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WO2018106643A1 - Azoles hétérocycliques pour le traitement de maladies de démyélinisation - Google Patents

Azoles hétérocycliques pour le traitement de maladies de démyélinisation Download PDF

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Publication number
WO2018106643A1
WO2018106643A1 PCT/US2017/064629 US2017064629W WO2018106643A1 WO 2018106643 A1 WO2018106643 A1 WO 2018106643A1 US 2017064629 W US2017064629 W US 2017064629W WO 2018106643 A1 WO2018106643 A1 WO 2018106643A1
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Prior art keywords
alkyl
alkylene
oci
haloalkyl
independently selected
Prior art date
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PCT/US2017/064629
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English (en)
Inventor
Philip N. Collier
Robert J. Davies
Michael Paul Deninno
Elisabeth DOYLE
James Daniel Frantz
Brian Anthony GOLDMAN
Anne-Laure Grillot
Adrienne Lynne KOLPAK
Raul Eduardo KRAUSS
Brian Ledford
Yusheng Liao
Sanjay Shivayogi MAGAVI
Francois Maltais
Emanuele Perola
Elizabeth Jin-Sun RYU
Joshua Syken
Qing Tang
Tiansheng Wang
Original Assignee
Vertex Pharmaceuticals Incorporated
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Publication of WO2018106643A1 publication Critical patent/WO2018106643A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/48—Nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • MS Multiple sclerosis
  • Activation and CNS infiltration of the peripheral immune system is typical in early stages of the disease, but can become less prevalent as disease progresses.
  • a hallmark of MS is loss of myelin, accompanied by the death of associated oligodendrocytes (see, Merrill, J.E. et al, Neuropathology and Applied Neurobiology , 25, 435-458, 1999).
  • Myelin which is produced by oligodendrocytes, ensheathes axons and dramatically increases conduction velocity of neural impulses while providing trophic support to the neuron.
  • Myelin is thought to regenerate early in disease, as oligodendroycte progenitor cells (OPCs) proliferate and generate new myelinating oligodendrocytes in response to demyelination events.
  • OPCs oligodendroycte progenitor cells
  • Leukodystrophies are degenerative white matter diseases characterized by dysmyelination or demyelination. Multiple genetic or metabolic disorders can lead to progressive white matter damage in pediatric or adult populations resulting in severe motor or cognitive deficits, mental retardation or death.
  • a compound that can delay myelin damage or promote repair of demyelinated axons could significantly alter the course of leukodystrophies and improve their outcome.
  • Such a compound could be also useful in combination with other therapies that can correct the disease-specific defect, metabolic, genetic or other, responsible for initiating or maintaining the disease in order to accelerate repair, restore function or prevent further damage.
  • Periventricular leukomalacia is a condition characterized by toxic death of OPCs in the
  • the present invention provides compounds or a pharmaceutically acceptable salt thereof and the methods, compositions and kits disclosed herein for treating or lessening the severity of, in a subject, a disease or disorder selected from a demyelinating disease, central pontine myelinolysis, a nerve injury disease or disorder, a leukoencephalopathy or a leukodystrophy.
  • X 2 is CR X2 or N;
  • X is CR X or N
  • X 4 is O or S
  • R 1 is selected from the group consisting of -OCi- 6 alkyl, -OCi- 6 haloalkyl, - 0-C 2 - 6 alkylene-OCi -4 alkyl, -0-C 2-6 alkylene-OH, -NHC(0)(Ci -4 alkyl), -N(Ci_ 4 alkyl)C(0)(Ci -4 alkyl), -C(0)NH 2 , -C(0)NH(Ci -4 alkyl), -C(0)N(Ci -4 alkyl)(Ci.
  • R 2 is selected from the group consisting of hydrogen, Ci -4 alkyl, Ci_ 4 haloalkyl, halogen, and -OCi -4 alkyl;
  • R is selected from the group consisting of hydrogen, halogen, Ci- 4 alkyl, Ci- 4 haloalkyl, and -0-Ci- 4 alkyl;
  • R X2 is selected from the group consisting of hydrogen, halogen, Ci- 4 alkyl, and Ci- 4 haloalkyl;
  • R X3 is selected from the group consisting of hydrogen, halogen, Ci- 4 alkyl, Ci- 4 haloalkyl, and -0-Ci- 4 alkyl;
  • L 1 is a bond, -0-, -0-Ci -4 alkylene-, -NR 5 -, -NR 5 -Ci -4 alkylene-, or - C(O)-, wherein R 5 is hydrogen or Ci- 4 alkyl;
  • L 2 is -0-Ci -4 alkylene-
  • G 1 is a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a Ci-3alkylene bridge between two non-adjacent ring atoms, G 1 being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- 4 alkyl, Ci_ 4 haloalkyl, halogen, hydroxyl, and oxo;
  • R 6 is (a) a 4- to 12-membered heterocycle containing 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the heterocycle being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- 4 alkyl, -CH 2 S(0) 2 phenyl, halogen, hydroxyl, oxo, - OCi- 4 alkyl, -Ci- 6 alkylene-OCi- 4 alkyl, and -Ci- 6 alkylene-OH; or (b) a 3- to 8- membered cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- 4 alkyl, halogen, hydroxyl, - C(0)OCi -4 alkyl, -C(0)OH, oxo, -OCi -4 alkyl, -Ci -6 alkylene-OCi -4 alkyl, and -Ci_ 6 alkylene-OH;
  • G 2 is a 4- to 12-membered heterocycle containing 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, G 2 being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- 4 alkyl, halogen, hydroxyl, oxo, cyano, -Ci- 6 alkylene-cyano, - C(0)Ci -4 alkyl, -C(0)-Ci -6 alkylene-OH, -C(0)C 3- ecycloalkyl, -C(0)OCi -4 alkyl, -C(0)OCi -4 haloalkyl, -C(0)NH 2 , -C(0)NH(Ci_ 4 alkyl), -C(0)N(Ci -4 alkyl)(Ci -4 alkyl), -C(0)NH(-Ci -6 alkylene-OCi -4 alkyl), - C(0)N(Ci -4 alkyl)(-Ci -6 alkylene-OCi -4 alky
  • G 3 is 3- to 8-membered cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of C ⁇ alkyl, Ci_ 4 haloalkyl, halogen, hydroxyl, oxo, cyano, -C(0)Ci- 4 alkyl, -C(0)C3- 6 cycloalkyl, - C(0)OCi -4 alkyl, -C(0)OCi -4 haloalkyl, -C(0)NH 2 , -C(0)NH(Ci -4 alkyl), -C(0)N(Ci_ 4 alkyl)(Ci -4 alkyl), -C(0)NH(-Ci -6 alkylene-OCi -4 alkyl), -C(0)N(Ci -4 alkyl)(-Ci. 6 alkylene-OCi -4 alkyl), -C(0)NH(-Ci -6 alkylene-OH), -C(0)N(Ci -4 alkyl
  • G 4 is phenyl optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- 4 alkyl, halogen, hydroxyl, cyano, phenyl, -C(0)Ci -4 alkyl, -C(0)C 3 - 6 cycloalkyl, -C(0)OCi -4 alkyl, -C(0)OCi_ 4 haloalkyl, -C(0)NH 2 , -C(0)NH(Ci -4 alkyl), -C(0)N(Ci -4 alkyl)(Ci -4 alkyl), - C(0)NH(-Ci -6 alkylene-OCi -4 alkyl), -C(0)N(Ci -4 alkyl)(-Ci -6 alkylene-OCi -4 alkyl), - C(0)NH(-Ci -6 alkylene-OH), -C(0)N(Ci -4 alkyl)(-Ci -6 alkylene-OH), -NH(Ci
  • R 4 is phenyl or a 5- or 6-membered heteroaryl containing 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur, R 4 being optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, hydroxyl, cyano, -S(0)2Ci -4 alkyl, -S(0)Ci -4 alkyl, -SCi -4 alkyl, Ci -4 alkyl, Ci_ 4 haloalkyl, -OCi -4 alkyl, -OCi -4 haloalkyl, -Ci- 4 alkylene-OCi -4 alkyl, -Ci -4 alkylene- N(Ci -4 alkyl)(Ci -4 alkyl), -NH(Ci -4 alkylene-OCi -4 alkyl), -NH(Ci -4 alkylene-OH), - N(Ci -4 alkyl)(Ci -4 alkylene-OCi -4 alkyl),
  • R 1 is not -0-C 2-6 alkylene-OC 1 - 4 alkyl, - 0-C2- 6 alkylene-OH, G 2 , -O-G 2 , or -0-Ci -4 alkylene-G 2 , where G 2 is an optionally substituted monocyclic heterocycle containing at least one nitrogen atom, when X 1 is N, X 3 is N, X 2 is CH, and R 4 is optionally substituted phenyl; (ii) R 1 is not -OCi- alkyl when R 4 is optionally substituted phenyl or thiophene, and X 1 is CR X1 ; (iii) R 2 is other than H, when R is G 2 or -O-G , G is an optionally substituted monocyclic heterocycle containing at least one nitrogen atom, X 1 is CH, X 2 is CH and X 3 is N;
  • R is other than H, when R is G or -NR -Ci -4 alkylene-G , G is an optionally substituted monocyclic heterocycle containing at least one nitrogen atom, X 1 is CH, X 3 is CH and X 2 is N; or (v) the compound of formula (II) is not N-(4-chloro-6-(4- methylpiperazin-l-yl)pyridin-2-yl)-5-(pyridin-4-yl)thiazol-2-amine; and
  • G 2 is not morpholino when R 4 is phenyl substituted with cyano;
  • R 1 is not -0-Ci -4 alkyl when R 4 is optionally substituted phenyl; or
  • R 1 is not -NHC(0)(Ci- alkyl) when R 4 is pyridinyl.
  • X 1 is CR X1 or N;
  • X 2 is CR X2 or N;
  • X 3 is CR X3 or N;
  • R 1 is selected from the group consisting of hydrogen, Ci- 4 alkyl, Ci_
  • R 2 is selected from the group consisting of hydrogen, Ci- 4 alkyl, and Ci_ 4 haloalkyl;
  • R X1 is selected from the group consisting of hydrogen, halogen, Ci- 4 alkyl, Ci -4 haloalkyl, -0-Ci -4 alkyl, and G 2 ;
  • R 1 and R X1 do not simultaneously contain G 2 ;
  • R X2 is selected from the group consisting of hydrogen, halogen, Ci- 4 alkyl, and -OCi- 4 alkyl;
  • R X3 is selected from the group consisting of hydrogen, halogen, Ci- 4 alkyl,
  • L 1 is a bond, -0-, or -0-Ci -4 alkylene-;
  • L 2 is -O- or -0-Ci -4 alkylene-
  • G 1 is a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a bridge between two non-adjacent ring atoms, G 1 being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- 4 alkyl, Ci_ 4 haloalkyl, halogen, hydroxyl, and oxo;
  • R is (a) a 4- to 12-membered heterocycle containing 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the heterocycle being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- 4 alkyl, -CH 2 S(0) 2 phenyl, halogen, hydroxyl, oxo, - OCi- 4 alkyl, -Ci- 6 alkylene-OCi- 4 alkyl, and -Ci- 6 alkylene-OH;
  • G 2 is a 4- to 12-membered heterocycle containing 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, G 2 being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- 4 alkyl, halogen, hydroxyl, oxo, cyano, -Ci- 6 alkylene-cyano, - C(0)Ci -4 alkyl, -C(0)-Ci -6 alkylene-OH, -C(0)C 3- ecycloalkyl, -C(0)OCi -4 alkyl, -C(0)OCi -4 haloalkyl, -C(0)NH 2 , -C(0)NH(Ci_ 4 alkyl), -C(0)N(Ci -4 alkyl)(Ci -4 alkyl), -C(0)NH(-Ci -6 alkylene-OCi -4 alkyl), - C(0)N(Ci -4 alkyl)(-Ci -6 alkylene-OCi -4 alky
  • G 3 is 3- to 8-membered cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of C ⁇ alkyl, Ci_ 4 haloalkyl, halogen, hydroxyl, oxo, cyano, -C(0)Ci- 4 alkyl, -C(0)C3- 6 cycloalkyl, - C(0)OCi -4 alkyl, -C(0)OCi -4 haloalkyl, -C(0)NH 2 , -C(0)NH(Ci -4 alkyl), -C(0)N(Ci_ 4 alkyl)(Ci -4 alkyl), -C(0)NH(-Ci -6 alkylene-OCi -4 alkyl), -C(0)N(Ci -4 alkyl)(-Ci. 6 alkylene-OCi -4 alkyl), -C(0)NH(-Ci -6 alkylene-OH), -C(0)N(Ci -4 alkyl
  • G 4 is phenyl optionally substituted with 1-4 substituents independently selected from the group consisting of Ci -4 alkyl, Ci -4 haloalkyl, halogen, hydroxyl, cyano, phenyl, -C(0)Ci -4 alkyl, -C(0)C 3 - 6 cycloalkyl, -C(0)OCi -4 alkyl, -C(0)OCi_ 4 haloalkyl, -C(0)NH 2 , -C(0)NH(Ci -4 alkyl), -C(0)N(Ci -4 alkyl)(Ci -4 alkyl), - C(0)NH(-Ci -6 alkylene-OCi -4 alkyl), -C(0)N(Ci -4 alkyl)(-Ci -6 alkylene-OCi -4 alkyl), - C(0)NH(-Ci -6 alkylene-OH), -C(0)N(Ci -4 alkyl)(-Ci -6 alkylene
  • G 5 is a monocyclic 5- or 6-membered heteroaryl containing 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, G 5 being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- 4 alkyl, Ci -4 haloalkyl, halogen, hydroxyl, cyano, phenyl, -C(0)Ci -4 alkyl, -C(0)C 3- ecycloalkyl, -C(0)OCi -4 alkyl, -C(0)OCi -4 haloalkyl, -C(0)NH 2 , -C(0)NH(Ci_ 4 alkyl), -C(0)N(Ci -4 alkyl)(Ci -4 alkyl), -C(0)NH(-Ci -6 alkylene-OCi -4 alkyl), - C(0)N(Ci -4 alkyl)(-Ci -6 alkylene-OCi -4 alkyl), -C(0)NH(-Ci -6 al
  • R 4 is phenyl or a 5- or 6-membered heteroaryl containing 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur, R 4 being optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, hydroxyl, cyano, -S(0)2Ci- 4 alkyl, -S(0)Ci- 4 alkyl, -SCi- 4 alkyl, Ci- 4 alkyl, Ci_ 4 haloalkyl, -OCi- 4 alkyl, -Ci- 4 alkylene-OCi- 4 alkyl, -Ci- 4 alkylene- N(Ci -4 alkyl)(Ci -4 alkyl), - H(CMalkylene-OC M alk l), -NH(Ci -4 alkylene-OH), - N(CMalk l)(CMalk lene-OCMalkyl), -N(Ci -4 alkyl)(Ci -4 alkylene-
  • the present invention provides compounds of formula (I) or (IV).
