 haloalkyl” ) .
  • all of the haloalkyl hydrogen atoms are independently replaced with fluoro to provide a “perfluoroalkyl” group.
  • all of the haloalkyl hydrogen atoms are independently replaced with chloro to provide a “perchloroalkyl” group.
  • haloalkyl groups include –CHF 2 , -CH 2 F, -CF 3 , -CH 2 CF 3 , -CF 2 CF 3 , -CF 2 CF 2 CF 3 , -CCl 3 , -CFCl 2 , -CF 2 Cl, and the like.
  • heteroalkyl refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position (s) of the parent chain.
  • a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain ( “heteroC 1–20 alkyl” ) .
  • a heteroalkyl group refers to a saturated group having from 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain ( “heteroC 1–12 alkyl” ) . In some embodiments, a heteroalkyl group is a saturated group having 1 to 11 carbon atoms and 1 or more heteroatoms within the parent chain ( “heteroC 1–11 alkyl” ) . In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain ( “heteroC 1–10 alkyl” ) .
  • a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain ( “heteroC 1–9 alkyl” ) . In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain ( “heteroC 1–8 alkyl” ) . In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain ( “heteroC 1–7 alkyl” ) .
  • a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain ( “heteroC 1–6 alkyl” ) . In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain ( “heteroC 1–5 alkyl” ) . In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1or 2 heteroatoms within the parent chain ( “heteroC 1–4 alkyl” ) .
  • a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain ( “heteroC 1–3 alkyl” ) . In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain ( “heteroC 1–2 alkyl” ) . In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ( “heteroC 1 alkyl” ) .
  • a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain ( “heteroC 2-6 alkyl” ) .
  • each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl” ) or substituted (a “substituted heteroalkyl” ) with one or more substituents.
  • the heteroalkyl group is an unsubstituted heteroC 1–12 alkyl.
  • the heteroalkyl group is a substituted heteroC 1–12 alkyl.
  • alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds) .
  • an alkenyl group has 2 to 20 carbon atoms ( “C 2-20 alkenyl” ) .
  • an alkenyl group has 2 to 12 carbon atoms ( “C 2–12 alkenyl” ) .
  • an alkenyl group has 2 to 11 carbon atoms ( “C 2–11 alkenyl” ) .
  • an alkenyl group has 2 to 10 carbon atoms ( “C 2–10 alkenyl” ) . In some embodiments, an alkenyl group has 2 to 9 carbon atoms ( “C 2–9 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 7 carbon atoms ( “C 2–7 alkenyl” ) . In some embodiments, an alkenyl group has 2 to 6 carbon atoms ( “C 2–6 alkenyl” ) .
  • an alkenyl group has 2 to 5 carbon atoms ( “C 2–5 alkenyl” ) . In some embodiments, 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.
  • alkenyl examples include heptenyl (C 7 ) , octenyl (C 8 ) , octatrienyl (C 8 ) , and the like.
  • each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl” ) or substituted (a “substituted alkenyl” ) with one or more substituents.
  • the alkenyl group is an unsubstituted C 2- 20 alkenyl.
  • the alkenyl group is a substituted C 2-20 alkenyl.
  • heteroalkenyl refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position (s) of the parent chain.
  • a heteroalkenyl group refers to a group having from 2 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ( “heteroC 2–20 alkenyl” ) .
  • a heteroalkenyl group refers to a group having from 2 to 12 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ( “heteroC 2–12 alkenyl” ) .
  • a heteroalkenyl group refers to a group having from 2 to 11 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ( “heteroC 2–11 alkenyl” ) .
  • a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ( “heteroC 2–10 alkenyl” ) .
  • a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain ( “heteroC 2–9 alkenyl” ) . In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ( “heteroC 2–8 alkenyl” ) . In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ( “heteroC 2–7 alkenyl” ) .
  • a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ( “heteroC 2–6 alkenyl” ) . In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain ( “heteroC 2–5 alkenyl” ) . In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain ( “heteroC 2–4 alkenyl” ) .
  • a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain ( “heteroC 2–3 alkenyl” ) . In some embodiments, a heteroalkenyl group has 2 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain ( “heteroC 2 alkenyl” ) . In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain ( “heteroC 2–6 alkenyl” ) .
  • each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl” ) or substituted (a “substituted heteroalkenyl” ) with one or more substituents.
  • the heteroalkenyl group is an unsubstituted heteroC 2–20 alkenyl.
  • the heteroalkenyl group is a substituted heteroC 2–20 alkenyl.
  • alkynyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) ( “C 1-20 alkynyl” ) .
  • an alkynyl group has 2 to 10 carbon atoms ( “C 2-10 alkynyl” ) .
  • an alkynyl group has 2 to 9 carbon atoms ( “C 2-9 alkynyl” ) .
  • an alkynyl group has 2 to 8 carbon atoms ( “C 2-8 alkynyl” ) .
  • an alkynyl group has 2 to 7 carbon atoms ( “C 2-7 alkynyl” ) . In some embodiments, an alkynyl group has 2 to 6 carbon atoms ( “C 2-6 alkynyl” ) . In some embodiments, an alkynyl group has 2 to 5 carbon atoms ( “C 2-5 alkynyl” ) . In some embodiments, 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” ) .
  • 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.
  • 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. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl” ) or substituted (a “substituted alkynyl” ) with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C 2-20 alkynyl. In certain embodiments, the alkynyl group is a substituted C 2-20 alkynyl.
  • heteroalkynyl refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position (s) of the parent chain.
  • a heteroalkynyl group refers to a group having from 2 to 20 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ( “heteroC 2–20 alkynyl” ) .
  • a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ( “heteroC 2–10 alkynyl” ) . In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ( “heteroC 2–9 alkynyl” ) . In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ( “heteroC 2–8 alkynyl” ) .
  • a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ( “heteroC 2–7 alkynyl” ) . In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ( “heteroC 2–6 alkynyl” ) . In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain ( “heteroC 2–5 alkynyl” ) .
  • a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain ( “heteroC 2–4 alkynyl” ) . In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain ( “heteroC 2–3 alkynyl” ) . In some embodiments, a heteroalkynyl group has 2 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain ( “heteroC 2 alkynyl” ) .
  • a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain ( “heteroC 2– 6 alkynyl” ) .
  • each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl” ) or substituted (a “substituted heteroalkynyl” ) with one or more substituents.
  • the heteroalkynyl group is an unsubstituted heteroC 2–20 alkynyl.
  • the heteroalkynyl group is a substituted heteroC 2–20 alkynyl.
  • carbocyclyl or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms ( “C 3-14 carbocyclyl” ) and zero heteroatoms in the non-aromatic ring system.
  • a carbocyclyl group has 3 to 14 ring carbon atoms ( “C 3-14 carbocyclyl” ) .
  • a carbocyclyl group has 3 to 13 ring carbon atoms ( “C 3-13 carbocyclyl” ) .
  • a carbocyclyl group has 3 to 12 ring carbon atoms ( “C 3-12 carbocyclyl” ) .
  • a carbocyclyl group has 3 to 11 ring carbon atoms ( “C 3-11 carbocyclyl” ) . In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms ( “C 3-10 carbocyclyl” ) . In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ( “C 3-8 carbocyclyl” ) . In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ( “C 3-7 carbocyclyl” ) . In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ( “C 3-6 carbocyclyl” ) .
  • a carbocyclyl group has 4 to 6 ring carbon atoms ( “C 4-6 carbocyclyl” ) . In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms ( “C 5-6 carbocyclyl” ) . In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ( “C 5-10 carbocyclyl” ) .
  • Exemplary C 3-6 carbocyclyl groups include 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 3-8 carbocyclyl groups include 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 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.