  • compositions comprising a pharmaceutically acceptable carrier and therapeutically effective amounts of a compound of formula (I) or (IV), or a pharmaceutically acceptable salt thereof.
  • the invention provides compounds of formula (I) or (IV), or a pharmaceutically acceptable salt thereof, which promote remyelination of demyelinated axons.
  • the invention provides compounds of formula (I) or (IV), or a pharmaceutically acceptable salt thereof, which differentiate endogenous oligodendrocyte precursor cells.
  • the invention provides methods of treating multiple sclerosis by administering to a patient in need thereof a therapeutically effective amount of a compound or composition of formula (I) or (IV), or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating, preventing or ameliorating one or more symptoms of a subject with multiple sclerosis or another neurological disease.
  • the invention provides the use of a compound of formula (I) or (IV), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of multiple sclerosis, the promotion of remyelination of demyelinated axons, or the differentiation of endogenous oligodendrocyte precursor cells.
  • the invention provides compounds of formula (I) or (IV), or a pharmaceutically acceptable salt thereof, for use in treating multiple sclerosis, promoting remyelination of demyelinated axons, or differentiating endogenous oligodendrocyte precursor cells.
  • the invention provides compounds of formula (I) or (IV), or a pharmaceutically acceptable salt thereof for treating or lessening the severity of, in a subject, a disease or disorder selected from a demyelinating disease, central pontine myelinolysis, a nerve injury disease or disorder, a leukoencephalopathy or a leukodystrophyin.
  • a disease or disorder selected from a demyelinating disease, central pontine myelinolysis, a nerve injury disease or disorder, a leukoencephalopathy or a leukodystrophyin.
  • the invention provides compounds of formula (I) or (IV), or a pharmaceutically acceptable salt thereof
  • the invention provides compounds of formula (I) or (IV), or a pharmaceutically acceptable salt thereof can be employed in combination therapies, that is, the compounds and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures.
  • kits comprising compounds of formula
  • compounds of the invention can optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention.
  • substituents such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention.
  • the variables in formula I encompass specific groups, such as, for example, alkyl and cycloalkyl.
  • combinations of substituents envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein.
  • a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
  • a ring substituent such as a heterocycloalkyl
  • substituents envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds.
  • alkyl as used herein, means a straight or branched chain saturated hydrocarbon.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.
  • alkylene means a divalent group derived from a straight or branched chain saturated hydrocarbon.
  • Representative examples of alkylene include, but are not limited to, -CH 2 - -CH 2 CH 2 - -CH 2 CH 2 CH 2 -, - CH 2 CH(CH 3 )CH 2 - and -CH 2 CH(CH 3 )CH(CH 3 )CH 2 -.
  • alkoxy means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, and hexyloxy.
  • aryl means phenyl or a bicyclic aryl.
  • the bicyclic aryl is naphthyl, dihydronaphthalenyl, tetrahydronaphthalenyl, indanyl, or indenyl.
  • the phenyl and bicyclic aryls are attached to the parent molecular moiety through any carbon atom contained within the phenyl or bicyclic aryl.
  • halogen means a chlorine, bromine, iodine, or fluorine atom.
  • haloalkyl means an alkyl, as defined herein, in which one, two, three, four, five, six, or seven hydrogen atoms are replaced by halogen.
  • representative examples of haloalkyl include, but are not limited to, 2-fluoroethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,2- trifluoro-l,l-dimethylethyl, and the like.
  • haloalkoxy means an alkoxy group, as defined herein, in which one, two, three, four, five, or six hydrogen atoms are replaced by halogen.
  • Representative examples of haloalkoxy include, but are not limited to, trifiuoromethoxy, difiuoromethoxy, 2,2,2-trifluoroethoxy, 2,2-difluoroethoxy, 2- fluoroethoxy, and pentafluoroethoxy.
  • heteroaryl means an aromatic heterocycle, i.e., an aromatic ring that contains at least one heteroatom.
  • a heteroaryl may contain from 5 to 12 ring atoms.
  • a heteroaryl may be a 5- to 6-membered monocyclic heteroaryl or an 8- to 12-membered bicyclic heteroaryl.
  • a 5-membered monocyclic heteroaryl ring contains two double bonds, and one, two, three, or four heteroatoms as ring atoms.
  • 5-membered monocyclic heteroaryls include, but are not limited to, furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, and triazolyl.
  • a 6- membered heteroaryl ring contains three double bonds, and one, two, three or four heteroatoms as ring atoms.
  • 6-membered monocyclic heteroaryls include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.
  • the bicyclic heteroaryl is an 8- to 12-membered ring system having a monocyclic heteroaryl fused to an aromatic, saturated, or partially saturated carbocyclic ring, or fused to a second monocyclic heteroaryl ring.
  • bicyclic heteroaryl include, but are not limited to, benzofuranyl, benzoxadiazolyl, 1,3-benzothiazolyl, benzimidazolyl, benzothienyl, indolyl, indazolyl, isoquinolinyl, naphthyridinyl, oxazolopyridine, quinolinyl, thienopyridinyl, 5,6,7,8-tetrahydroquinolinyl, and 6,7-dihydro-5H-cyclopenta[b]pyridinyl.
  • the heteroaryl groups are connected to the parent molecular moiety through any substitutable carbon atom or any substitutable nitrogen atom contained within the groups.
  • cycloalkyl as used herein, means a monocyclic all-carbon ring containing zero heteroatoms as ring atoms, and zero double bonds.
  • examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • the cycloalkyl groups described herein can be appended to the parent molecular moiety through any substitutable carbon atom.
  • cycloalkenyl as used herein, means a monocyclic non-aromatic all-carbon 5- to 6-membered ring containing zero heteroatoms as ring atoms and one double bond.
  • examples of cycloalkenyl include cyclopentenyl and cyclohexenyl.
  • cycloalkenyl groups described herein can be appended to the parent molecular moiety through any substitutable carbon atom.
  • heterocycle refer generally to ring systems containing at least one heteroatom as a ring atom where the heteroatom is selected from oxygen, nitrogen, and sulfur. In some embodiments, a nitrogen or sulfur atom of the heterocycle is optionally substituted with oxo.
  • Heterocycles may be a monocyclic heterocycle, a fused bicyclic heterocycle, or a spiro heterocycle.
  • the monocyclic heterocycle is generally a 4, 5, 6, 7, or 8-membered non-aromatic ring containing at least one heteroatom selected from O, N, or S.
  • the 4-membered ring contains one heteroatom and optionally one double bond.
  • the 5-membered ring contains zero or one double bond and one, two or three heteroatoms.
  • the 6, 7, or 8-membered ring contains zero, one, or two double bonds, and one, two, or three heteroatoms.
  • monocyclic heterocycle include, but are not limited to, azetidinyl, azepanyl, diazepanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl , 4,5- dihydroisoxazol-5-yl, 3,4-dihydropyranyl, 1 ,3-dithiolanyl, 1 ,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolid
  • the fused bicyclic heterocycle is a 7-12-membered ring system having a monocyclic heterocycle fused to a phenyl, to a saturated or partially saturated carbocyclic ring, or to another monocyclic heterocyclic ring, or to a monocyclic heteroaryl ring.
  • fused bicyclic heterocycle include, but are not limited to, l ,3-benzodioxol-4-yl, 1,3-benzodithiolyl, 3-azabicyclo[3.1.0]hexanyl, hexahydro-lH-furo[3,4-c]pyrrolyl, 2,3-dihydro-l,4- benzodioxinyl, 2,3-dihydro-l-benzofuranyl, 2,3-dihydro-l -benzothienyl, 2,3-dihydro- lH-indolyl, 5,6,7,8-tetrahydroimidazo[l,2-a]pyrazinyl, and 1,2,3,4- tetrahydroquinolinyl.
  • Spiro heterocycle means a 4, 5-, 6-, 7-, or 8-membered monocyclic heterocycle ring wherein two of the substituents on the same carbon atom form a second ring having 3, 4, 5, 6, 7, or 8- members.
  • Examples of a spiro heterocycle include, but are not limited to, l,4-dioxa-8-azaspiro[4.5]decanyl, 2-oxa-7- azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.3]heptanyl, and 8-azaspiro[4.5]decane.
  • the monocyclic heterocycle groups of the present invention may contain an alkylene bridge of 1, 2, or 3 carbon atoms, linking two non-adjacent atoms of the group.
  • bridged heterocycle examples include, but are not limited to, 2,5- diazabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2.2]octanyl, and oxabicyclo[2.2.1]heptanyl.
  • the monocyclic, fused bicyclic, and spiro heterocycle groups are connected to the parent molecular moiety through any substitutable carbon atom or any substitutable nitrogen atom contained within the group.
  • oxo refers to an oxygen atom bonded to the parent molecular moiety.
  • An oxo may be attached to a carbon atom or a sulfur atom by a double bond.
  • an oxo may be attached to a nitrogen atom by a single bond, i.e., an N-oxide.
  • C is an alkyl group with three carbon atoms (i.e., n-propyl, isopropyl).
  • C the members of the group that follows may have any number of carbon atoms falling within the recited range.
  • a “Ci- 4 alkyl,” for example, is an alkyl group having from 1 to 4 carbon atoms, however arranged (i.e., straight chain or branched).
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Thus, included within the scope of the invention are tautomers of compounds of formula (I) or (IV).
  • the structures also include zwitterioinc forms of the compounds or salts of formula I where appropriate.
  • R 1 is selected from the group consisting of -OCi- -0-Ci -6 alkylene-OH, -NHC(0)(Ci -4 alkyl), - C(0)N(Ci -4 alkyl)(Ci -4 alkyl), -C(0)NH(Ci -4 haloalkyl), -C(0)NH(-Ci. 6 alkylene-OCi. 4 alkyl), -I ⁇ -G -R 6 , -L x -G 2 , -L x -G 3 , and -L 2 -G 4 ;
  • R 2 is selected from the group consisting of hydrogen, Ci -4 alkyl, Ci -4 haloalkyl, halogen, and -OCi -4 alkyl;
  • R X1 is selected from the group consisting of hydrogen and -0-Ci -4 alkyl
  • R X2 is selected from the group consisting of hydrogen, halogen, and Ci -4 alkyl
  • R X3 is selected from the group consisting of hydrogen, Ci -4 alkyl, and -0-Ci -4 alkyl;
  • L 1 is a bond, -0-, -0-Ci -4 alkylene- -NR 5 -, or -C(O)-, wherein R 5 is hydrogen or Ci- 4 alkyl;
  • L 2 is -0-Ci -4 alkylene-;
  • G 1 is a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from nitrogen;
  • R 6 is a 4- to 12-membered heterocycle containing 1-4 heteroatoms independently selected from oxygen, the heterocycle being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci -4 alkyl, Ci_ haloalkyl, -CH 2 S(0) 2 phenyl, halogen, hydroxyl, oxo, -OCi -4 alkyl, -Ci- 6 alkylene- OCi- 4 alkyl, and -Ci- 6 alkylene-OH;
  • G 2 is a 4- to 12-membered heterocycle containing 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, G 2 being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci -4 alkyl, -C(0)OCi_ 4 alkyl, and a -Chalky lene substituted by 2 groups independently selected from hydroxyl and halogen;
  • G 3 is 3- to 8-membered cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- 4 alkyl and -OCi- 4 alkyl;
  • G 4 is phenyl optionally substituted with 1-4 substituents independently selected from the group consisting of-OCi- 4 alkyl; and R 4 is phenyl or a 6-membered heteroaryl containing 1-3 nitrogen, R 4 being optionally substituted with 1-3 substituents independently selected from the group consisting of halogen.
  • X 4 is S (i.e., formula (II)).
  • X 1 is CR X1 (e.g., CH)
  • X 3 is CR X3 (e.g., CH).
  • X 3 is N
  • X 1 is CR X1 (e.g., CH)
  • X 2 is CR X2 (e.g., CH, C-halogen, C- Ci -4 alkyl).
  • X 1 is N
  • X 2 is CR X2 (e.g., C-Ci -4 alkyl)
  • X 3 is CR X3 (e.g., CH).
  • X 3 is N
  • X 1 is N
  • X 2 is CR X2 (e.g., CH, C-halogen, C-Ci -4 alkyl).
  • X 1 is N
  • X 2 is N
  • X 3 is CR X3 (e.g., CH, C-Ci -4 alkyl).
  • X 1 is CR X1 (e.g., CH)
  • X 2 is CR X2 (e.g., CH, C-halogen)
  • X 3 is CR X3 e.g., CH).
  • X 4 is O (i.e., formula (III)).
  • X 1 is CR X1 (e.g., CH, C-OCi -4 alkyl)
  • X 2 is CR X2 (e.g., CH, C-halogen)
  • X 3 is CR X3 (e.g., CH).
  • X 2 is N
  • X 1 is CR X1 (e.g., CH)
  • X 3 is CR X3 (e.g., CH).
  • X 3 is N, X 1 is CR X1 (e.g., CH), and X 2 is CR X2 (e.g., CH, C-halogen, C-Ci -4 alkyl). In other embodiments, X 1 is N, X 2 is CR X2 (e.g., C-Ci -4 alkyl), and X 3 is CR X3 (e.g., CH). In other embodiments, X 3 is N, X 1 is N, and X 2 is CR X2 (e.g., CH, C-halogen, C-Ci -4 alkyl). In other embodiments, X 1 is N, X 2 is N, and X 3 is CR X3 (e.g., CH, C-Ci -4 alkyl).
  • X 1 is CR X1 (e.g., CH, C-OCi-4alkyl)
  • X 2 is CR X2 (e.g., CH, C-halogen)
  • X 3 is CR X3 (e.g., CH, C-OC M alkyl).
  • X 2 is N
  • X 1 is CR X1 (e.g., CH, C-Ci -4 alkyl, C-halogen, C-OCi -4 alkyl, C- G 2 )
  • X 3 is CR X3 (e.g., CH).
  • X 3 is N, X 1 is CR X1 (e.g., CH), and X 2 is CR X2 (e.g., CH, C-halogen, C-Ci -4 alkyl). In other embodiments, X 1 is N, X 2 is CR X2 (e.g., C-Ci -4 alkyl), and X 3 is CR X3 (e.g., CH). In other embodiments, X 3 is N, X 1 is N, and X 2 is CR X2 (e.g., CH, C-halogen, C-Ci -4 alkyl).
  • X 1 is N
  • X 2 is N
  • X 3 is CR X3 (e.g., CH, C-Ci -4 alkyl).
  • X 2 is N
  • X 3 is N
  • X 1 is CR X1 (e.g., CH).
  • R 1 is -I ⁇ -G ⁇ R 6 (i.e., (II-l)), wherein G 1 , L 1 , and R 6 are as defined herein.
  • R 1 is -I ⁇ -G 1 - R 6 (i.e., (III-l)), wherein G 1 , L 1 , and R 6 are as defined herein.
  • R is -L -G -R (i.e., (IV- 1)), wherein G 1 , L 1 , and R 6 are as defined herein.
  • G 1 is a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a Ci-3alkylene bridge between two non-adjacent ring atoms, G 1 being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- 4 alkyl, Ci_ 4 haloalkyl, halogen, hydroxyl, and oxo.
  • G 1 is a 4- to 8- membered optionally substituted monocyclic heterocycle containing a first nitrogen atom and optionally a second heteroatom independently selected from oxygen and nitrogen, and optionally containing one double bond and/or a bridge between two non-adjacent ring atoms.
  • G 1 is connected to the parent molecular moiety (i.e., at L 1 ) through the first nitrogen atom.
  • G 1 is attached to L 1 at a ring carbon atom of G 1 .
  • G 1 is a 4- to 6-membered optionally substituted monocyclic heterocycle containing a first nitrogen atom and optionally a second heteroatom independently selected from oxygen and nitrogen, and optionally containing one double bond and/or a bridge between two non-adjacent ring atoms, G 1 being connected to the parent molecular moiety through the first nitrogen atom.
  • G 1 is a 4- to 8-membered monocyclic heterocycle containing 1 or 2 nitrogen atoms, the monocyclic heterocycle optionally containing one double bond and/or a bridge between two non-adjacent ring atoms, G 1 being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- 4 alkyl, halogen, hydroxyl, and oxo.
  • G 1 contains one nitrogen atom. In other embodiments, G 1 contains two nitrogen atoms.
  • the heterocycles at G 1 may be unsubstituted or substituted.
  • G 1 may be piperazinyl, homopiperazinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-dihydro-lH- pyrrolyl, oxetanyl, morpholino, tetrahydropyranyl, or 1,2,3,6-tetrahydropyridinyl, each unsubstituted or substituted as described herein.
  • the piperazinyl, homopiperazinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, 2,5- diazabicyclo[2.2.1]heptanyl, 2,5-dihydro-lH-pyrrolyl, oxetanyl, mo holino, tetrahydropyranyl, or 1,2,3,6-tetrahydropyridinyl are optionally substituted with 1-4 substituents independently selected from 1 hydroxyl, 1-2 halogen, 1 oxo, and 1-4 Ci_ 4 alkyl groups.
  • a pyrrolidinyl and/or piperidinyl is optionally substituted with halogen, 1 hydroxyl, or 1 oxo and the piperazinyl is optionally substituted with oxo.
  • G 1 is piperazin-l-yl optionally substituted with oxo.
  • G 1 may have a bridge between two non-adjacent ring atoms (e.g., 2,5-diazabicyclo[2.2. l]heptanyl). In other embodiments, G 1 is without a bridge between two non-adjacent ring atoms.
  • the heterocycles of G 1 may be appended to the parent molecule (i.e., at L 1 ) by any substitutable carbon or nitrogen atom.
  • L 1 is -O- and G 1 is attached to L 1 at a ring carbon atom of G 1 .
  • L 1 is a bond and G 1 is attached to L 1 at a ring nitrogen atom of G 1 .
  • G 1 examples include piperazin-l-yl, 2-oxo-piperazin-l-yl, homopiperazin-l-yl, azetidin-l-yl, azetidin-3-yl, pyrrolidin-3-yl, 3-hydroxy-pyrrolidin-3-yl, 3-fluoro-pyrrolidin-3-yl, piperidin-l-yl, piperidin-3-yl, piperidin-4-yl, 3-hydroxypiperidin-4-yl, 4- hydroxypiperidin-4-yl, 3-fluoropiperidin-4-yl, 4-fluoropiperidin-4-yl, 3,3- difiuoropiperidin-4-yl, azepan-3-yl, 2,5-diazabicyclo[2.2.1]heptan-2-yl, 2,5-dihydro- lH-pyrrol-3-yl, or l,2,3,6-tetrahydropyridin-4-
  • R 6 is a 4- to 12-membered heterocycle containing 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the heterocycle being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- 4 alkyl, -CH 2 S(0) 2 phenyl, halogen, hydroxyl, oxo, - OCi- 4 alkyl, -Ci- 6 alkylene-OCi- 4 alkyl, and -Ci- 6 alkylene-OH.
  • the 4- to 12-membered heterocycle at R 6 may be a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a bridge between two non- adjacent ring atoms and being optionally substituted with 1-4 substituents
  • R is a 4- to 6-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen and nitrogen, and sulfur, the heterocycle being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- 4 alkyl, halogen, hydroxyl, oxo, and -OCi- 4 alkyl.
  • R 6 is an oxetanyl, a tetrahydrofuranyl, a tetrahydropyranyl, a morpholinyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 1,4-oxazepanyl, 3-oxa- 8-azabicyclo[3.2.1]octanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, a pyrrolidinyl, piperidinyl, thiomorpholinyl, a thietanyl, piperazinyl, or azetidinyl, each being optionally substituted as described herein.
  • R 6 is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, pyrrolidinyl, or thietanyl, each being optionally substituted with 1-4 substituents independently selected from Ci- 4 alkyl and oxo.
  • the oxetanyl, tetrahydrofuranyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, or thietanyl each being optionally substituted with 1-4 substituents independently selected from Ci- 4 alkyl and oxo.
  • tetrahydropyranyl, morpholinyl, pyrrolidinyl, thietanyl, piperazinyl, and azetidinyl are each optionally substituted with 1-4 substituents independently selected from halogen, Ci- 4 alkyl and oxo.
  • the oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, pyrrolidinyl, thietanyl, and piperazinyl are each optionally substituted with Ci- 4 alkyl, and the pyrrolidinyl, piperazinyl, and thietanyl further optionally substituted with 1-2 oxo groups.
  • R 6 is a 4- to 8-membered monocyclic heterocycle containing 1 oxygen atom (e.g., an oxetanyl, a tetrahydrofuranyl, a tetrahydropyranyl).
  • R 6 is a 4-membered monocyclic heterocycle containing 1 oxygen atom and optionally substituted with Ci_ 4 alkyl or -CH 2 S(0) 2 phenyl.
  • R 6 is a 4-membered monocyclic heterocycle containing 1 oxygen atom and optionally substituted with Ci- 4 alkyl.
  • R 6 is a 4- to 8-membered monocyclic heterocycle containing 1 sulfur atom (e.g., thietanyl, tetrahydrothiophenyl, tetrahydro-2H-thiopyranyl). In other embodiments, R 6 is a 4-membered monocyclic heterocycle containing 1 sulfur atom and optionally substituted with 1-2 oxo groups.
  • R 6 is a 4- to 8-membered monocyclic heterocycle containing 1 nitrogen atom and optionally 1 oxygen atom or 1 sulfur atom (e.g., azetidinyl, pyrrolidinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, piperazinyl) and optionally substituted with oxo (e.g., 2-oxopyrrolidin-l-yl).
  • the heterocycles of R 6 may be appended to the parent molecule (i.e., to G 1 ) by any substitutable carbon atom or nitrogen atom in R 6 .
  • the oxygen-containing heterocycle is oxetan-3-yl
  • the sulfur-containing heterocycle is thietan-3-yl, tetrahydrothiophen-3- yl, tetrahydro-2H-thiopyran-3-yl, or tetahydro-2H-thiopyran-4-yl.
  • the heterocycle containing 1 nitrogen atom and optionally 1 oxygen or sulfur atom is e.g., piperidin-l-yl, morpholin-4-yl, azetidin-l-yl, piperazin-l-yl, 2- oxa-5-azabicyclo[2.2.1]heptan-5-yl, 6-oxa-3-azabicyclo[3.1.1]heptan-3-yl, 1,4- oxazepan-4-yl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, 8-oxa-3-azabicyclo[3.2.1]octan- 3-yl, thiomorpholin-4-yl, or 2-oxopyrrolidin-l-yl.
  • the oxygen- and sulfur-containing heterocycles may be unsubstituted or substituted as described herein.
  • the oxygen-containing heterocycle may be oxetan-3-yl, 3-methyloxetan-3-yl or 3-((phenylsulfonyl)methyl)oxetan-3-yl and the sulfur-containing heterocycle may be thietan-3-yl or l,l-dioxothietan-3-yl.
  • R 6 is oxetanyl, tetrahydrofuranyl, 1,4-dioxanyl, morpholino, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- 4 alkyl, Ci_ 4 haloalkyl, halogen, hydroxyl, oxo, and -OCi- 4 alkyl.
  • the 4- to 12-membered heterocycle at R 6 may be a 7- to 12-membered spiro heterocycle comprising a first ring and a second ring, the first ring being a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from nitrogen and oxygen and being attached to G 1 , the second ring being a Cs-gcycloalkyl or a 4- to 8-membered monocyclic heterocycle containing 1-2 oxygen atoms wherein two atoms of the second ring are attached to one carbon of the first ring to form a spirocycle optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- 4 alkyl, Ci_ 4 haloalkyl, halogen, hydroxyl, and oxo.
  • the spirocyclic R 6 is optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- 4 alkyl, -CH 2 S(0) 2 phenyl, halogen, hydroxyl, oxo, - OCi- 4 alkyl, -Ci- 6 alkylene-OCi- 4 alkyl, and -Ci- 6 alkylene-OH.
  • 1-4 substituents independently selected from the group consisting of Ci- 4 alkyl, -CH 2 S(0) 2 phenyl, halogen, hydroxyl, oxo, - OCi- 4 alkyl, -Ci- 6 alkylene-OCi- 4 alkyl, and -Ci- 6 alkylene-OH.
  • R 6 is a 7- to 12-membered spiro heterocycle consisting of the first ring and a second ring, as described herein.
  • the first ring is attached to G 1 through any substitutable carbon or nitrogen atom.
  • the first ring is attached to G 1 through a nitrogen atom.
  • the first ring of R 6 includes, but is not limited to, heterocycles such as azetidine, pyrrolidine, piperidine, azepane, morpholine, azocane, piperazine, and homopiperazine.
  • the first ring of R 6 is a 4- to 8-membered monocyclic heterocycle containing 1 -2 nitrogen atoms or 1 nitrogen atom and 1 oxygen atom.
  • the first ring is morpholino, piperazin-l -yl, or piperidin-l -yl.
  • the second ring includes a C3- gcycloalkyl, e.g., cyclopropyl, cyclobutyl cyclopentyl.
  • the second ring is formed by the attachment of two atoms of the second ring to a single carbon atom of the first ring such that the first ring and the second ring share one carbon atom in common.
  • R 6 is 4-oxa-7-azaspiro[2.5]octanyl (e.g., 4-oxa-7- azaspiro[2.5]octan-7-yl).
  • the 4- to 12-membered heterocycle at R 6 may be a 7- to 12-membered fused bicyclic heterocycle containing 1 -3 heteroatoms independently selected from oxygen, nitrogen, and sulfur and being optionally substituted with 1 -4 substituents independently selected from the group consisting of Ci- 4 alkyl, halogen, hydroxyl, and oxo.
  • R 6 is a 7- to 12-membered fused bicyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur and being optionally substituted with 1 -4 substituents independently selected from the group consisting of Ci- 4 alkyl, Ci_ 4 haloalkyl, halogen, hydroxyl, oxo, -OCi- 4 alkyl, -Ci- 6 alkylene-OCi- 4 alkyl, and -Ci- 6 alkylene-OH.
  • the fused bicyclic heterocycle is a 7- 12- membered ring system having a monocyclic heterocycle, as defined herein, fused to another monocyclic heterocyclic ring.
  • R 6 is 2- oxa-5-azabicyclo[4.1.0]heptanyl (e.g., 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl).
  • R 6 may be a 3- to 8-membered cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- 4 alkyl, halogen, hydroxyl, -C(0)OCi- 4 alkyl, -C(0)OH, and oxo.
  • R 6 is optionally substituted with 1 -4 substituents independently selected from the group consisting of Ci- 4 alkyl, halogen, hydroxyl, -C(0)OCi -4 alkyl, -C(0)OH, oxo, -OCi -4 alkyl, -Ci -6 alkylene-OCi -4 alkyl, and -C h alky lene-OH.
  • R 6 is cyclopropyl, cyclobutyl, or cyclopentyl, each being optionally substituted with -C(0)OCi- 4 alkyl, - C(0)OH, hydroxyl or 1 -2 halogen.
  • R 6 is cyclopropyl.
  • R is cyclobutyl.
  • R is 3,3- difiuorocyclobutyl.
  • R 6 is a cyclobutane carboxylic acid.