  • Exemplary C 3-8 carbocyclyl groups include the aforementioned C 3-10 carbocyclyl groups as well as cycloundecyl (C 11 ) , spiro [5.5] undecanyl (C 11 ) , cyclododecyl (C 12 ) , cyclododecenyl (C 12 ) , cyclotridecane (C 13 ) , cyclotetradecane (C 14 ) , and the like.
  • the carbocyclyl group is either monocyclic ( “monocyclic carbocyclyl” ) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system ( “bicyclic carbocyclyl” ) or tricyclic system ( “tricyclic carbocyclyl” ) ) and can be saturated or can contain one or more carbon-carbon double or triple bonds.
  • 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 unsubstituted (an “unsubstituted carbocyclyl” ) or substituted (a “substituted carbocyclyl” ) with one or more substituents.
  • the carbocyclyl group is an unsubstituted C 3-14 carbocyclyl.
  • the carbocyclyl group is a substituted C 3-14 carbocyclyl.
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms ( “C 3-14 cycloalkyl” ) .
  • a cycloalkyl group has 3 to 10 ring carbon atoms ( “C 3-10 cycloalkyl” ) .
  • a cycloalkyl group has 3 to 8 ring carbon atoms ( “C 3-8 cycloalkyl” ) .
  • a cycloalkyl group has 3 to 6 ring carbon atoms ( “C 3-6 cycloalkyl” ) .
  • a cycloalkyl group has 4 to 6 ring carbon atoms ( “C 4-6 cycloalkyl” ) . In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ( “C 5-6 cycloalkyl” ) . In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ( “C 5-10 cycloalkyl” ) . Examples of C 5-6 cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 5 ) .
  • 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 3-6 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.
  • heterocyclyl refers to a radical of a 3-to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ( “3–14 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 polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system ( “bicyclic heterocyclyl” ) or tricyclic system ( “tricyclic heterocyclyl” ) ) , and can be saturated or can contain one or more carbon-carbon double or triple bonds.
  • Heterocyclyl polycyclic 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 unsubstituted (an “unsubstituted heterocyclyl” ) or substituted (a “substituted heterocyclyl” ) with one or more substituents.
  • the heterocyclyl group is an unsubstituted 3–14 membered heterocyclyl.
  • the heterocyclyl group is a substituted 3–14 membered heterocyclyl.
  • the heterocyclyl is substituted or unsubstituted, 3-to 7-membered, monocyclic heterocyclyl, wherein 1, 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits.
  • 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, and sulfur ( “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 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include azirdinyl, oxiranyl, and thiiranyl.
  • Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include azetidinyl, oxetanyl, and thietanyl.
  • Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-dione.
  • Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include dioxolanyl, oxathiolanyl and dithiolanyl.
  • Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl.
  • Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include triazinyl.
  • Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include azepanyl, oxepanyl and thiepanyl.
  • Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include azocanyl, oxecanyl and thiocanyl.
  • Exemplary bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1, 8-naphthyridinyl, octahydropyrrolo [3, 2-b] pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo [e] [1, 4] di
  • 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 ⁇ electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ( “C 6-14 aryl” ) .
  • an aryl group has 6 ring carbon atoms ( “C 6 aryl” ; e.g., phenyl) .
  • an aryl group has 10 ring carbon atoms ( “C 10 aryl” ; e.g., naphthyl such as 1–naphthyl and 2-naphthyl) .
  • an aryl group has 14 ring carbon atoms ( “C 14 aryl” ; e.g., anthracyl) .
  • Aryl also includes ring systems wherein the aryl ring, as defined 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.
  • each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl” ) or substituted (a “substituted aryl” ) with one or more substituents.
  • the aryl group is an unsubstituted C 6-14 aryl.
  • the aryl group is a substituted C 6-14 aryl.
  • Alkyl is a subset of “alkyl” and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl moiety.
  • heteroaryl refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ 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 ( “5-14 membered heteroaryl” ) .
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl polycyclic 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 polycyclic (aryl/heteroaryl) ring system.
  • Polycyclic 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, e.g., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl) .
  • the heteroaryl is substituted or unsubstituted, 5-or 6-membered, monocyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.
  • the heteroaryl is substituted or unsubstituted, 9-or 10-membered, bicyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.
  • 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 unsubstituted (an “unsubstituted heteroaryl” ) or substituted (a “substituted heteroaryl” ) with one or more substituents.
  • the heteroaryl group is an unsubstituted 5-14 membered heteroaryl.
  • the heteroaryl group is a substituted 5-14 membered heteroaryl.
  • Exemplary 5-membered heteroaryl groups containing 1 heteroatom include pyrrolyl, furanyl, and thiophenyl.
  • Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing 1 heteroatom include pyridinyl.
  • Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing 1 heteroatom include azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5, 6-bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
  • Exemplary 6, 6-bicyclic heteroaryl groups include naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • Exemplary tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.
  • Heteroaralkyl is a subset of “alkyl” and refers to an alkyl group substituted by a heteroaryl group, wherein the point of attachment is on the alkyl moiety.
  • unsaturated or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.
  • saturated or “fully saturated” refers to a moiety that does not contain a double or triple bond, e.g., the moiety only contains single bonds.
  • alkylene is the divalent moiety of alkyl
  • alkenylene is the divalent moiety of alkenyl
  • alkynylene is the divalent moiety of alkynyl
  • heteroalkylene is the divalent moiety of heteroalkyl
  • heteroalkenylene is the divalent moiety of heteroalkenyl
  • heteroalkynylene is the divalent moiety of heteroalkynyl
  • carbocyclylene is the divalent moiety of carbocyclyl
  • heterocyclylene is the divalent moiety of heterocyclyl
  • arylene is the divalent moiety of aryl
  • heteroarylene is the divalent moiety of heteroaryl.
  • a group is optionally substituted unless expressly provided otherwise.
  • the term “optionally substituted” refers to being substituted or unsubstituted.
  • alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted.
  • Optionally substituted refers to a group which is substituted or unsubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “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 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 and includes 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.
  • the invention is not limited in any manner by the exemplary substituents described herein.
  • each instance of R aa is, independently, selected from C 1–20 alkyl, C 1–20 perhaloalkyl, C 1–20 alkenyl, C 1–20 alkynyl, heteroC 1–20 alkyl, heteroC 1–20 alkenyl, heteroC 1–20 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 of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, 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 1–20 alkyl, C 1–20 perhaloalkyl, C 1–20 alkenyl, C 1–20 alkynyl, heteroC 1–20 alkyl, heteroC 1–20 alkenyl, heteroC 1–20 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, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;
  • each instance of R ee is, independently, selected from C 1–10 alkyl, C 1–10 perhaloalkyl, C 1–10 alkenyl, C 1–10 alkynyl, heteroC 1–10 alkyl, heteroC 1–10 alkenyl, heteroC 1–10 alkynyl, C 3-10 carbocyclyl, C 6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, 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 1–10 alkyl, C 1–10 perhaloalkyl, C 1–10 alkenyl, C 1–10 alkynyl, heteroC 1–10 alkyl, heteroC 1–10 alkenyl, heteroC 1–10 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 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;
  • each X - is a counterion.
  • each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C 1-6 alkyl, -OR aa , -SR aa , -N (R bb ) 2 , –CN, –SCN, or –NO 2 .
  • each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen moieties) or unsubstituted C 1–10 alkyl, -OR aa , -SR aa , -N (R bb ) 2 , –CN, –SCN, or –NO 2 , wherein R aa is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C 1–10 alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-
  • the molecular weight of a carbon atom substituent is lower than 250, lower than 200, lower than 150, lower than 100, or lower than 50 g/mol.
  • a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and/or silicon atoms.
  • a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and/or nitrogen atoms.
  • a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and/or iodine atoms.
  • a carbon atom substituent consists of carbon, hydrogen, fluorine, and/or chlorine atoms.
  • halo refers to fluorine (fluoro, -F) , chlorine (chloro, -Cl) , bromine (bromo, -Br) , or iodine (iodo, -I) .