  • R 6 may be represented by the following formulas, wherein R' and R 6b are the optional R 6 substituents, respectively, for the 4-12 membered heterocycle or C3- 8 cycloalkyl of R 6 and s is an integer from 0-4:
  • G may be represented by the following formulas, wherein R l is the optional G 1 substituent and m is an integer from 0-4:
  • G ⁇ R 6 may also be represented by the following formulas, wherein R l , R 6a , R 6b , m and s are as defined herein:
  • -G 1 -!* 6 together may be 4-(oxetan-3-yl)piperazin-l-yl, 4-(3-methyloxetan-
  • -G 1 -!* 6 together may represent 3-(l- hydroxycyclobutyl)piperazin-l-yl; 4-cyclopropylpiperazin-l-yl; 4- cyclobutylpiperazin-l-yl; 4-cyclopentylpiperazin-l-yl; l-cyclopropylpiperidin-4-yl; l-cyclopropylpiperidin-3-yl; l-cyclobutylpiperidin-4-yl, l-cyclopentylpiperidin-4-yl, 4-(3,3-difluorocyclobutyl)piperazin-l-yl; or 5-cyclopropyl-2,5- diazabicyclo[2.2. l]heptan-2-yl.
  • L 1 is a bond or -0-.
  • R 2 is hydrogen, Ci- 4 alkyl, or
  • R X1 is hydrogen.
  • R X2 is hydrogen or halogen.
  • R X3 is hydrogen or -OCi- 4 alkyl.
  • G 1 is a 4- to 8-membered or 4- to 6-membered optionally substituted monocyclic heterocycle as described above.
  • R 6 is an optionally substituted 4- to 8- membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a bridge between two non-adjacent ring atoms.
  • L 1 is a bond or -0-;
  • R 2 is hydrogen, Ci- 4 alkyl, or Ci_ 4 haloalkyl;
  • R is hydrogen;
  • R is hydrogen or halogen;
  • R is hydrogen or -OCi- 4alkyl;
  • G 1 is a 4- to 8-membered optionally substituted monocyclic heterocycle containing a first nitrogen atom and optionally a second heteroatom independently selected from oxygen and nitrogen, the monocyclic heterocycle optionally containing one double bond and/or a bridge between two non-adjacent ring atoms;
  • R 6 is an optionally substituted 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a Ci_ 3 alkylene bridge between two non-adjacent ring atoms.
  • L 1 is a bond and G 1 is a 4- to 8-membered optionally substituted monocyclic heterocycle containing a first nitrogen atom and optionally a second heteroatom independently selected from oxygen and nitrogen, the monocyclic heterocycle optionally containing one double bond and/or a bridge between two non-adjacent ring atoms, G 1 being connected to the parent molecular moiety through the first nitrogen atom.
  • L 1 is a bond and G -R 6 is combination with the foregoing, L
  • G is a 4- to 8-membered optionally substituted monocyclic heterocycle containing a first nitrogen atom and optionally a second heteroatom independently selected from oxygen and nitrogen, the monocyclic heterocycle optionally containing one double bond and/or a bridge between two non-adjacent ring atoms, wherein G 1 is connected to the parent molecular moiety through a carbon atom of G 1 .
  • L 1 is -O-
  • L 1 is a bond.
  • R 2 is hydrogen, Ci- 4 alkyl, or Ci- 4 haloalkyl.
  • R X1 is hydrogen.
  • R X2 is hydrogen or halogen.
  • R X3 is hydrogen.
  • G 1 is a 4- to 8-membered or 4- to 6-membered optionally substituted monocyclic heterocycle as described above.
  • R 6 is an optionally substituted 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a Ci-3alkylene bridge between two non-adjacent ring atoms.
  • R 6 is an optionally substituted 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a Ci-3alkylene bridge between two non-adjacent ring atoms.
  • L is a bond; R is Ci- 4 alkyl; R is hydrogen; R is hydrogen; R X3 is hydrogen; G 1 is an optionally substituted 4- to 8-membered monocyclic heterocycle containing a first nitrogen atom and optionally a second heteroatom independently selected from oxygen and nitrogen, the monocyclic heterocycle optionally containing one double bond and/or a bridge between two non- adjacent ring atoms, G 1 being connected to the parent molecular moiety through the first nitrogen atom; and R 6 is an optionally substituted 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a bridge between two non-adjacent ring atoms.
  • L 1 is a bond and G ⁇ R 6 is
  • L 1 is a bond and G ⁇ R 6 is
  • R 1 is -L x -G 2 (i.e., ( ⁇ -2)), wherein G 2 and L 1 are as defined herein.
  • R 1 is -L x -G 2 (i.e., (III-2)), wherein G 2 and L 1 are as defined herein.
  • R 1 is -L x -G 2 (i.e., (IV-2)), wherein G 2 and L 1 are as defined herein.
  • G 2 is a 4- to 12-membered heterocycle containing 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, G 2 being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- 4 alkyl (e.g., methyl, ethyl, isopropyl), Ci -4 haloalkyl (e.g., -CF 3 , -CH 2 CF 3 , - CH 2 CHF 2 ), halogen (e.g., fluoro), hydroxyl, oxo, cyano, -Ci- 6 alkylene-cyano, - C(0)Ci -4 alkyl (e.g., -C(0)CH 3 ), -C(0)-Ci -6 alkylene-OCi -4 alkyl, -C(0)-Ci_ ealkylene-OH, -C(0)C 3-6 cycloalkyl, -C(0)OC M alkyl (e.g., -C(0)OC M al
  • G 2 is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, Ci -4 alkyl, -C(0)OCi -4 alkyl, -OCi -4 alkyl, -N(Ci_ 4 alkyl)(Ci- 4 alkyl), -Ci- 6 alkylene-OCi -4 alkyl, and -Ci- 6 alkylene substituted by 2 groups independently selected from hydroxyl and halogen.
  • G 2 may be substituted with one substituent selected from the foregoing group and further optionally substituted with 1-3 substituents selected from the group consisting of Ci_ 4 alkyl and halogen.
  • the heterocycles of G 2 may be appended to the parent molecule (i.e., at L 1 ) by any substitutable carbon or nitrogen atom.
  • L 1 is -0-, -O- Ci- 4 alkylene-, or -NR 5 - and G 2 is attached to L 1 at a ring carbon atom of G 2 .
  • L 1 is a bond or -C(O)- and G 2 is attached to L 1 at a ring nitrogen atom of G 2 .
  • the 4- to 12-membered heterocycle at G 2 is a 4- to 8- membered monocyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a Ci -3 alkylene bridge between two non-adjacent ring atoms, G 2 being optionally substituted with 1-4 substituents as described herein.
  • G 2 is an optionally substituted 4- to 8-membered monocyclic heterocycle containing a first nitrogen atom and optionally a second nitrogen atom, an oxygen or sulfur atom, and optionally containing one double bond and/or a Ci_ 3 alkylene bridge between two non-adjacent ring atoms, G 2 being connected to L 1 through the first nitrogen atom.
  • G 2 is an optionally substituted 4- to 6-membered monocyclic heterocycle containing a first nitrogen atom and optionally a second heteroatom independently selected from oxygen and nitrogen, and optionally containing one double bond and/or a Ci -3 alkylene bridge between two non- adjacent ring atoms, G 2 being connected to the parent molecular moiety through a nitrogen atom.
  • G 2 is an optionally substituted 4- to 6- membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen and nitrogen, G 2 being connected to the parent molecular moiety through ring carbon atom of G 2 .
  • G 2 is a 6-membered monocyclic heterocycle containing 1 or 2 nitrogen atoms and substituted with Ci- 4 alkyl.
  • G 2 is piperazin-l-yl optionally substituted with Ci- 4 alkyl.
  • G 2 may be 4-Ci- 4 alkyl-piperazin-l-yl.
  • G 2 may be
  • G 2 may be an optionally substituted 4- to 8- membered monocyclic heterocycle containing one oxygen atom and optionally one double bond (e.g., oxetanyl, tetrahydrofuranyl, 2,5-dihydrofuranyl).
  • G 2 may be an optionally substituted 4- to 8-membered monocyclic heterocycle containing one nitrogen and optionally a second nitrogen atom, an oxygen or sulfur atom, and optionally containing one double bond and/or a
  • G 2 may be morpholinyl, homomorpholinyl, thiomorpholinyl, piperazinyl,
  • G 2 may have a Ci- 3 alkylene bridge between two non-adjacent ring atoms (e.g., 2,5- diazabicyclo[2.2.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 3-oxa-8- azabicyclo[3.2.1]octanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl).
  • G 2 is without a bridge between two non-adjacent ring atoms.
  • the heterocycles of G 2 may be appended to the parent molecule (i.e., at L 1 ) by any substitutable carbon or nitrogen atom (e.g., morpholin-4-yl, homomorpholin-4-yl, thiomorpholin-4-yl, 4-thiomorpholine 1,1 -dioxide, piperazin-l-yl, homopiperazin-1- yl, azetidin-l-yl, azetidin-3-yl, pyrrolidin-l-yl, pyrrolidin-3-yl, 2-oxooxazolidin-3-yl, 2-oxooxazolidin-5-yl, piperidin-l-yl, piperidin-3-yl, piperidin-4-yl, azepan-l-yl, azepan-3-yl, 2,5-diazabicyclo[2.2.1]heptan-2-yl, 6-oxa-3-azabicyclo[3.1.1]h
  • G 2 may be represented by the following formulas, wherein R 2a is the optional G 2 substituent and m is an integer between 0 and 4.
  • the 4- to 12-membered heterocycle at G 2 is a 7- to 12- membered spiro heterocycle comprising a first ring and a second ring, the first ring being a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from nitrogen and oxygen and being attached to L 1 , the second ring being a C3- 8 cycloalkyl or a 4- to 8-membered monocyclic heterocycle containing 1-2 oxygen atoms wherein two atoms of the second ring are attached to one carbon of the first ring to form a spirocycle, and wherein G 2 is optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- 4 alkyl, Ci_ 4haloalkyl, halogen, hydroxyl, and oxo.
  • G 2 is connected to the parent molecular moiety through a nitrogen atom of the first ring (e.g., when L 1 is a bond).
  • G 2 is a 7- to 12-membered spiro heterocycle consisting of the first ring and a second ring, as described herein.
  • the first ring of the spiro heterocycle includes, but is not limited to, heterocycles such as azetidine, pyrrolidine, piperidine, azepane, morpholine, azocane, piperazine, and homopiperazine.
  • the first ring is a 4- to 8-membered monocyclic heterocycle containing 1 -2 nitrogen atoms or 1 nitrogen atom and 1 oxygen atom. In another embodiment, the first ring is a 4- to 6-membered monocyclic heterocycle containing
  • the first ring may be attached to the parent molecule through a nitrogen atom (e.g., azetidin-l-yl, pyrrolidin-l -yl, piperazin-l -yl, or piperidin-l -yl).
  • the second ring includes, but is not limited to, heterocycles such as oxetane, tetrahydrofuran, tetrahydropyran, dioxolane, etc.
  • the second ring has one oxygen atom. In other embodiments, the second ring has two oxygen atoms.
  • the second ring is a C3- 8 cycloalkyl, e.g., cyclopropyl, cyclobutyl cyclopentyl.
  • the second ring is formed by the attachment of two atoms of the second ring to a single carbon atom of the first ring such that the first ring and the second ring share one carbon atom in common.
  • the second ring may be joined with the first ring at the 4-position of a first ring piperidin-l -yl or the 3- position of a first ring azetidin-l -yl, pyrrolidin-l-yl, piperidin-l -yl, or piperazin-l -yl.
  • G 2 is l,4-dioxa-8-azaspiro[4.5]decanyl, 2-oxa-6- azaspiro[3.5]nonanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-5,8- diazaspiro[3.5]nonanyl, 2,5-dioxa-8-azaspiro[3.5]nonanyl, l-oxa-8- azaspiro[4.5]decanyl, 5-oxa-8-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, 6- oxa-2-azaspiro[3.4]octanyl, l-oxa-6-azaspiro[3.3]heptanyl, or 2-oxa-6- azaspiro[3.3]heptanyl, 2-oxa-8-azaspiro[4.5]decanyl, 2,6-diazas
  • inventions include l ,4-dioxa-8-azaspiro[4.5]decan-8-yl, 2-oxa-7- azaspiro[3.5]nonan-7-yl, 2-oxa-7-azaspiro[4.4]nonan-7-yl, 5-methyl-2-oxa-5,8- diazaspiro[3.5]nonan-8-yl, 2-oxa-6-azaspiro[3.4]octan-6-yl, 2-oxa-5- azaspiro[3.4]octan-5-yl, l-oxa-6-azaspiro[3.3]heptan-6-yl, 2-oxa-6- azaspiro[3.5]nonan-6-yl, 2,5-dioxa-8-azaspiro[3.5]nonan-8-yl, l-oxa-8- azaspiro[4.5]decan-8-yl, 5-oxa-8-azaspiro[3.5]nonan
  • G 2 is selected from the group consisting of 2,6-diazaspiro[3.3]heptan-
  • the 4- to 12-membered heterocycle at G 2 is a 7- to 12- membered fused bicyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- 4 alkyl, Ci_ 4 haloalkyl, halogen, hydroxyl, -OCi- 4 alkyl, and oxo.
  • the fused bicyclic heterocycle is a 7-12-membered ring system having a monocyclic
  • G 2 may be substituted with on
  • L 1 is a bond, -0-, -0-Ci- 4 alkylene- -NR 5 -, or -C(O)-.
  • R 2 is hydrogen, Ci- 4 alkyl,
  • R X1 is hydrogen.
  • R X2 is hydrogen or halogen.
  • R X3 is hydrogen.
  • G 2 is an optionally substituted 4- to 8-membered monocyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a bridge between two non-adjacent ring atoms.
  • L 1 is a bond, -0-, -0-Ci -4 alkylene-, -NR 5 -, or -C(O)-;
  • R 2 is hydrogen, Ci- 4 alkyl, or halogen;
  • R X1 is hydrogen;
  • R X2 is hydrogen or halogen;
  • R X3 is hydrogen or -OCi- 4 alkyl;
  • G 2 is an optionally substituted 4- to 8- membered monocyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a bridge between two non-adjacent ring atoms.