  • hydroxyl refers to the group -OH.
  • amino refers to the group -NH 2 .
  • substituted amino by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino. In certain embodiments, the “substituted amino” is a monosubstituted amino or a disubstituted amino group.
  • trisubstituted amino refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from -N (R bb ) 3 and -N (R bb ) 3 + X - , wherein R bb and X - are as defined herein.
  • acyl groups include aldehydes (-CHO) , carboxylic acids (-CO 2 H) , ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas.
  • Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy
  • Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms.
  • each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C 1-6 alkyl or a nitrogen protecting group.
  • the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an “amino protecting group” ) .
  • Nitrogen 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, 3 rd edition, John Wiley &Sons, 1999, incorporated herein by reference.
  • each nitrogen protecting group is independently selected from the group consisting of formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N’-dithiobenzyloxyacylamino) acetamide, 3- (p-hydroxyphenyl) propanamide, 3- (o-nitrophenyl) propanamide, 2-methyl-2- (o-nitrophenoxy) propanamide, 2-methyl-2- (o-phenylazophenoxy) propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitroc
  • each nitrogen protecting group is independently selected from the group consisting of methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc) , 9- (2-sulfo) fluorenylmethyl carbamate, 9- (2, 7-dibromo) fluoroenylmethyl carbamate, 2, 7-di-t-butyl- [9- (10, 10-dioxo-10, 10, 10, 10-tetrahydrothioxanthyl) ] methyl carbamate (DBD-Tmoc) , 4-methoxyphenacyl carbamate (Phenoc) , 2, 2, 2-trichloroethyl carbamate (Troc) , 2-trimethylsilylethyl carbamate (Teoc) , 2-phenylethyl carbamate (hZ) , 1– (1-adamantyl) -1
  • each nitrogen protecting group is independently selected from the group consisting of p-toluenesulfonamide (Ts) , benzenesulfonamide, 2, 3, 6-trimethyl-4-methoxybenzenesulfonamide (Mtr) , 2, 4, 6-trimethoxybenzenesulfonamide (Mtb) , 2, 6-dimethyl-4-methoxybenzenesulfonamide (Pme) , 2, 3, 5, 6-tetramethyl-4-methoxybenzenesulfonamide (Mte) , 4-methoxybenzenesulfonamide (Mbs) , 2, 4, 6-trimethylbenzenesulfonamide (Mts) , 2, 6-dimethoxy-4-methylbenzenesulfonamide (iMds) , 2, 2, 5, 7, 8-pentamethylchroman-6-sulfonamide (Pmc) , methan
  • each nitrogen protecting group is independently selected from the group consisting of phenothiazinyl- (10) -acyl derivatives, N’-p-toluenesulfonylaminoacyl derivatives, N’-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4, 5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts) , N-2, 3-diphenylmaleimide, N-2, 5-dimethylpyrrole, N-1, 1, 4, 4-tetramethyldisilylazacyclopentane adduct (STABASE) , 5-substituted 1, 3-dimethyl-1, 3, 5-triazacyclohexan-2-one, 5-substituted 1, 3-dibenzyl-1, 3,
  • At least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.
  • each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C 1-6 alkyl or an oxygen protecting group.
  • the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “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, 3 rd edition, John Wiley &Sons, 1999, incorporated herein by reference.
  • each oxygen protecting group is selected from the group consisting of methyl, methoxymethyl (MOM) , methylthiomethyl (MTM) , t-butylthiomethyl, (phenyldimethylsilyl) methoxymethyl (SMOM) , benzyloxymethyl (BOM) , p-methoxybenzyloxymethyl (PMBM) , (4-methoxyphenoxy) methyl (p-AOM) , guaiacolmethyl (GUM) , t-butoxymethyl, 4-pentenyloxymethyl (POM) , siloxymethyl, 2-methoxyethoxymethyl (MEM) , 2, 2, 2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl, 2- (trimethylsilyl) ethoxymethyl (SEMOR) , tetrahydropyranyl (THP) , 3-bromotetrahydropyranyl (THP) , 3-bromotetrahydropyranyl (TH
  • At least one oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl.
  • each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C 1-6 alkyl or a sulfur protecting group.
  • the molecular weight of a substituent is lower than 250, lower than 200, lower than 150, lower than 100, or lower than 50 g/mol.
  • a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and/or silicon atoms.
  • a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and/or nitrogen atoms.
  • a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and/or iodine atoms.
  • a substituent consists of carbon, hydrogen, fluorine, and/or chlorine atoms. In certain embodiments, a substituent comprises 0, 1, 2, or 3 hydrogen bond donors. In certain embodiments, a substituent comprises 0, 1, 2, or 3 hydrogen bond acceptors.
  • a “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality.
  • An anionic counterion may be monovalent (e.g., including one formal negative charge) .
  • An anionic counterion may also be multivalent (e.g., including more than one formal negative charge) , such as divalent or trivalent.
  • Exemplary counterions include halide ions (e.g., F – , Cl – , Br – , I – ) , NO 3 – , ClO 4 – , OH – , H 2 PO 4 – , HCO 3 - , HSO 4 – , sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p–toluenesulfonate, benzenesulfonate, 10–camphor sulfonate, naphthalene–2–sulfonate, naphthalene–1–sulfonic acid–5–sulfonate, ethan–1–sulfonic acid–2–sulfonate, and the like) , carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, glucon
  • Exemplary counterions which may be multivalent include CO 3 2- , HPO 4 2- , PO 4 3- , B 4 O 7 2- , SO 4 2- , S 2 O 3 2- , carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like) , and carboranes.
  • carboxylate anions e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like
  • At least one instance refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.
  • non-hydrogen group refers to any group that is defined for a particular variable that is not hydrogen.
  • salt refers to any and all salts, and encompasses pharmaceutically acceptable salts.
  • Salts include ionic compounds that result from the neutralization reaction of an acid and a base.
  • a salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) so that the salt is electrically neutral (without a net charge) .
  • Salts of the compounds of this invention include those derived from inorganic and organic acids and bases.
  • acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, per
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1–4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • solvate refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding.
  • Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like.
  • the compounds described herein may be prepared, e.g., in crystalline form, and may be solvated.
  • Suitable solvates include pharmaceutically acceptable solvates 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 a crystalline solid.
  • “Solvate” encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.
  • hydrate refers to a compound that is associated with water.
  • the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R ⁇ x H 2 O, wherein R is the compound, and x is a number greater than 0.
  • a given compound may form more than one type of hydrate, including, e.g., monohydrates (x is 1) , lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R ⁇ 0.5 H 2 O) ) , and polyhydrates (x is a number greater than 1, e.g., dihydrates (R ⁇ 2 H 2 O) and hexahydrates (R ⁇ 6 H 2 O) ) .
  • monohydrates x is 1
  • lower hydrates x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R ⁇ 0.5 H 2 O)
  • polyhydrates x is a number greater than 1, e.g., dihydrates (R ⁇ 2 H 2 O) and hexahydrates (R ⁇ 6 H 2 O) ) .
  • tautomers or “tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa) .
  • the exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base.
  • Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to- (a different enamine) tautomerizations.
  • 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” .
  • 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” .
  • polymorph refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof) . All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.
  • co-crystal refers to a crystalline structure comprising at least two different components (e.g., a compound and an acid) , wherein each of the components is independently an atom, ion, or molecule. In certain embodiments, none of the components is a solvent. In certain embodiments, at least one of the components is a solvent.
  • a co-crystal of a compound and an acid is different from a salt formed from a compound and the acid. In the salt, a compound is complexed with the acid in a way that proton transfer (e.g., a complete proton transfer) from the acid to a compound easily occurs at room temperature.
  • a compound is complexed with the acid in a way that proton transfer from the acid to a herein does not easily occur at room temperature.
  • Co-crystals may be useful to improve the properties (e.g., solubility, stability, and ease of formulation) of a compound.