  • L 1 is a bond, -0-, -O-Ci- 4 alkylene- -NR 5 -, or -C(O)-;
  • R 2 is Ci -4 alkyl, Ci -4 haloalkyl, or halogen;
  • R X1 is hydrogen;
  • R is hydrogen or halogen;
  • R is hydrogen or -OCi- 4 alkyl;
  • G is an optionally substituted 4- to 8-membered monocyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a Ci-3alkylene bridge between two non-adjacent ring atoms.
  • L 1 is a bond, -0-, -O-Ci- 4 alkylene-, -NR 5 -, or -C(O)-;
  • R 2 is hydrogen, Ci- 4 alkyl, or halogen;
  • R is hydrogen;
  • R is hydrogen or halogen;
  • R is hydrogen or -OCi- 4 alkyl;
  • G is an optionally substituted 4- to 8-membered monocyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a
  • X 3 is R X3 .
  • L 1 is a bond, -0-, -O-Ci. 4 alkylene-, -NR 5 -, or -C(O)-;
  • R 2 is hydrogen, Ci- 4 alkyl, or halogen;
  • R is hydrogen;
  • R is hydrogen or halogen;
  • R is hydrogen or -OCi- 4 alkyl;
  • G is an optionally substituted 4- to 8-membered monocyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a bridge between two non-adjacent ring atoms; and
  • R 4 is optionally substituted pyridinyl.
  • L 1 is a bond, -0-, -O-Ci- 4 alkylene-, -NR 5 -, or -C(O)-;
  • R 2 is hydrogen, Ci- 4 alkyl, or halogen;
  • R is hydrogen; R is hydrogen or halogen; R is hydrogen or -OCi- 4 alkyl; G is an optionally substituted 4- to 8-membered monocyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a bridge between two non-adjacent ring atoms; and X 1 is R X1 .
  • L 1 is a bond, -0-, -O-Ci- 4 alkylene-, -NR 5 -, or -C(O)-;
  • R 2 is hydrogen, Ci- 4 alkyl, or halogen;
  • R is hydrogen; R is hydrogen or halogen; R is hydrogen or -OCi- 4 alkyl; G is an optionally substituted 4- to 8-membered monocyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a bridge between two non-adjacent ring atoms; and X 2 is R X2 .
  • X 1 is CR X1 ;
  • X 3 is CR X3 ;
  • X 2 is N;
  • R is hydrogen;
  • R is hydrogen;
  • R is Ci- 4 alkyl, or halogen;
  • L is a bond, -0-, -0-Ci-4alkylene-, -NR 5 -, or -C(O)-;
  • G 2 is an optionally substituted 4- to 8-membered monocyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a bridge between two non-adjacent ring atoms; and
  • R 4 is optionally substituted phenyl or pyridinyl.
  • R 4 is phenyl substituted with phenyl (e.g., 3,5-difluorophenyl). In another subembodiment, R 4 is pyridin-2-yl.
  • X 1 is CR X1 ;
  • X 2 is CR X2 ;
  • X 3 is
  • N is a bond, -0-, -0-Ci- 4 alkylene-, -NR 5 -, or -C(O)-;
  • G 2 is an optionally substituted 4- to 8-membered monocyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a bridge between two non-adjacent ring atoms; and
  • R 4 is optionally substituted pyridinyl. In one subembodiment, R 4 is pyridin-2-yl.
  • L 1 is a bond, -0-, -O-Ci. 4 alkylene-, -NR 5 -, or -C(O)-;
  • R 2 is hydrogen, Ci- 4 alkyl, or halogen;
  • R is hydrogen;
  • R is hydrogen or halogen;
  • R is hydrogen or -OCi- 4 alkyl;
  • G is an optionally substituted 4- to 8-membered monocyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a
  • R 4 is optionally substituted pyridinyl.
  • L 1 is a bond, -0-, -O-Ci. 4 alkylene-, -NR 5 -, or -C(O)-;
  • R 2 is hydrogen, Ci- 4 alkyl, or halogen;
  • R is hydrogen;
  • R is hydrogen or halogen;
  • R is hydrogen or -OCi- 4 alkyl;
  • G is an optionally substituted 4- to 8-membered monocyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a
  • R 4 is phenyl or pyridinyl.
  • L 1 is a bond or -C(O)-
  • G 2 is connected to L 1 through a nitrogen atom of G 2 .
  • L 1 is a bond or — N >— OC 1 -4 alkyl — N >— N(C 1-4 alkyl) 2
  • R g2a is C 1-4 alkyl, -C(0)OCi.
  • L 1 is -0-, -O-Ci- 4alkylene-, or -NR 5 -, and G 2 is connected to L 1 through a carbon atom of G 2 .
  • L is -0-, -0-Ci- 4 alkylene-, or -NR -, and G is "
  • R 2a is C M alkyl, -C(0)OC M alkyl, -Ci -6 alkylene-OCi -4 alkyl, or -Ci_ 6alkylene substituted by 2 groups independently selected from hydroxyl and halogen.
  • L 1 is a bond.
  • R 2 is hydrogen, Ci_ 4 alkyl, C 1-4 haloalkyl, or halogen.
  • R 2 is hydrogen.
  • R X1 is hydrogen.
  • R X2 is hydrogen or halogen.
  • R X2 is hydrogen.
  • R X3 is hydrogen.
  • L is a bond
  • G is ;
  • R a is
  • Ci- 4 alkyl Ci- 4 alkyl
  • m is 0 or 1.
  • L 1 is a
  • G is N— / , 4 N— / , , or 3 ⁇ 4 V- ; and R 2a is Ci -4 alkyl.
  • R 1 is -L x -G 3 (i.e., ( ⁇ -3)), wherein G and L 1 are as defined herein.
  • R 1 is -L x -G 3 (i.e., ( ⁇ -3)), wherein G and L 1 are as defined herein.
  • R 1 is -L x -G 3 (i.e., (IV-3)), wherein G and L 1 are as defined herein.
  • G 3 is a 3- to 8-membered cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of Ci-4alkyl, Ci- 4 haloalkyl, halogen, hydroxyl, oxo, cyano, -C(0)Ci- 4 alkyl, -C(0)C3- 6 cycloalkyl, - C(0)OCi -4 alkyl, -C(0)OCi -4 haloalkyl, -C(0)NH 2 , -C(0)NH(Ci -4 alkyl), -C(0)N(Ci_ 4 alkyl)(Ci -4 alkyl), -C(0)NH(-Ci -6 alkylene-OCi -4 alkyl), -C(0)N(Ci -4 alkyl)(-Ci. 6 alkylene-OCi -4 alkyl), -C(0)NH(-Ci -6 alkylene-OH), -C(0)N(Ci -4 alkylene-
  • G 3 is optionally substituted C3- 5 cycloalkyl. In some embodiments, G 3 is optionally substituted cyclopropyl or cyclobutyl.
  • L 1 is -O- or -0-Ci -4 alkylene-.
  • R 2 is Ci -4 alkyl.
  • R X1 is hydrogen.
  • R X2 is hydrogen.
  • R X3 is hydrogen.
  • L 1 is -O- or -0-Ci -4 alkylene-;
  • R 2 is Ci -4 alkyl;
  • R X1 is hydrogen;
  • R is hydrogen;
  • R is hydrogen; and G is optionally substituted C3-
  • G 3 is cyclopropyl
  • L 1 is a bond or -0-.
  • R 2 is hydrogen.
  • R X1 is hydrogen.
  • R X2 is hydrogen.
  • R X3 is hydrogen.
  • L is a bond or -0-; R is hydrogen; R is hydrogen; R is hydrogen; R X3 is hydrogen; and G 3 is optionally substituted C3-6cycloalkyl.
  • R 1 is -L 2 -G 4 (i.e., ( ⁇ -4)), wherein G 4 and L 2 are as defined herein.
  • R 1 is -L 2 -G 4 (i.e., (III-4)), wherein G 4 and L 2 are as defined herein.
  • R 1 is -L 2 -G 4 (i.e., (IV-4)), wherein G 4 and L 2 are as defined herein.
  • G 4 is phenyl optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- 4 alkyl, Ci -4 haloalkyl, halogen, hydroxyl, cyano, phenyl, -C(0)Ci -4 alkyl, -C(0)C 3 - 6 cycloalkyl, -C(0)OCi -4 alkyl, -C(0)OCi_ 4 haloalkyl, -C(0)NH 2 , -C(0)NH(Ci -4 alkyl), -C(0)N(Ci -4 alkyl)(Ci -4 alkyl), - C(0)NH(-Ci -6 alkylene-OCi -4 alkyl), -C(0)N(Ci -4 alkyl)(-Ci -6 alkylene-OCi -4 alkyl), - C(0)NH(-Ci -6 alkylene-OH), -C(0)N(Ci -4 alkyl)(-Ci -6 alkylene
  • G 4 is phenyl optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- 4 alkyl, halogen, hydroxyl, cyano, -or OCi- 4 alkyl. In further embodiments, G 4 is phenyl optionally substituted with OCi- 4 alkyl.
  • L 1 is -0-Ci- 4 alkylene-.
  • R 2 is Ci- 4 alkyl.
  • R X1 is hydrogen.
  • R X2 is Ci- 4 alkyl.
  • R X3 is hydrogen.
  • L is -0-Ci- 4 alkylene-; R is Ci- 4 alkyl; R is hydrogen; R is Ci- 4 alkyl; R X3 is hydrogen; and G 4 is phenyl optionally substituted with OCi- 4 alkyl.
  • L 1 is -0-Ci- 4 alkylene-.
  • R 2 is hydrogen.
  • R X1 is hydrogen.
  • R X2 is hydrogen.
  • R X3 is hydrogen.
  • L is -0-Ci- 4 alkylene-; R is hydrogen; R is hydrogen; R is hydrogen; R X3 is hydrogen; and G 4 is phenyl.
  • R 1 is -G 5 (i.e., (IV-5)), wherein G 5 is as defined herein.
  • G is a monocyclic 5- or 6-membered heteroaryl containing 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, G 5 being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- 4 alkyl, halogen, hydroxyl, cyano, phenyl, -C(0)Ci- 4 alkyl, -C(0)C 3- ecycloalkyl, -C(0)OCi -4 alkyl, -C(0)OCi -4 haloalkyl, -C(0)NH 2 , -C(0)NH(Ci_
  • G 5 is optionally substituted with Ci- 4 alkyl. In some embodiments, G 5 is an optionally substituted monocyclic 5- membered heteroaryl containing 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, G 5 is an optionally substituted monocyclic 5-membered heteroaryl containing 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur (e.g., thiazole, oxazole, imidazole).
  • R 1 is selected from the group consisting of -OCi- 6 alkyl, -OCi- 6 haloalkyl, -0-C 2 - 6 alkylene- OCi- 4 alkyl, -0-C 2-6 alkylene-OH, -NHC(0)(Ci -4 alkyl), -N(Ci -4 alkyl)C(0)(Ci -4 alkyl), -C(0)NH 2 , -C(0)NH(Ci -4 alkyl), -C(0)N(Ci -4 alkyl)(Ci -4 alkyl), -C(0)NH(Ci_
  • R ⁇ R°, X 1 , X ⁇ X and X" are as defined herein.
  • R is optionally substituted phenyl.
  • R 4 is optionally substituted pyridinyl.
  • R 1 is selected from the group consisting of -OCi- 6 alkyl, -OCi- 6 haloalkyl, -0-C 2-6 alkylene-OCi- 4 alkyl, -0-C 2-6 alkylene-OH, -NHC(0)(Ci -4 alkyl), -C(0)N(Ci -4 alkyl)(Ci -4 alkyl), - C(0)NH(Ci -4 haloalkyl), and -C(0)NH(-C 2-6 alkylene-OCi -4 alkyl);
  • R 2 is selected from the group consisting of hydrogen, Ci -4 alkyl, Ci -4 haloalkyl, halogen, and -OCi- 4 alkyl;
  • X 1 is CH or N;
  • X 2 is CR X2 or N;
  • X 3 is CR X3 or N;
  • R X2 is hydrogen or Ci -4 alkyl; and R X3 is hydrogen or
  • R 1 is selected from the group consisting of -OCi -6 haloalkyl, -NHC(0)(Ci -4 alkyl), -C(0)N(Ci_ 4 alkyl)(Ci -4 alkyl), -C(0)NH(Ci -4 haloalkyl), and -C(0)NH(-C 2-6 alkylene-OCi.
  • R 2 is selected from the group consisting of hydrogen, Ci -4 alkyl, Ci -4 haloalkyl, halogen, and -OCi -4 alkyl;
  • X 1 is CH or N;
  • X 2 is CR X2 or N;
  • X 3 is CR X3 or N;
  • R X2 is hydrogen or Ci -4 alkyl; and
  • R X3 is hydrogen or Ci -4 alkyl.
  • R 4 is optionally substituted phenyl.
  • R 4 is optionally substituted pyridinyl.
  • R 1 is selected from the group consisting of -OCi- 6 alkyl or -NHC(0)(Ci- 4 alkyl);
  • R 2 is Ci- 4 alkyl;
  • X 1 is CH;
  • X 2 is CH;
  • X 3 is CH; and
  • R 4 is optionally substituted phenyl.
  • R 1 is -OCi- 6 alkyl
  • R 2 is hydrogen
  • X 1 is CH
  • X 2 is CH
  • X 3 is CH
  • R 4 is optionally substituted pyridinyl
  • R 1 is selected from the group consisting of -OCi- 6 haloalkyl, -0-C 2 - 6 alkylene-OCi- 4 alkyl, -0-C 2- 6 alkylene-OH, -NHC(0)(Ci -4 alkyl), -C(0)N(Ci -4 alkyl)(Ci -4 alkyl), -C(0)NH(Ci_ 4 haloalkyl), and -C(0)NH(-C 2 - 6 alkylene-OCi- 4 alkyl);
  • R 2 is selected from the group consisting of hydrogen, Ci- 4 alkyl, halogen, and -OCi- 4 alkyl;
  • X 1 is CH or N;
  • X 2 is CR X2 or N;
  • X 3 is CR X3 or N;
  • R X2 is hydrogen or C M alk l; and
  • R X3 is hydrogen or Ci- 4 alkyl.