  • prodrugs refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds described herein, which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgaard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985) .
  • Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy) alkyl esters or (alkoxycarbonyl) oxy) alkylesters.
  • C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds described herein may be preferred.
  • composition and “formulation” are used interchangeably.
  • a “subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult) ) or non-human animal.
  • the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey) , commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog) , or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey) ) .
  • the non-human animal is a fish, reptile, or amphibian.
  • the non-human animal may be a male or female at any stage of development.
  • the non-human animal may be a transgenic animal or genetically engineered animal.
  • patient refers to a human subject in need of treatment of a disorder or a disease.
  • administer refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disorder or disease described herein.
  • treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed.
  • treatment may be administered in the absence of signs or symptoms of the disorder.
  • treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of exposure to a pathogen) . Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.
  • an effective amount of a compound described herein refers to an amount sufficient to elicit the desired biological response.
  • An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, severity of side effects, disease, or disorder, the identity, pharmacokinetics, and pharmacodynamics of the particular compound, the condition being treated, the mode, route, and desired or required frequency of administration, the species, age and health or general condition of the subject.
  • an effective amount is a therapeutically effective amount.
  • an effective amount is a prophylactic treatment.
  • an effective amount is the amount of a compound described herein in a single dose.
  • an effective amount is the combined amounts of a compound described herein in multiple doses.
  • the desired dosage is delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks.
  • the desired dosage is delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations) .
  • a “therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the 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 condition.
  • the term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent.
  • a therapeutically effective amount is an amount sufficient for dual TYK2/JAK1 kinase inhibition.
  • a therapeutically effective amount is an amount sufficient for treating a CNS disorder.
  • a therapeutically effective amount is an amount sufficient for dual TYK2/JAK1 kinase inhibition and treating a CNS disorder.
  • prevent, ” “preventing, ” or “prevention” refers to a prophylactic treatment of a subject who is not and was not with a disorder but is at risk of developing the disorder or who was with a disorder, is not with the disorder, but is at risk of regression of the disorder.
  • the subject is at a higher risk of developing the disorder or at a higher risk of regression of the disorder than an average healthy member of a population.
  • the term “inhibit” or “inhibition” in the context of enzymes refers to a reduction in the activity of the enzyme.
  • the term refers to a reduction of the level of enzyme activity, e.g., Janus family kinase activity, to a level that is statistically significantly lower than an initial level, which may, for example, be a baseline level of enzyme activity.
  • the term refers to a reduction of the level of enzyme activity, e.g., Janus family kinase activity, to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001%of an initial level, which may, for example, be a baseline level of enzyme activity.
  • the level of enzyme activity e.g., Janus family kinase activity
  • the term “dual TYK2/JAK1 inhibition” or “dual TYK2/JAK1 kinase inhibition” in the context of enzymes refers to a reduction in TYK2 kinase activity and JAK1 kinase activity. In some embodiments, the term refers to a reduction in the level of enzyme activities, e.g., TYK2 kinase activity and JAK1 kinase activity, to levels that are statistically significantly lower than an initial level of TYK2 kinase activity and an initial level of JAK1 kinase activity, which may, for example, be baseline levels of enzyme activities.
  • the term refers to a reduction of the levels of enzyme activities, e.g., TYK2 kinase activity and JAK1 kinase activity, to levels that are less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001%of an initial level of TYK2 kinase activity and an initial level of JAK1 kinase activity, which may, for example, be baseline levels of enzyme activities.
  • enzyme activities e.g., TYK2 kinase activity and JAK1 kinase activity
  • the term “dual TYK2/JAK1 inhibitor” or “dual TYK2/JAK1 kinase inhibitor” in the context of enzymes refers to a compound capable of reducing TYK2 kinase activity and JAK1 kinase activity.
  • the term refers to a compound capable of reducing the level of enzyme activities, e.g., TYK2 kinase activity and JAK1 kinase activity, to levels that are statistically significantly lower than an initial level of TYK2 kinase activity and an initial level of JAK1 kinase activity, which may, for example, be baseline levels of enzyme activities.
  • the term refers to a compound capable of reducing the level of enzyme activities, e.g., TYK2 kinase activity and JAK1 kinase activity, to levels that are less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001%of an initial level of TYK2 kinase activity and an initial level of JAK1 kinase activity, which may, for example, be baseline levels of enzyme activities.
  • TYK2 kinase activity and JAK1 kinase activity e.g., TYK2 kinase activity and JAK1 kinase activity
  • the effective amount is an amount effective for inhibiting the activity of a protein kinase by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 98%. In certain embodiments, the effective amount is an amount effective for inhibiting the activity of a Janus family kinase by not more than 10%, not more than 20%, not more than 30%, not more than 40%, not more than 50%, not more than 60%, not more than 70%, not more than 80%, not more than 90%, not more than 95%, or not more than 98%. In certain embodiments, the effective amount is an amount effective for inhibiting the activity of a Janus family kinase by a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive.
  • a “kinase” is a type of enzyme that transfers phosphate groups from high energy donor molecules, such as ATP, to specific substrates, referred to as phosphorylation.
  • Kinases are part of the larger family of phosphotransferases.
  • One of the largest groups of kinases are protein kinases, which act on and modify the activity of specific proteins.
  • Kinases are used extensively to transmit signals and control complex processes in cells.
  • Various other kinases act on small molecules such as lipids, carbohydrates, amino acids, and nucleotides, either for signaling or to prime them for metabolic pathways.
  • Kinases are often named after their substrates. More than 500 different protein kinases have been identified in humans.
  • exemplary human protein kinases include, but are not limited to, AAK1, ABL, ACK, ACTR2, ACTR2B, AKT1, AKT2, AKT3, ALK, ALK1, ALK2, ALK4, ALK7, AMPKa1, AMPKa2, ANKRD3, ANPa, ANPb, ARAF, ARAFps, ARG, AurA, AurAps1, AurAps2, AurB, AurBps1, AurC, AXL, BARK1, BARK2, BIKE, BLK, BMPR1A, BMPR1Aps1, BMPR1Aps2, BMPR1B, BMPR2, BMX, BRAF, BRAFps, BRK, BRSK1, BRSK2, BTK, BUB1, BUBR1, CaMK1a, CaMK1b, CaMK1d, CaMK1g, CaMK2a, CaMK2b, CaMK2d, CaMK2g,
  • the present disclosure is based at least in part on the unexpected results that compounds of Formulae (I) - (III) are selective dual TYK2/JAK1 kinase inhibitors that have a good ability to penetrate the blood-brain barrier.
  • Described herein are methods for treating CNS disorders such as those described herein using an effective amount of a compound of Formulae (I) - (III) , or salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a composition comprising a compound of Formulae (I) - (III) , or salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
  • compositions comprising a compound of Formulae (I) - (III) , or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient.
  • the pharmaceutical composition described herein comprises a compound of Formulae (I) - (III) , or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, and a pharmaceutically acceptable excipient.
  • the compound described herein is provided in an effective amount in the pharmaceutical composition.
  • the effective amount is a therapeutically effective amount.
  • the effective amount is a prophylactically effective amount.
  • the effective amount is an amount effective for treating a CNS disorder in a subject in need thereof.
  • the effective amount is an amount effective for preventing a CNS disorder in a subject in need thereof.
  • the effective amount is an amount effective for reducing the risk of developing a CNS disorder in a subject in need thereof.
  • the effective amount is an amount effective for inhibiting the activity (e.g., aberrant activity, such as increased activity) of a protein kinase in a subject or cell.
  • compositions described herein can be prepared by any method known in the art of pharmaceutics.
  • such preparatory methods include bringing the compound described herein (i.e., the “active ingredient” ) into association with a carrier or excipient, and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping, and/or packaging the product into a desired single-or multi-dose unit.
  • compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses.
  • a “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
  • the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.
  • Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered.
  • the composition may comprise between 0.1%and 100% (w/w) active ingredient.
  • compositions used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.
  • Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils) , glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents,
  • the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • the conjugates described herein are mixed with solubilizing agents such as alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.
  • sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol.
  • acceptable vehicles and solvents that can be employed are water, Ringer’s solution, U.S.P., and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono-or di-glycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) release control polymers such as various grades of hydroxypropyl methylcellulose (HPMC
  • Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient (s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • encapsulating compositions which can be used include polymeric substances and waxes.
  • Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the active ingredient can be in a micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art.
  • the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch.
  • Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient (s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • encapsulating agents which can be used include polymeric substances and waxes.
  • compositions suitable for administration to humans are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation.
  • compositions described herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.
  • a compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and/or prophylactically active agents) .
  • the compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and/or efficacy) in treating a disorder in a subject in need thereof, in preventing a disorder in a subject in need thereof, in reducing the risk to develop a disorder in a subject in need thereof, and/or in inhibiting the activity of a protein kinase in a subject or cell) , improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in a subject or cell.
  • additional pharmaceutical agents e.g., therapeutically and/or prophylactically active agents.
  • additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and/or efficacy) in treating a disorder in a
  • a pharmaceutical composition described herein including a compound described herein and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both.
  • the additional pharmaceutical agent achieves a desired effect for the same disorder.
  • the additional pharmaceutical agent achieves different effects.
  • the compound or composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies.
  • Pharmaceutical agents include therapeutically active agents.
  • Pharmaceutical agents also include prophylactically active agents.
  • Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S.
  • the additional pharmaceutical agent is a pharmaceutical agent useful for treating and/or preventing a CNS disorder.
  • Each additional pharmaceutical agent may be administered at a dose and/or on a time schedule determined for that pharmaceutical agent.
  • the additional pharmaceutical agents may also be administered together with each other and/or with the compound or composition described herein in a single dose or composition or administered separately in different doses or compositions.
  • the particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent (s) and/or the desired therapeutic and/or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent (s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.
  • the additional pharmaceutical agents include, but are not limited to, anti-proliferative agents, anti-cancer agents, anti-angiogenesis agents, steroidal or non-steroidal anti-inflammatory agents, immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol-lowering agents, anti-diabetic agents, anti-allergic agents, contraceptive agents, pain-relieving agents, anesthetics, anti–coagulants, inhibitors of an enzyme, steroidal agents, steroidal or antihistamine, antigens, vaccines, antibodies, decongestant, sedatives, opioids, analgesics, anti–pyretics, hormones, and prostaglandins.
  • the additional pharmaceutical agent is an anti-proliferative agent.
  • the additional pharmaceutical agent is an anti-cancer agent. In certain embodiments, the additional pharmaceutical agent is an anti-viral agent. In certain embodiments, the additional pharmaceutical agent is an binder or inhibitor of a protein kinase. In certain embodiments, the additional pharmaceutical agent is selected from the group consisting of epigenetic or transcriptional modulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors) , lysine methyltransferase inhibitors) , antimitotic drugs (e.g., taxanes and vinca alkaloids) , hormone receptor modulators (e.g., estrogen receptor modulators and androgen receptor modulators) , cell signaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors) , modulators of protein stability (e.g., proteasome inhibitors) , Hsp90 inhibitors, glucocorticoids, all-trans retinoic acids, and other agents that promote
  • the compounds described herein or pharmaceutical compositions can be administered in combination with an anti-cancer therapy including, but not limited to, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation) , immunotherapy, and chemotherapy.
  • an anti-cancer therapy including, but not limited to, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation) , immunotherapy, and chemotherapy.
  • Additional pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved by the US Food and Drug Administration as provided in the Code of Federal Regulations (CFR) ) , peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins and cells.
  • drug compounds e.g., compounds approved by the US Food and Drug Administration as provided in the Code of Federal Regulations (CFR)
  • CFR Code of Federal Regulations
  • kits e.g., pharmaceutical packs
  • the kits provided may comprise a pharmaceutical composition or compound described herein and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container) .
  • a container e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container
  • provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or compound described herein.
  • the pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form one unit dosage form.
  • kits including a first container comprising a compound or pharmaceutical composition described herein.
  • the kits are useful for treating a CNS disorder in a subject in need thereof.
  • the kits are useful for preventing a CNS disorder in a subject in need thereof.
  • the kits are useful for reducing the risk of developing a CNS disorder in a subject in need thereof.
  • the kits are useful for inhibiting the activity (e.g., aberrant activity, such as increased activity) of a protein kinase in a subject or cell.
  • kits described herein further includes instructions for using the kit.
  • a kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA) .
  • the information included in the kits is prescribing information.
  • the kits and instructions provide for treating a CNS disorder in a subject in need thereof.
  • the kits and instructions provide for preventing a CNS disorder in a subject in need thereof.
  • the kits and instructions provide for reducing the risk of developing a CNS disorder in a subject in need thereof.
  • kits and instructions provide for inhibiting the activity (e.g., aberrant activity, such as increased activity) of a protein kinase in a subject or cell.
  • a kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.
  • the present disclosure provides methods of treating a CNS disorder (or symptoms thereof) comprising administering an effective amount of a compound of the present disclosure, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a composition comprising an effective amount of a compound of the present disclosure, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, to a subject in need thereof.
  • Treating encompasses therapeutic treatment.
  • the subject is identified as in need thereof.
  • the method further comprises wherein the subject is treated; that is, the disease, disorder, or symptom thereof is ameliorated.
  • the effective amount is a therapeutically effective amount.
  • the method slows the progress of a CNS disorder in the subject.
  • the method improves the condition of the subject suffering from a CNS disorder.
  • the subject has a suspected or confirmed CNS disorder.
  • the effective amount is a prophylactically effective amount.
  • the method prevents or reduces the likelihood of a CNS disorder, e.g., in certain embodiments, the method comprises administering a compound of the present disclosure to a subject in need thereof in an amount sufficient to prevent or reduce the likelihood of a CNS disorder.
  • the subject is at risk of developing a CNS disorder.
  • Exemplary CNS disorders include, but are not limited to, neurotoxicity and/or neurotrauma, stroke, multiple sclerosis, spinal cord injury, epilepsy, a mental disorder, a sleep condition, a movement disorder, nausea and/or emesis, amyotrophic lateral sclerosis, Alzheimer’s disease and drug addiction.
  • the CNS disorder is neurotoxicity and/or neurotrauma, e.g., for example, as a result of acute neuronal injury (e.g., traumatic brain injury (TBI) , stroke, epilepsy) or a chronic neurodegenerative disorder (e.g., multiple sclerosis, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, Alzheimer’s disease) .
  • acute neuronal injury e.g., traumatic brain injury (TBI) , stroke, epilepsy
  • a chronic neurodegenerative disorder e.g., multiple sclerosis, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, Alzheimer’s disease
  • the compound of the present invention provides a neuroprotective effect, e.g., against an acute neuronal injury or a chronic neurodegenerative disorder.
  • the CNS disorder is stroke (e.g., ischemic stroke) .
  • the CNS disorder is multiple sclerosis.
  • the CNS disorder is spinal cord injury.
  • the CNS disorder is epilepsy.
  • the CNS disorder is a mental disorder, e.g., for example, depression, anxiety or anxiety-related conditions, a learning disability or schizophrenia.
  • the CNS disorder is depression.
  • “Depression” includes, but is not limited to, depressive disorders or conditions, such as, for example, major depressive disorders (e.g., unipolar depression) , dysthymic disorders (e.g., chronic, mild depression) , bipolar disorders (e.g., manic-depression) , seasonal affective disorder, and/or depression associated with drug addiction (e.g., withdrawal) .
  • the depression can be clinical or subclinical depression.