  • R 1 is selected from the group consisting of hydrogen, Ci- 4 alkyl, -0-Ci- 4 alkyl, OH, - NH-Ci -4 alkyl, and -NH 2 ; and R 2 , R 8 , X 1 , X 2 , X 3 , and X 4 are as defined herein.
  • R 1 is selected from the group consisting of hydrogen, Ci- 4 alkyl, and -0-Ci- 4 alkyl
  • R 2 is hydrogen or Ci -4 alkyl
  • X 1 is CR X1 or N
  • X 2 is CH or N
  • X 3 is CH or N
  • CR X1 is hydrogen, halogen, or -OCi- 4 alkyl.
  • R 4 is phenyl or a 5- or 6-membered heteroaryl containing 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur, R 4 being optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, hydroxyl, cyano, -S(0) 2 Ci- 4 alkyl, -S(0)Ci- 4 alkyl, -SCi- 4 alkyl, Ci- 4 alkyl, Ci_ 4 haloalkyl, -OCi- 4 alkyl, -Ci- 4 alkylene-OCi- 4 alkyl, -Ci- 4 alkylene- N(Ci -4 alkyl)(Ci -4 alkyl), - H(CMalkylene-OC M alk l), -NH(Ci -4 alkylene-OH), - N(C M alk l)(C M alk lene-OC M alkyl), -N(Ci -4 alkyl)(Ci -4 alkylene
  • R 4 is phenyl, a 5-membered heteroaryl such as thiazolyl, or a 6- membered heteroaryl such as pyrazinyl, pyrimidinyl, pyridazinyl, or pyridinyl, each optionally substituted as defined above.
  • the 6-membered heteroaryl at R 4 includes a pyridone ring, which is defined herein by the tautomeric hydroxypyridine form, whether or not the pyridone or the hydroxypyridine tautomer predominates.
  • R 4 is phenyl, the phenyl being optionally substituted with one substituent selected from the foregoing list of substituents and optionally substituted with 1-2 substituents independently selected from the group consisting of halogen and Ci-4alkyl.
  • R 4 is pyrazinyl, the pyrazinyl being optionally substituted with 1-3 Ci- 4 alkyl groups.
  • R 4 is pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), the pyridinyl being optionally substituted with one substituent selected from the group consisting of halogen, hydroxyl, Ci- 4 alkyl, Ci_ 4 haloalkyl, -OCi- 4 alkyl, C 3- 6 cycloalkyl, and a 4- to 8-membered monocyclic heterocycle containing 1-2 nitrogen atoms, the 4- to 8-membered monocyclic heterocycle being independently optionally substituted with 1-2 substituents independently selected from the group consisting of pyridyl, the R 4 pyridinyl being further optionally substituted with 1-2 substituents selected from halogen and Ci_ 4 alkyl.
  • substituents selected from the group consisting of halogen, hydroxyl, Ci- 4 alkyl, Ci_ 4 haloalkyl, -OCi- 4 alkyl
  • R 4 is phenyl optionally substituted with 1-3 substituents independently selected from the group consisting of halogen and Ci- 4 alkyl.
  • R 4 is phenyl optionally substituted with 1-2 fluoro atoms or 1 fluoro and 1 methyl group.
  • R 4 is independently any of phenyl, 3,5-difluorophenyl, 3 -fluorophenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, or 3-fiuoro-5-methylphenyl.
  • R 4 is pyrazine, which is unsubstituted.
  • R 4 is phenyl or a 6-membered heteroaryl containing 1-3 nitrogen atoms and optionally substituted with 1-3 halogen. In some embodiments, R 4 is optionally substituted pyridinyl.
  • R 4 is phenyl or a 5- or 6-membered heteroaryl containing 1-3 heteroatoms independently selected from nitrogen and sulfur, R 4 being optionally substituted with 1 -3 substituents independently selected from the group consisting of halogen, cyano, Ci- 4 alkyl, -OCi- 4 alkyl, C 3- 6 cycloalkyl, or a 4- to 8- membered monocyclic heterocycle containing 1-2 nitrogen atoms, the 4- to 8- membered monocyclic heterocycle being independently optionally substituted with pyridyl.
  • the compound is 6- isopropoxy-N-(l-thiazol-4-ylimidazol-4-yl)pyridin-2-amine; 6-isopropoxy-N-[l-(2- pyridyl)imidazol-4-yl]pyridin-2-amine; 6-(cyclobutoxy)-N-[l-(3-pyridyl)imidazol-4- yl]pyridin-2-amine; N-[l -(3,5-difluorophenyl)imidazol-4-yl]-6-isopropoxy-pyridin-2- amine; 6-ethoxy-N-(l -phenylimidazol-4-yl)pyridin-2-amine; N-[l -(3,4- difluorophenyl)imidazol-4-yl]-6-isopropoxy-pyridin-2-amine; 6-isopropoxy-N-[l-(3- pyr
  • the compound is N-[6- methyl-4-[4-(oxetan-3-yl)piperazin-l -yl]-2-pyridyl]-5-(2-pyridyl)thiazol-2-amine; N- (4-methyl-6-te ⁇ jahydropyran-3-yloxy-2-pyridyl)-5-(2-pyridyl)thiazol-2-amine; N-[2- methyl-6-[4-(oxetan-3-yl)piperazin-l-yl]pyrimidin-4-yl]-5-(2-pyridyl)thiazol-2- amine; N-(6-ethoxy-4-methyl-2-pyridyl)-5-(2-pyridyl)thiazol-2-amine; N-[4-methyl- 6-[4-(oxetan-3-yl)piperazin-l-yl]-2-pyridyl]-5-(2-pyridyl]thiazol-2-amine
  • the compound is N-[4- (difluoromethyl)-6-[4-(oxetan-3-yl)piperazin-l -yl]-2-pyridyl]-5-(3- fluorophenyl)oxazol-2-amine; N-[4-(difluoromethyl)-6-[4-(oxetan-3-yl)piperazin-l - yl]-2-pyridyl]-5-phenyl-oxazol-2-amine; N-(3-isopropoxy-5-methyl-phenyl)-5- phenyl-oxazol-2-amine; N-[3-methyl-5-[4-(3-methyloxetan-3-yl)piperazin-l - yl] phenyl] -5 -phenyl-oxazol-2-amine; N-[3-ethyl-5-[[5-(3-fluoroph
  • the compounds of formula (I) or (IV) include isotope-labelled forms thereof.
  • An isotope-labelled form of a compound of formula (I) or (IV) is identical to this compound apart from the fact that one or more atoms of the compound have been replaced by an atom or atoms having an atomic mass or mass number which differs from the atomic mass or mass number of the atom which usually occurs in greater natural abundance.
  • isotopes which are readily commercially available and which can be incorporated into a compound of formula (I) or (IV) by well-known methods include isotopes of hydrogen, carbon, nitrogen,
  • the present invention features a compound of formula I or ⁇ and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.
  • an isotope-labelled compound of formula (I) or (IV) can be used in a number of beneficial ways.
  • an isotope-labelled compound of formula (I) or (IV) into which, for example, a radioisotope, such as H or 14 C, has been incorporated is suitable for a medicament and/or for substrate tissue distribution assays.
  • a radioisotope such as H or 14 C
  • tritium ( H) and carbon-14 ( 14 C) are particularly preferred owing to simple preparation and excellent detectability.
  • incorporation of heavier isotopes, for example deuterium ( 2 H), into a compound of formula (I) or (IV) have therapeutic advantages owing to the higher metabolic stability of this isotope-labelled compound. Higher metabolic stability translates directly into an increased in vivo half-life or lower dosages, which under most circumstances would represent a preferred embodiment of the present invention.
  • An isotope-labelled compound of formula I or ⁇ can usually be prepared by carrying out the procedures disclosed in the synthesis schemes and the related description, in the example part and in the preparation part in the present text, replacing a non-isotope-labelled reactant by a readily available isotope-labelled reactant.
  • Deuterium ( 2 H) can also be incorporated into a compound of formula (I) or (IV) for the purpose of manipulating the oxidative metabolism of the compound by way of the primary kinetic isotope effect.
  • the primary kinetic isotope effect is a change of the rate for a chemical reaction that results from exchange of isotopic nuclei, which in turn is caused by the change in ground state energies necessary for covalent bond formation after this isotopic exchange. Exchange of a heavier isotope usually results in a lowering of the ground state energy for a chemical bond and thus causes a reduction in the rate-limiting bond breakage.
  • the product distribution ratios can be altered substantially.
  • S. L. Harbeson and R. D. Tung Deuterium In Drug Discovery and Development, Ann. Rep. Med. Chem. 2011, 46, 403-417, incorporated in its entirety herein by reference.
  • pharmacokinetic profiles of compounds of formula (I) or (IV) are thereby obtained, and can be expressed quantitatively in terms of increases in the in vivo half-life (tm), concentration at maximum therapeutic effect (Cmax), area under the dose response curve (AUC), and bioavailability; and in terms of reduced clearance, dose and materials costs.
  • a compound of formula (I) or (IV) which has multiple potential sites of attack for oxidative metabolism for example benzylic hydrogen atoms and hydrogen atoms bonded to a nitrogen atom, is prepared as a series of analogues in which various combinations of hydrogen atoms are replaced by deuterium atoms, so that some, most or all of these hydrogen atoms have been replaced by deuterium atoms.
  • Half-life determinations enable favourable and accurate determination of the extent to which the improvement in resistance to oxidative metabolism has improved. In this way, it is determined that the half-life of the parent compound can be extended by up to 100% as the result of deuterium- hydrogen exchange of this type.
  • deuterium-hydrogen exchange in a compound of formula (I) or (IV) can be used to achieve a favourable modification of the metabolite spectrum of the starting compound in order to diminish or eliminate undesired toxic metabolites.
  • a toxic metabolite arises through oxidative carbon- hydrogen (C-H) bond cleavage
  • C-H oxidative carbon- hydrogen
  • Salts Compositions. Uses. Formulation. Administration and Additional Agents
  • the compounds of formula (I) or (IV) of the present invention and the methods, compositions and kits disclosed herein are useful for the treatment of neurodegenerative or neurological diseases or disorders related to axonal damage, demyelinating diseases, central pontine myelinolysis, nerve injury diseases or disorders, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, a leukoencephalopathy or a leukodystrophy.
  • said neurodegenerative or neurological diseases or disorders related to axonal damage, demyelinating diseases, central pontine myelinolysis, nerve injury diseases or disorders, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, a leukoencephalopathy or a leukodystrophy include, but are not limited to spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated
  • ischemic demyelination neuromyelitis optics, adrenoleukodystrophy, Alexander's disease, Niemann-Pick disease, Pelizaeus Merzbacher disease, periventricular leukomalatia, globoid cell leucodystrophy ( K tab he's disease), Wallerian degeneration, optic neuritis, transverse myelitis, amylotrophic lateral sclerosis (Lou Gehrig's diseae), Huntington's disease, Alzheimer's disease, Parkinson's disease, Tay-Sacks disease, Gaucher ' s disease, Hurler Syndrome, traumatic brain injury, post radiation injury, neurologic complications of chemotherapy, neuropathy, acute ischemic optic neuropathy.
  • leukodystrophy acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, schizophrenia, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraparesis/human T-lymphotropic virus 1 ( HTLV- 1 ) associated myelopathy, essential tremor or osmotic hyponatremia.
  • HTLV- 1 human T-lymphotropic virus 1
  • the compounds of formula ( 1 ) or ( IV) of the present invention and the methods, compositions and kits disclosed herein are useful for treating, preventing or ameliorating one or more symptoms of multiple sclerosis or another neurodegenerative disease selected from auditory impairment, optic neuritis, decreased visual acuity, diplopia, nystagmus, ocular dysmetria, internuclear ophthal moplegia, movement and sound phosphenes. afferent pupillary defect, paresis, monoparesis, paraparesis, hemi paresis, quadraparesis, plegia. paraplegia, hemiplegia. tetraplegia, quadraplegia.
  • spasticity dysarthria, motor dysfunction, walking impairment, muscle atrophy, spasms, cramps, hypotonia, clonus, myoclonus, myokymia, restless leg syndrome, gait disturbances, footdrop. dysfunctional reflexes, pallesthesia, anaesthesia, neuralgia, neuropathic and neurogenic pain. L'hermitte's. proprioceptive dysfunction, trigeminal neuralgia, ataxia, intention tremor, dysmetria. vestibular ataxia, vertigo, speech ataxia, dystonia, disability progression,
  • compositions comprising any of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle.
  • these compositions optionally further comprise one or more additional therapeutic agents.
  • the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or vehicles.
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgement, 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.
  • a “pharmaceutically acceptable salt” means any non-toxic salt or salt of an ester of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof.
  • the term "inhibitorily active metabolite or residue thereof means that a metabolite or residue thereof is also useful for treating or lessening the severity of, in a subject, a disease or disorder selected from neurodegenerative or neurological diseases or disorders related to axonal damage, demyelinating diseases, central pontine myelinolysis, nerve injury diseases or disorders, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, a leukoencephalopathy or a leukodystrophy.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • suitable inorganic and organic acids and bases include those derived from suitable inorganic and organic acids and bases.
  • 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 used 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 + (Ci-4 alkyl) 4 salts.
  • This invention also envisions the quatemization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersable products may be obtained by such quaternization.
  • 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.
  • the pharmaceutically acceptable compositions of the invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • a pharmaceutically acceptable carrier, adjuvant, or vehicle which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and
  • pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene- poly oxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as com starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;
  • powdered tragacanth malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
  • oils
  • the invention features a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the invention and a pharmaceutically acceptable carrier.
  • the invention features a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof of the compounds of formula (I) or (IV) and one or more pharmaceutically acceptable carriers or vehicles.
  • the methods described herein also provide a method of promoting oligodendrocyte proliferation, differentiation or survival comprising contacting oligodendrocytes with a compound of formula (I) or (IV) or a composition thereof.