  • the depression can be associated with or premenstrual syndrome and/or premenstrual dysphoric disorder.
  • the CNS disorder is anxiety.
  • “Anxiety” includes, but is not limited to anxiety and anxiety-related conditions, such as, for example, clinical anxiety, panic disorder, agoraphobia, generalized anxiety disorder, specific phobia, social phobia, obsessive-compulsive disorder, acute stress disorder, post-traumatic stress disorder, adjustment disorders with anxious features, anxiety disorder associated with depression, anxiety disorder due to general medical conditions, and substance-induced anxiety disorders, anxiety associated with drug addiction (e.g., withdrawal, dependence, reinstatement) and anxiety associated with nausea and/or emesis.
  • This treatment may also be to induce or promote sleep in a subject (e.g., for example, a subject with anxiety) .
  • the CNS disorder is a learning disorder (e.g., attention deficit hyperactivity disorder (ADHD) ) .
  • ADHD attention deficit hyperactivity disorder
  • the CNS disorder is Schizophrenia.
  • the CNS disorder is a sleep condition.
  • sleep conditions include, but are not limited to, insomnia, narcolepsy, sleep apnea, restless legs syndrome (RLS) , delayed sleep phase syndrome (DSPS) , periodic limb movement disorder (PLMD) , hypopnea syndrome, rapid eye movement behavior disorder (RBD) , shift work sleep condition (SWSD) , and sleep problems (e.g., parasomnias) such as nightmares, night terrors, sleep talking, head banging, snoring, and clenched jaw and/or grinding of teeth (bruxism) .
  • sleep problems e.g., parasomnias
  • nightmares e.g., night terrors, sleep talking, head banging, snoring, and clenched jaw and/or grinding of teeth (bruxism) .
  • the CNS disorder is a movement disorder, e.g., basal ganglia disorders, such as, for example, Parkinson’s disease, levodopa-induced dyskinesia, Huntington’s disease, Gilles de la Tourette’s syndrome, tardive dyskinesia and dystonia.
  • basal ganglia disorders such as, for example, Parkinson’s disease, levodopa-induced dyskinesia, Huntington’s disease, Gilles de la Tourette’s syndrome, tardive dyskinesia and dystonia.
  • the CNS disorder is Alzheimer’s disease.
  • the CNS disorder is amyotrophic lateral sclerosis (ALS) .
  • ALS amyotrophic lateral sclerosis
  • the CNS disorder is frontotemporal dementia (FTD) .
  • FTD frontotemporal dementia
  • the CNS disorder is Parkinson’s disease.
  • the CNS disorder is nausea and/or emesis.
  • the CNS disorder is drug addiction (e.g., for instance, addiction to opiates, nicotine, cocaine, psychostimulants or alcohol) .
  • drug addiction e.g., for instance, addiction to opiates, nicotine, cocaine, psychostimulants or alcohol.
  • the CNS disorder is modulated by the JAK-STAT pathway. In certain embodiments, the CNS disorder is modulated by JAK1. In certain embodiments, the CNS disorder is modulated by TYK2. In certain embodiments, the CNS disorder is modulated by TYK2 andJAK1.
  • the CNS disorder is Alzheimer’s Disease, Parkinson’s Disease, amyotrophic lateral sclerosis, dementia, frontotemporal dementia, mild cognitive impairment (MCI) , or neuroinflammation.
  • the CNS disorder is amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) .
  • ALS/FTD amyotrophic lateral sclerosis/frontotemporal dementia
  • the subject is an animal.
  • the animal may be of either sex and may be at any stage of development.
  • the subject described herein is a human.
  • the subject is a non-human animal.
  • the subject is a mammal.
  • the subject is a non-human mammal.
  • the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat.
  • the subject is a companion animal, such as a dog or cat.
  • the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat.
  • the subject is a zoo animal.
  • the subject is a research animal, such as a rodent (e.g., mouse, rat) , dog, pig, or non-human primate.
  • the animal is a genetically engineered animal.
  • the animal is a transgenic animal (e.g., transgenic mice and transgenic pigs) .
  • the subject is a fish or reptile.
  • any of the methods described herein may further include administering to the subject an additional pharmaceutical agent, which can be an anti-CNS disorder
  • additional pharmaceutical agent which can be an anti-CNS disorder
  • antipsychotics selected from butyrophenone, phenothiazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, mesoridazine, promazine, triflupromazine, levomepromazine, promethazine, thioxanthene, chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, asenapine, paliperidone, aripiprazole, a dopamine partial agonist, lamotrigine, memantine, tetrabenazine, cann
  • Any anti-CNS disorder agent known in the art can be co-used with a compound of Formulae (I) - (III) , or salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, to achieve the intended therapeutic effects.
  • the compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral) , parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops) , mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol.
  • enteral e.g., oral
  • parenteral intravenous, intramuscular, intra-arterial, intramedullary
  • intrathecal subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal
  • topical as by powders, ointments, creams, and/or drops
  • Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection) , regional administration via blood and/or lymph supply, and/or direct administration to an affected site.
  • intravenous administration e.g., systemic intravenous injection
  • regional administration via blood and/or lymph supply e.g., via blood and/or lymph supply
  • direct administration e.g., direct administration to an affected site.
  • the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract) , and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration) .
  • the compound or pharmaceutical composition described herein is suitable for topical administration to the eye of a subject.
  • any two doses of the multiple doses include different or substantially the same amounts of a compound described herein.
  • the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks.
  • the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is one dose per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is two doses per day.
  • the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses per day.
  • the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell.
  • the duration between the first dose and last dose of the multiple doses is three months, six months, or one year.
  • the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell.
  • a dose (e.g., a single dose, or any dose of multiple doses) described herein includes independently between 0.1 ⁇ g and 1 ⁇ g, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a compound described herein.
  • a dose described herein includes independently between 1 mg and 3 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of a compound described herein.
  • an effective amount of a compound for administration one or more times a day to a 70 kg adult human comprises about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form.
  • the compounds of the invention may be administered orally or parenterally at dosage levels sufficient to deliver from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and more preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult.
  • the amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.
  • Step 1 To a 250mL three-neck flask was added IIIa (3.4 g, 0.0126 mol, 1.0 eq) , DCM (100 mL) , EDCI (4.9 g, 0.0254 mol, 2.0 eq) , HOBT (3.4 g, 0.0254 mol, 2.0 eq) , and acetic acid (1.2g 0.02 mol, 1.59 eq) .
  • IIIa 3.4 g, 0.0126 mol, 1.0 eq
  • DCM 100 mL
  • EDCI 4.9 g, 0.0254 mol, 2.0 eq
  • HOBT 3.4 g, 0.0254 mol, 2.0 eq
  • acetic acid 1.2g 0.02 mol, 1.59 eq
  • Step 2 To a 100 mL flask was added IIIb (2.9 g, 9.3 mmol, 1.0 eq) , p-toluenesulfonic acid (0.2 g) , and diphenyl ether (30 mL) . The reaction was heated at 190°C for 1h. TLC indicated the reaction was complete. The reaction was cooled to rt and sat. NaHCO 3 (50 mL) was added. The resulting mixture was extracted with EA twice. The organic layers were combined, washed with brine, concentrated, dried and purified by column chromatography. The purified residue was triturated with MTBE to obtain compound III (1.1 g) as a white solid. Yield: 40.2%.
  • the tests were conducted by Reaction Biology Corp, Malvern, PA (Anastassiadis et al. Nat Biotechnol. 2011; 29 (11) : 1039-45) .
  • the step is briefly described as follows, using the basic reaction buffer: 20 mM Hepes (pH 7.5) , 10mM MgCl 2 , 1 mM EGTA, 0.02%Brij35, 0.02 mg/ml BSA, 0.1 mM Na 3 VO 4 , 2 mM DTT and 1%DMSO.
  • the required cofactor was added to each kinase reaction respectively.
  • Each reaction was performed according to the following reaction steps: 1) Preparing the designated substrate in the newly prepared basic reaction buffer; 2) Transferring the required cofactor to the above matrix solution; 3) Transferring the designated kinase to the substrate solution and mixing well slightly; 4) Transferring a compound of Formula (I) in DMSO to the kinase reaction mixture with Acoustic technique (Echo550; nanoliter range) , culturing for 20 minutes at room temperature; 5) Introducing 33 P-ATP (specific activity: 10 ⁇ Ci/ ⁇ l) to the reaction mixture to trigger a reaction; 6) Culturing at room temperature and conducting a kinase reaction for 2 hours; 7) Plotting the reaction on P81 ion exchange paper; and 8) Testing the kinase activity with a filter binding assay.
  • the results shown in Table 1 indicate that compounds of Formulae (I) - (III) are potent and selective TYK2/JAK1 inhibitors.
  • This testing was performed to test cellular TYK2 activity using IL-12 and IL-18 stimulated IFN ⁇ excretion assay in NK92 cells.
  • the testing was performed according to the following procedure: 1) Replace NK92 cell media containing IL-2 with media not containing IL-2, maintain overnight; 2) Plate NK92 cells to 96-well plate at density of ⁇ 150,000 cell/well; 3) Add different concentrations of test article to wells, maintain in incubator at 37 °C and 5%CO 2 for 1 hour; 4) Add IL-12 (final concentration: 2ng/ml) and IL-18 (final concentration: 5ng/ml) to stimulate for 24 hours in the above incubator; 5) After 24 hours, centrifuge at 2000 rpm for 5 min, take the supernatant and analyze according to instructions of the ELISA kit.
  • compounds of Formulae (II) and (III) had IC 50 ⁇ 100 nM.
  • This testing was performed to test cellular JAK1 activity using the IL-6 stimulated STAT3 phosphorylation assay in PBMC cells.
  • the testing was performed according to the following procedure: 1) Plate PBMC cells to 96-well plate at density of ⁇ 300,000 cell/well; 2) Add different concentrations of test article to wells, maintain in incubator at 37 °C and 5%CO 2 for 1 hour; 3) Add IL-6 (final concentration: 100ng/ml) to stimulate for 25 min in the above incubator; 4) After stimulation, transfer the suspension to 1.5mL tube, centrifuge at 200g for 5 min, collect cells, add 100 ⁇ L 1X lysate, lyse on ice for 1 hour; 5) Centrifuge at 4 °C and 12000rpm for 10 min, take the supernatant and analyze according to instructions of the ELISA kit. In this assay, compounds of Formulae (II) and (III) had IC 50 ⁇ 300 nM.
  • This testing was performed to test the ability of compounds to alleviate the injury of HT22 cells induced by LPS activated BV2 cells.
  • the testing was performed according to the following procedure: 1) Microglia BV2 cells were co-cultured on transwell inserts with HT22 hippocampal neurons. BV2 cells were stimulated with LPS (200 ng/ml) for 96 h after treatment with a compound of Formula (II) at 1.7 ⁇ M. 2) HT22 cells were pre-treated with a compound of Formula (II) at 1.7 ⁇ M for 30 min and subsequently stimulated with LPS (200 ng/ml) for 96 h. 3) BV2 cells were treated using LPS. IL-6, TNF and MCP-1 productions were measured in cell supernatants using CBA assay.
  • the protective effects of a compound of Formula (II) on microglial activation-induced neuronal death were evaluated in a BV2 microglia/HT22 neuron co-culture.
  • LPS 200 ng/mL
  • Pre-treatment of BV2 microglia with a compound of Formula (II) at 1.7 ⁇ M significantly reduced toxicity to HT22 cells as a result of stimulating BV2 microglia with LPS (FIG. 1A) .
  • Treatment with a compound of Formula (II) did not affect viability of HT22 cells in the presence or absence of LPS (FIG. 1B) .
  • This testing was performed to test the ability of compounds to penetrate the blood-brain-barrier in rats.
  • the testing was performed according to the following procedure: 1) For each compound, take 3 male rats with body weight of 217 –228g, formulate compound using 0.5%HPMC/water suspension at concentration of 1 mg/ml; 2) After fasting overnight, administer compound at 10 mg/kg by oral gavage; 3) Take plasma samples at 1, 2, 4, 8 hours post-dosing; 4) At 8 hour post-dosing, also take brain tissues and cerebrospinal fluid (CSF) ; 5) Analyze compound concentration in plasma, brain tissue, and CSF using LC-MS/MS method. Table 2 shows that compounds of Formulae (II) and (III) penetrate the blood-brain-barrier in rats.
  • This testing was performed to test the ability of compounds to penetrate the blood-brain-barrier in mice.
  • the testing was performed according to the following procedure: 1) for each compound, take 3 male C57BL/6 mice with body weight of 17 –18g, formulate compound using 0.5%HPMC/water suspension at concentration of 3 mg/ml; 2) After fasting overnight, administer compound at 30 mg/kg by oral gavage; 3) Take plasma samples at 1, 2, 4 hours post-dosing; 4) At 4-hour post-dosing, also take brain tissues and cerebrospinal fluid (CSF) fluid; 5) Analyze compound concentration in plasma, brain tissue, and CSF fluid using LC-MS/MS method. Table 3 shows that compounds of Formulae (II) and (III) penetrate the blood-brain-barrier in mice.
  • Example 8 In Vivo Efficacy Evaluation in a Myelin Oligodendrocyte Glycoprotein (MOG 35-55 ) Induced Experimental Autoimmune Encephalomyelitis (MOG 35-55 -EAE) Model in Female C57BL/6 Mice
  • MOG-EAE is one of the most common and widely used animal models for multiple sclerosis, which is a chronic inflammatory disease in the central nervous system that is characterized by axon demyelination and degeneration.
  • MOG myelin oligodendrocyte glycoprotein
  • CFA Complete Freund’s Adjuvant
  • mice developed chronic inflammation in the central nervous system, which led to axon dysfunction, and associated movement disabilities and paralysis.
  • the disease onset usually starts from Day 10 and lasts for 20-30 days. This model allows specific investigation of the neuroinflammatory signaling pathways and evaluation of the efficacy of novel anti-inflammatory therapies.
  • mice Female C57BL/6 mice weighing 19 –22g were injected subcutaneously with 200 ⁇ l MOG35-55/CFA emulsion containing 100 ⁇ g MOG-EAE35-55 (100 ⁇ l into each leg flank) . Two hours later, mice received an intraperitoneal injection of 100 ⁇ l of pertussis toxin (200 ng/mouse) . On Day 2, a second dose of 100 ⁇ l pertussis toxin (200 ng/mouse) was injected. After MOG induction, the animals were checked daily for morbidity and mortality.
  • Disease score and body weight measurements were conducted in a Laminar Flow Cabinet. The body weights and disease score were measured by using StudyDirectorTM software (version 3.1.399.19) .
  • Test article was formulated as 0.5%HPMC/water suspension at concentration of 3 mg/ml, and the treatments by oral gavage started on Day 10 when disease onset began. Compared to the vehicle control group, mice receiving treatment of a compound of Formula (II) at 30 mg/kg twice per day (BID) showed reduced disease activity on Days 10-26 (FIG. 3) .
  • FIGs. 4A-4B show that a greater number of mice treated with a compound of Formula (II) had a lower DAI than mice treated with vehicle. Treatment with a compound of Formula (II) significantly reduced body weight loss in mice with experimental autoimmune encephalomyelitis (EAE) .
  • EAE experimental autoimmune encephalomyelitis
  • the present disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim.
  • any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim.
  • elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element (s) can be removed from the group. It should it be understood that, in general, where the present disclosure, or aspects of the present disclosure, is/are referred to as comprising particular elements and/or features, certain embodiments of the present disclosure or aspects of the present disclosure consist, or consist essentially of, such elements and/or features.