  • a method of the present invention comprises promoting oligodendrocyte proliferation, differentiation or survival.
  • a method of the present invention comprises promoting oligodendrocyte proliferation, differentiation or survival with a compound of formula (I) or (IV) or a composition thereof.
  • a method of the present invention is useful for treating or lessening the severity of a disease or disorder selected from a disease or disorder associated with a lack of oligodendrocyte proliferation, differentiation or survival comprising administering a therapeutically effective amount of the compounds of formula (I) or (IV) or compositions thereof to a subject in need thereof.
  • a method of the present invention comprises promoting myelination by contacting neuronal cells, oligodendrocyte cells or oligodendrocyte precursor cells. In one embodiment, a method of the present invention comprises promoting myelination by contacting neuronal cells, oligodendrocyte cells or oligodendrocyte precursor cells with a compound of formula (I) or (IV) or a composition thereof.
  • a method of the present invention comprises promoting survival of cells of the nervous system.
  • a method of the present invention comprises promoting survival of cells of the nervous system comprising contacting the cells with a compound or composition of formula (I) or (IV).
  • the cells of the nervous system comprise brain cells, cortical neurons, oligodendroctyes or oligodendrocyte precursor cells.
  • a method of the present invention is useful for treating or lessening the severity of a disease or disorder selected from a disease or condition associated with demyelination comprising administering a therapeutically effective amount of the compounds of formula (I) or (IV) or compositions thereof to a subject in need thereof.
  • the disease or condition associated with demyelination is a CNS disorder or a CNS demyelinating disease as described herein.
  • the disease is multiple sclerosis.
  • the subject has, or is at risk of having, multiple sclerosis.
  • the subject with multiple sclerosis can be at any stage of treatment or disease.
  • the subject with multiple sclerosis has one or more of: benign multiple sclerosis, relapsing remitting multiple sclerosis, quiescent relapsing remitting multiple sclerosis, active relapsing remitting multiple sclerosis, primary progressive multiple sclerosis, or secondary progressive multiple sclerosis, clinically isolated syndrome, or clinically defined multiple sclerosis.
  • the type of multiple sclerosis is primar ' progressive multiple sclerosis.
  • the type of multiple sclerosis is relapsing-remitting multiple sclerosis.
  • the type of multiple sclerosis is secondary progressive multiple sclerosis. In still a further embodiment, the type of multiple sclerosis is progressive relapsing multiple sclerosis. In another embodiment, the subject is asymptomatic. In another embodiment, the subject has one or more multiple sclerosis-like symptoms, such as those having clinically isolated syndrome or clinically defined multiple sclerosis. In yet other embodiments, the subject has one or more multiple sclerosis relapses.
  • the subject has a relapsing form of multiple sclerosis such as relapsing remitting multiple sclerosis or relapsing secondary progressive multiple sclerosis.
  • the subject has relapsing remitting multiple sclerosis and has one or more ongoing clinical exacerbations.
  • the subject has relapsing remitting multiple sclerosis and one or more subclinical activities.
  • the clinical exacerbation or subclinical activity is shown by gadolinium enhancement of white matter lesions using T1/T2 magnetic resonance imaging.
  • the clinical exacerbation or subclinical activity is shown by development of new or enlarged white matter lesions on magnetic resonance imaging of the brain or spinal cord.
  • the development of new or enlarged white matter lesions is monitored by T1/T2 magnetic resonance imaging.
  • the development of new or enlarged white matter lesions is monitored by Proton Density magnetic resonance imaging.
  • the development of new or enlarged white matter lesions is monitored by MTR magnetic resonance imaging. See also, Gaitan, M. I. and Reich, D. S. (2014) MRI in Diagnosis and Disease Monitoring, in Multiple Sclerosis and CNS Inflammatory Disorders (eds L. M. Samkoff and A. D. Goodman), John Wiley & Sons, Ltd., Chichester, UK.
  • the clinical exacerbations or subclinical activities are monitored by a functional readout such as ambulatory changes (gait changes, sway changes, etc.), T25W changes and/or EDSS changes.
  • a functional readout such as ambulatory changes (gait changes, sway changes, etc.), T25W changes and/or EDSS changes.
  • the clinical exacerbations or subclinical activities are monitored by a visual evoked potential assay, a visual acuit ' assay or a measurement of optic nerve thickness.
  • the clinical exacerbations or subclinical activities are monitored by a myelin labelling assay.
  • the subject with multiple sclerosis can be at any stage of treatment or disease and treatment with compounds of formula (I) or (IV) of the present invention result in improvement of the disease or symptoms.
  • improvement in the disease or symptoms is evidenced by a reduction or disappearance of one or more white matter lesions in the brain.
  • improvement in the disease or symptoms is evidenced by improved function such as improved ambulation, improved gait, reduced sway, improved T25W scores or improved EDSS scores.
  • improvement in the disease or symptoms is evidenced by improvements in a visual acuity assay or a visual evoked potential assay.
  • improvement in the disease or symptoms is evidenced by enhanced optic nerve thickness.
  • improvement in the disease or symptoms is evidenced by increased myelination in a myelin labelling assay.
  • the compounds of formula (I) or (IV) of the present invention and the methods, compositions and kits disclosed herein are useful for promoting myelin regeneration in progressive demyelinating diseases.
  • the compounds of formula (I) or (IV) of the present invention and the methods, compositions and kits disclosed herein are useful for promoting myelin regeneration in primary progressive multiple sclerosis.
  • the compounds of formula (I) or (IV) of the present invention and the methods, compositions and kits disclosed herein are useful for promoting myelin regeneration in secondary progressive multiple sclerosis.
  • the compounds of formula (I) or (IV) of the present invention and the methods, compositions and kits disclosed herein are useful for promoting myelin regeneration in relapsing-remitting multiple sclerosis.
  • the compounds of formula (I) or (IV) of the present invention and the methods, compositions and kits disclosed herein are useful for promoting myelin regeneration in progressive relapsing multiple sclerosis.
  • the compounds of formula (I) or (IV) of the present invention and the methods, compositions and kits disclosed herein are useful for promoting remyelination at the cellular level wherein oligodendrocyte cells are stimulated to regenerate or differentiate.
  • the compounds of formula (I) or (IV) of the present invention and the methods, compositions and kits disclosed herein are useful for promoting remyelination at the cellular level wherein oligodendrocyte cells are stimulated to remyelinate axons.
  • the compounds of formula (I) or (IV) of the present invention and the methods, compositions and kits disclosed herein are useful for promoting remyelination at the cellular level whereby oligodendrocyte cells are stimulated to regenerate or differentiate thereby treating demyelinating diseases or disorders.
  • the compounds of formula (I) or (IV) of the present invention and the methods, compositions and kits disclosed herein are useful for promoting remyelination at the cellular level whereby axons are remyelinated by oligodendrocyte cells thereby treating demyelinating diseases or disorders.
  • the compounds of formula (I) or (IV) of the present invention and the methods, compositions and kits disclosed herein are useful for inducing endogenous oligodendrocytes or oligodendrocyte precursor cells to contact an axon and produce myelin.
  • the present invention provides a method of treating or lessening the severity of, in a subject, a disease or disorder selected from a demyelinating disease, central pontine myelinolysis, a nerve injury disease or disorder, a leukoencephalopathy or a leukodystrophy comprising administering an effective amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula (I) or (IV).
  • the present invention provides a method of treating or lessening the severity of, in a subject, a disease or disorder selected from spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy.
  • encephalomyelitis central pontine myelolysis, hypoxic demyelination.
  • ischemic demyelination neuromyelitis optics, adrenoleukodystrophy, Alexander's disease, Nieniann-Pick disease, Peli/aeus Merzbacher disease, periventricular leukomalatia.
  • globoid cell leucodvstrophy Ki abbe's disease
  • Wallerian degeneration optic neuritis
  • transverse myelitis amylotrophic lateral sclerosis (Lou Gehrig's diseae).
  • Huntington's disease Alzheimer's disease, Parkinson's disease, Tax -Sacks disease, Gaucher " s disease, Hurler Syndrome, traumatic brain injury, post radiation injur ', neurologic complications of chemotherapy, neuropathy, acute ischemic optic neuropathy, neuromyelitis optica, vitamin B 12 deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, Leber's hereditary optic atrophy /Leber congenital amaurosis, Marchiafava-Bignami syndrome, metachromatic
  • leukodystrophy acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, schizophrenia, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraparesis numan T-lymphotropic virus 1 (HTLV-1 ) associated myelopathy, essential tremor or osmotic hyponatremia comprising administering an effective amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula ( I ) or (IV).
  • HTLV-1 T-lymphotropic virus 1
  • the present invention provides a method of treating, preventing or ameliorating one or more symptoms of multiple sclerosis or another neurodegenerative disease selected from auditor)' impairment, optic neuritis, decreased visual acuity, diplopia, nystagmus, ocular dysmetria, internuclear ophthalmoplegia, movement and sound phosphenes, afferent pupillary defect, paresis, monoparesis, paraparesis, hemiparesis, quadraparesis, plegia, paraplegia, hemiplegia, tetraplegia, quadraplegia, spasticity, dysarthria, motor dysfunction, walking impairment, muscle atrophy, spasms, cramps, hypotonia, clonus, myoclonus, myokymia, restless leg syndrome, gait disturbances, footdrop, dysfunctional reflexes, paraesthesia, anaesthesia, neuralgia, neuropathic and neurogenic pain,
  • dysdiadochokinesia frequent micturation, bladder spasticity, flaccid bladder, detrusor- sphincter dyssynergia, erectile dysfunction or anorgasmy comprising administerin an effective amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula ( I ) or (IV).
  • the present invention provides a method of treating or lessenin the severity of. in a subject, a disease or disorder selected from a demyelinating disease, central pontine myelinolysis. a nerve injury disease or disorder, a leukoencephalopathy or a leukodystrophy comprising administering an effective amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula (I) or ( IV ) with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound or pharmaceutical composition.
  • a disease or disorder selected from a demyelinating disease, central pontine myelinolysis.
  • a nerve injury disease or disorder, a leukoencephalopathy or a leukodystrophy comprising administering an effective amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula (I) or ( IV ) with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound or pharmaceutical composition.
  • the present inv ention provides a method of treating or lessening the severity of, in a subject, a disease or disorder selected from spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital hypomyelination. encephalomyelitis, acute disseminated
  • encephalomyelitis central pontine myeloly sis, hypoxic demyelination, ischemic demyelination, neuromyelitis optics, adrenoleukodystrophy, Alexander's disease, Niemann-Pick disease, Pelizaeus Merzbacher disease, periventricular leukomalatia, globoid cell leucodystrophy (Krabbe's disease), Wallerian degeneration, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (Lou Gehrig's diseae), Huntington's disease, Alzheimer's disease, Parkinson's disease, Tax -Sacks disease, Gaucher " s disease, Hurler Syndrome, traumatic brain injury, post radiation injur ', neurologic complications of chemotherapy, neuropathy, acute ischemic optic neuropathy, neuromyelitis optica, vitamin B 1 2 deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, Leber's heredit
  • the present invention provides a method of treatin or lessening the severit ' of, in a subject, a type of multiple sclerosis selected from primary progressive multiple sclerosis, relapsing-remitting multiple sclerosis, secondary progressive multiple sclerosis or progressive relapsing multiple sclerosis.
  • the type of multiple sclerosis is primary progressive multiple sclerosis.
  • the type of multiple sclerosis is relapsing-remitting multiple sclerosis.
  • the t pe of multiple sclerosis is secondary progressive multiple sclerosis.
  • the type of multiple sclerosis is progressive relapsing multiple sclerosis.
  • the present invention provides a method for treating, preventing or ameliorating one or more symptoms of multiple sclerosis or another neurodegenerative disease selected from auditory 7 impairment, optic neuritis, decreased visual acuity, diplopia, nystagmus, ocular dysmetria, intemuclear ophthalmoplegia, movement and sound phosphenes, afferent pupillary defect, paresis, monoparesis, paraparesis, hemi paresis, quadraparesis, plegia, paraplegia, hemiplegia, tetraplegia, quadraplegia, spasticity, dysarthria, motor dysfunction, walking impairment, muscle atrophy, spasms, cramps, hypotonia, clonus, myoclonus, myoky mia, restless leg syndrome, gait disturbances, footdrop.
  • another neurodegenerative disease selected from auditory 7 impairment, optic neuritis, decreased visual acuity, diplopia, nys
  • dysdiadochokinesia frequent micturation, bladder spasticity, flaccid bladder, detrusor- sphincter dyssynergia, erectile dysfunction or anorgasmy
  • administering an effecti e amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula (I) or (IV) with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound or pharmaceutical composition.
  • the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treating or lessening the severity of, in a subject, a disease or disorder selected from a demyelinating disease, central pontine myelinolysis, a nerve injury disease or disorder or a leukoencephalopathy .
  • the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treating or lessening the severity of, in a subject, a disease or disorder selected from spinal cord injury, stroke, multiple sclerosis, progressive multifocal
  • leukoencephalopathy congenital hypomye!ination.
  • encephalomyelitis acute disseminated encephalomyelitis, central pontine myelolysis, hypoxic demyelination.
  • ischemic demyelination neuromyelitis optics, adrenoleukodystrophy, Alexander's disease, Niemann-Pick disease, Pelizaeus Merzbacher disease, periventricular leukomalatia, globoid cell leucodystrophy (Krabbe's disease), Wallerian degeneration, optic neuritis, transverse myelitis, amylotrophic lateral sclerosis (Lou Gehrig's diseae), Huntington's disease, Alzheimer's disease, Parkinson's disease, Tay -Sacks disease, Gaucher's disease, Hurler Syndrome, traumatic brain injury, post radiation injur ⁇ ', neurologic complications of chemotherapy, neuropathy, acute ischemic optic neuropathy, neuromyelitis optica, vitamin B
  • the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treating, preventing or ameliorating one or more symptoms of multiple sclerosis or another neurodegenerative disease selected from auditory impairment, optic neuritis, decreased visual acuity, diplopia, nystagmus, ocular dysmetria.
  • the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament in combination with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound or pharmaceutical composition.