  • Embodiments of the present disclosure include:
  • Embodiment 1 A method of treating a central nervous system (CNS) disorder, the method comprising administering to a subject in need thereof an effective amount of a compound of Formulae (I) - (III) :
  • Embodiment 2 The method of embodiment 1, wherein the compound is a dual TYK2/JAK1 kinase inhibitor.
  • Embodiment 3 The method of embodiment 1, wherein the CNS disorder is neurotoxicity and/or neurotrauma, stroke, multiple sclerosis, spinal cord injury, epilepsy, a mental disorder, a sleep condition, a movement disorder, nausea and/or emesis, amyotrophic lateral sclerosis, Alzheimer’s disease, Parkinson’s disease, or drug addiction.
  • the CNS disorder is neurotoxicity and/or neurotrauma, stroke, multiple sclerosis, spinal cord injury, epilepsy, a mental disorder, a sleep condition, a movement disorder, nausea and/or emesis, amyotrophic lateral sclerosis, Alzheimer’s disease, Parkinson’s disease, or drug addiction.
  • Embodiment 4 The method of embodiment 3, wherein the neurotoxicity and/or neurotrauma is a traumatic brain injury (TBI) , stroke, epilepsy, multiple sclerosis, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, or Alzheimer’s disease.
  • TBI traumatic brain injury
  • Embodiment 5 The method of embodiment 3, wherein the mental disorder is depression, anxiety or anxiety-related conditions, a learning disability, or schizophrenia.
  • Embodiment 6 The method of embodiment 3, wherein the sleep condition is insomnia, narcolepsy, sleep apnea, restless legs syndrome (RLS) , delayed sleep phase syndrome (DSPS) , periodic limb movement disorder (PLMD) , hypopnea syndrome, rapid eye movement behavior disorder (RBD) , shift work sleep condition (SWSD) , or sleep problems (e.g., parasomnias) such as nightmares, night terrors, sleep talking, head banging, snoring, or clenched jaw and/or grinding of teeth (bruxism) .
  • sleep problems e.g., parasomnias
  • nightmares nightmares
  • night terrors sleep talking
  • head banging snoring
  • clenched jaw and/or grinding of teeth bruxism
  • Embodiment 7 The method of embodiment 3, wherein the movement disorder is Parkinson’s disease, levodopa-induced dyskinesia, Huntington’s disease, Gilles de la Tourette’s syndrome, tardive dyskinesia, or dystonia.
  • Parkinson’s disease levodopa-induced dyskinesia
  • Huntington’s disease Huntington’s disease
  • Gilles de la Tourette’s syndrome tardive dyskinesia, or dystonia.
  • Embodiment 8 The method of embodiment 1, wherein the CNS disorder is modulated by TYK2 and JAK1.
  • Embodiment 9 The method of embodiment 1, wherein the CNS disorder is Alzheimer's disease, Parkinson's Disease, amyotrophic lateral sclerosis, dementia, frontotemporal dementia, mild cognitive impairment (MCI) , or neuroinflammation.
  • the CNS disorder is Alzheimer's disease, Parkinson's Disease, amyotrophic lateral sclerosis, dementia, frontotemporal dementia, mild cognitive impairment (MCI) , or neuroinflammation.
  • Embodiment 10 The method of embodiment 1, wherein the CNS disorder is Alzheimer's Disease.
  • Embodiment 11 The method of embodiment 1, wherein the CNS disorder is Parkinson’s disease.
  • Embodiment 12 The method of embodiment 1, wherein the CNS disorder is amyotrophic lateral sclerosis.
  • Embodiment 13 The method of embodiment 1, further comprising administering to the subject an additional pharmaceutical agent.
  • Embodiment 14 A method of treating a central nervous system (CNS) disorder, the method comprising administering to a subject in need thereof an effective amount of a composition comprising a compound of Formulae (I) - (III) :
  • Embodiment 15 The method of embodiment 14, wherein the compound is a dual TYK2/JAK1 kinase inhibitor.
  • Embodiment 16 The method of embodiment 14, wherein the CNS disorder is neurotoxicity and/or neurotrauma, stroke, multiple sclerosis, spinal cord injury, epilepsy, a mental disorder, a sleep condition, a movement disorder, nausea and/or emesis, amyotrophic lateral sclerosis, Alzheimer’s disease, and drug addiction.
  • the CNS disorder is neurotoxicity and/or neurotrauma, stroke, multiple sclerosis, spinal cord injury, epilepsy, a mental disorder, a sleep condition, a movement disorder, nausea and/or emesis, amyotrophic lateral sclerosis, Alzheimer’s disease, and drug addiction.
  • Embodiment 17 The method of embodiment 16, wherein the neurotoxicity and/or neurotrauma is a traumatic brain injury (TBI) , stroke, epilepsy, multiple sclerosis, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, or Alzheimer’s disease.
  • TBI traumatic brain injury
  • Embodiment 18 The method of embodiment 16, wherein the mental disorder is depression, anxiety or anxiety-related conditions, a learning disability, or schizophrenia.
  • Embodiment 19 The method of embodiment 16, wherein the sleep condition is insomnia, narcolepsy, sleep apnea, restless legs syndrome (RLS) , delayed sleep phase syndrome (DSPS) , periodic limb movement disorder (PLMD) , hypopnea syndrome, rapid eye movement behavior disorder (RBD) , shift work sleep condition (SWSD) , or sleep problems (e.g., parasomnias) such as nightmares, night terrors, sleep talking, head banging, snoring, or clenched jaw and/or grinding of teeth (bruxism) .
  • sleep problems e.g., parasomnias
  • nightmares nightmares
  • night terrors sleep talking
  • head banging snoring
  • clenched jaw and/or grinding of teeth bruxism
  • Embodiment 20 The method of embodiment 16, wherein the movement disorder is Parkinson’s disease, levodopa-induced dyskinesia, Huntington’s disease, Gilles de la Tourette’s syndrome, tardive dyskinesia, or dystonia.
  • Parkinson’s disease levodopa-induced dyskinesia
  • Huntington’s disease Huntington’s disease
  • Gilles de la Tourette’s syndrome tardive dyskinesia, or dystonia.
  • Embodiment 21 The method of embodiment 14, wherein the CNS disorder is modulated by TYK2 and JAK1.
  • Embodiment 22 The method of embodiment 14, wherein the CNS disorder is Alzheimer's Disease, Parkinson's Disease, amyotrophic lateral sclerosis, dementia, frontotemporal dementia, mild cognitive impairment (MCI) , or neuroinflammation.
  • the CNS disorder is Alzheimer's Disease, Parkinson's Disease, amyotrophic lateral sclerosis, dementia, frontotemporal dementia, mild cognitive impairment (MCI) , or neuroinflammation.
  • Embodiment 23 The method of embodiment 14, wherein the CNS disorder is Alzheimer's Disease.
  • Embodiment 24 The method of embodiment 14, wherein the CNS disorder is Parkinson’s disease.
  • Embodiment 25 The method of embodiment 14, wherein the CNS disorder is amyotrophic lateral sclerosis.
  • Embodiment 26 The method of embodiment 14, wherein the composition further comprises an additional pharmaceutical agent.
  • Embodiment 27 A compound of Formula (A) , or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof:
  • R 1 is C 1 -C 6 alkyl
  • X is CH 2 or O.
  • Embodiment 28 The compound of embodiment 27, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein R 1 is unsubstituted C 1 -C 6 alkyl.
  • Embodiment 29 The compound of embodiment 27, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein R 1 is methyl or ethyl, and X is CH 2 .
  • Embodiment 30 The compound of embodiment 27, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein R 1 is methyl or ethyl, and X is O.
  • Embodiment 31 The compound of embodiment 27, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein R 1 is methyl, and X is CH 2 .

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