  • the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treating or lessening the severity of, in a subject, a disease or disorder selected from a demyelinating disease, central pontine myelinolysis. a nerve injury disease or disorder or a leukoencephalopathy with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound or pharmaceutical composition.
  • the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treating or lessening the severity of, in a subject, a disease or disorder selected from spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy.
  • Wallerian degeneration optic neuritis, transverse myelitis, amylotrophic lateral sclerosis (Lou Gehrig's diseae), Huntington's disease, Alzheimer's disease, Parkinson's disease, Tay- Sacks disease, Gaucher's disease, Hurler Syndrome, traumatic brain injury, post radiation injury, neurologic complications of chemotherapy, neuropathy, acute ischemic optic neuropathy, neuromyelitis optica, vitamin B12 deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, Leber's hereditary optic atrophy /Leber congenital amaurosis, M arch i afa v a- B i gn ami syndrome, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, schizophrenia, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraparesis human T-lymphotropic
  • the present inv ention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treating or lessening the severity of, in a subject, a type of multiple sclerosis selected from primary progressive multiple sclerosis, relapsing-remittin multiple sclerosis, secondary progressive multiple sclerosis or progressive relapsing multiple sclerosis.
  • a type of multiple sclerosis selected from primary progressive multiple sclerosis, relapsing-remittin multiple sclerosis, secondary progressive multiple sclerosis or progressive relapsing multiple sclerosis.
  • the type of multiple sclerosis is primary progressive multiple sclerosis.
  • the type of multiple sclerosis is relapsing-remittin multiple sclerosis.
  • the type o multiple sclerosis is secondary progressive multiple sclerosis.
  • the type of multiple sclerosis is progressive relapsing multiple sclerosis.
  • the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treating, preventing or ameliorating one or more symptoms of multiple sclerosis or another neurodegenerative disease selected from auditory impairment, optic neuritis, decreased visual acuity, diplopia, nystagmus, ocular dysmetria, internuclear ophthalmoplegia, movement and sound phosphenes, afferent pupillary defect, paresis, monoparesis, paraparesis, hemi paresis, quadraparesis, plegia, paraplegia, hemiplegia, tetraplegia, quadraplegia, spasticity, dysarthria, motor dysfunction, walking impairment, muscle atrophy, spasms, cramps, hypotonia, clonus, myoclonus, myokymia, restless leg syndrome, gait disturbances, footdrop, dysfunctional reflexes, para
  • an "effective amount" of the compound, a pharmaceutically acceptable salt thereof or pharmaceutically acceptable composition is that amount effective for treating or lessening the severity of, in a subject, a disease or disorder selected from one or more of a demyelinating disease, central pontine myelinolysis, a nerve injury disease or disorder or a
  • the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease, the particular agent, its mode of administration, and the like.
  • the compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
  • dosage unit form refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular patient 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 compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.
  • patient means an animal, preferably a mammal, and most preferably a human
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally,
  • the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and 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.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain 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 (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol,
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also 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.
  • the acceptable vehicles and solvents that may 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 diglycerides.
  • 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.
  • microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide.
  • biodegradable polymers such as polylactide-polyglycolide.
  • the rate of compound release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly (anhydrides).
  • Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound 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-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) wetting agents such as, for example, cetyl
  • Solid compositions of a similar type may also 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 pharmaceutical formulating art. They may optionally contain opacifying agents and can also 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. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also 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 polethylene glycols and the like.
  • the active compounds can also be in microencapsulated 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 compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also 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 also comprise buffering agents. They may optionally contain opacifying agents and can also 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. Examples of embedding compositions that can be used include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms are prepared by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • the compounds of formula (I) or ( IV ) of the present invention and the methods, compositions and kits disclosed herein can be employed in combination therapies, that is, the compounds and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures.
  • the particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved.
  • the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects).
  • additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated.” Additional appropriate therapeutic agents or approaches are described generally in The Merck Manual, Nineteenth Edition, Ed. Robert S. Porter and Justin L. Kaplan, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., 2011, and the Food and Drug Administration website, www.fda.gov, the entire contents of which are hereby incorporated by reference. [00218] In one embodiment, the additional therapeutic agents is an
  • immunomodulatory agent such as an IFN- ⁇ 1 molecule including but not limited to an interferon beta la (Avonex®, Rebif®) or an interferon beta lb (Betaseron®, Betaferon®, Extavia®). Immunomodulatory agents also include other interferons and fragments, analogues, homologues, derivatives, and natural variants thereof with substantially similar biological activity to interferon beta la molecules.
  • the additional therapeutic agent is a polymer of glutamic acid, lysine, alanine and tyrosine such as glatiramer acetate (Copaxone®).
  • the additional therapeutic agent is an antibody or fragment thereof against alpha-4 integrin (e.g., natalizumab (Tysabri®)).
  • the additional therapeutic agent is an
  • anthracenedione molecule such as mitoxantrone (Novantrone®).
  • the additional therapeutic agent is a sphingosine 1- phosphate receptor modulator such as fingolimod (Gilenya®) and those described in WO 2012/109108 the entire contents of which is hereby incorporated by reference.
  • the additional therapeutic agent is a dimethyl fumarate such as an oral dimethyl fumarate (Tecfidera®).
  • the additional therapeutic agent is an antibody to the alpha subunit of the IL-2 receptor of T cells such as daclizumab (Zenapax®).
  • the additional therapeutic agent is an antibody against CD52 such as alemtuzumab (Lemtrada®).
  • the additional therapeutic agent is an inhibitor of a dihydroorotate dehydrogenase such as teriflunomide (Aubagio®).
  • the additional therapeutic agent is an antibody to CD20 such as ocrelizumab, rituximab or ofatumumab.
  • the additional therapeutic agent is a corticosteroid such as, but not limited to methylprednisolone, Depo-Medrol®, Solu-Medrol®, Deltasone®, Delta-Cortef®, Medrol®, Decadron® or Acthar®.
  • a corticosteroid such as, but not limited to methylprednisolone, Depo-Medrol®, Solu-Medrol®, Deltasone®, Delta-Cortef®, Medrol®, Decadron® or Acthar®.
  • the additional therapeutic agent is an anti-VLA4 antibody, such as Natalizumab (Tysabri®) or a related VLA-4 antibodies such as those described in US 5,840,299, US 6,602,503, Sanchez-Madrid et al, (1986) Eur. J. Immunol 16: 1343-1349; Hemler et al, (1987) J Biol. Chem. 2: 11478-11485; Issekutz et al. (1991) J Immunol 147: 109 (TA-2 mab); Pulido et al. (1991) J Biol. Chem. 266: 10241-10245; and U.S. Pat. No. 5,888,507 the entire contents of each patent or publication hereby incorporated by reference in their entirety.
  • Natalizumab Tysabri®
  • VLA-4 antibodies such as those described in US 5,840,299, US 6,602,503, Sanchez-Madrid et al, (1986) Eur. J. Immuno
  • the additional therapeutic agent is a LINGO-1 antagonist (e.g., an antibody against LINGO (e.g., LINGO-1, LINGO-2, LINGO-3, LINGO-4) or a Nogo receptor-1 (NgRl) modulator and compositions thereof such as those disclosed in WO2004/085648, WO2006/002437, WO2007/008547,
  • LINGO-1 antagonist e.g., an antibody against LINGO (e.g., LINGO-1, LINGO-2, LINGO-3, LINGO-4)
  • NgRl Nogo receptor-1
  • the additional therapeutic agent is a TAJ modulator, such as those disclosed in WO2006/017673, which is hereby incorporated by reference in its entirety.
  • the additional therapeutic agent is a TrkA antagonist such as those disclosed in WO2008/013782 or a TrkB antagonist such as those disclosed in WO2009/048605, each of which is hereby incorporated by reference in its entirety.
  • the additional therapeutic agent is a sclerostin modulator such as those disclosed in WO2013/063095, which is hereby incorporated by reference in its entirety.
  • the additional therapeutic agent is an autotaxin (ATX) inhibitor or LPA receptor antagonist, such as those described in
  • WO2010051031 WO2010051030, WO2009046841, WO2009046842,
  • the additional therapeutic agent is a Nox4 modulator such as those described in WO2013/037499, which is hereby incorporated by reference in its entirety.
  • the additional therapeutic agent is a remyelinating antibody such as rHIgM22.
  • the additional therapeutic agent is dalfampridine (Ampyra®)
  • the additional therapeutic agent is a death receptor 6 (DR6) antagonist, a p75 antagonist or a combination thereof such as those disclosed in US8894999 and WO2014106104 each of which is incorporated herein by reference in its entirety.
  • DR6 death receptor 6
  • p75 antagonist a combination thereof such as those disclosed in US8894999 and WO2014106104 each of which is incorporated herein by reference in its entirety.
  • the additional therapeutic agent is CethrinTM.
  • the additional therapeutic agent is an activin receptor modulator such as those described in WO2015/001352, which is hereby incorporated by reference in its entirety.
  • the additional therapeutic agent is a GLP-1 like peptide or a derivative of GLP-1 like peptides such as those disclosed in
  • the GLP-1 derivative is Liraglutide or Semaglutide.
  • the additional therapeutic agent is a RXR modulator such as those disclosed in US2015/0038585 and WO2013056232 each of which is incorporated herein by reference in its entirety.
  • the RXR modulator is HX630.
  • the additional therapeutic agent is an activator of the NRF2/KE AP 1 / ARE pathway such as those disclosed in WO2014/197818 which is hereby incorporated by reference in its entirety.
  • the additional therapeutic agent is a PPAR agonist such as those disclosed in WO2014/165827 which is hereby incorporated by reference in its entirety.
  • the additional therapeutic agent is an inhibitor of HDAC4 such as those disclosed in WO2013/080120 which is hereby incorporated by reference in its entirety.
  • the additional therapeutic agent is a gamma secretase inhibitor such as DAPT.
  • the additional therapeutic agent is an antipsychotic medication such as quetiapine.
  • the additional therapeutic agent is a thyroid hormone.
  • the additional therapeutic agent is a thyroid translocator protein (TSPO) such as etifoxine.
  • TSPO thyroid translocator protein
  • the additional therapeutic agent is insulin-like growth factor 1 (IGF-1).
  • IGF-1 insulin-like growth factor 1
  • the additional therapeutic agent is an
  • anticholinergic such as benzatropine
  • the additional therapeutic agent is an
  • antihistamine/anti cholinergic such as clemastine or clemastine fumarate.
  • the additional therapeutic agent is one that removes antiaquaporin by plasmapheresis.
  • the additional therapeutic agent is a hyaluronan inhibitor or antagonist such as those described in WO2015023691, which is hereby incorporated by reference in its entirety.
  • the additional therapeutic agent is a hyaluronidase inhibitor such as a PH20 inhibitor or those described in WO2013/102144,
  • the additional therapeutic agent is a Toll-Like Receptor-2 (TLR-2) inhibitor.
  • the additional therapeutic agent is a Semaphorin 3A antagonist or antibody such as those disclosed in WO2014123186, which is hereby incorporated by reference in its entirety.
  • the additional therapeutic agent is a CXCR2 inhibitor or antagonist.
  • the additional therapeutic agent is a Semaphorin 3F agonist.
  • the additional therapeutic agent is a Wnt polypeptide or Wnt inhibitor such as those disclosed in WO 2013/040309 and WO 2012/097093, each of which is hereby incorporated by reference in its entirety.
  • the additional therapeutic agent is a mitochondrial pore modulator such as Olesoxime.
  • the additional therapeutic agent is a PSA NCAM antagonist, a CXCR2 inhibitor or antagonist, a MRF agonist, a GM-98 agonist, a Tcf4 inhibitor, a retinoid, a neuregulin 1-erbB signaling modulator, a zpfl91 activator, an miR219 activator, an miR338 activator or an miR138 activator.
  • the additional agent is an immunomodulatory agent such as an IFN- ⁇ 1 molecule which is administered intravenously,
  • the IFN- ⁇ 1 molecule is administered at 20-45 microgram once a week by intramuscular injection. In another embodiment, the IFN- ⁇ 1 molecule is administered at 20-30 microgram three times a week by intramuscular injection. In another embodiment, the IFN- ⁇ 1 molecule is administered at 40-50 micrograms once a week, by subcutaneous injection.
  • the IFN- ⁇ 1 molecule is administered in an amount of between 10 and 50 ⁇ g intramuscularly three times a week.
  • the IFN- ⁇ 1 molecule is administered in an amount of between 10 and 50 ⁇ g intramuscularly every five to ten days.
  • the IFN- ⁇ 1 molecule is administered in an amount between 200 and 600 ⁇ g every other day by subcutaneous injection.
  • the IFN- ⁇ 1 molecule is an interferon ⁇ -lb (Betaseron®, Betaferon®, or Extavia®).
  • interferon ⁇ -lb Betaseron®, Betaferon®, or Extavia®.
  • bladder problems e.g., Botox®, DDAVP Nasal Spray®, Detrol®, Ditropan®, Ditropan XL®, Enablex®, Flomax®, Hytrin®, Minipress®, Oxytrol®, Pro-Banthine®, Sanctura®, Tofranil®, Vesicare®
  • infections Bactrim®, Septra®, Cipro®, Macrodantin®, Hiprex®, Pyridium®
  • bowel dysfunction Colace®, Dulcolax®, Enemeez®, Fleet enema, Mineral oil, Metamucil®, Milk of Magnesia®, glycerin suppositories
  • the amount of additional therapeutic agent present in or with the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
  • the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
  • the present invention features a kit comprising a compound and/or pharmaceutical composition of formula (I) or (IV) of the present invention and instructions for use thereof.
  • kits of the present invention further comprise one or more additional therapeutic agent(s).
  • the additional therapeutic agent is selected from an immunomodulatory agent, such as an IFN- ⁇ 1 molecule including but not limited to an interferon beta la (Avonex®, Rebif®) or an interferon beta lb (Betaseron®, Betaferon®, Extavia®).
  • the additional therapeutic agent is a polymer of glutamic acid, lysine, alanine and tyrosine such as glatiramer acetate (Copaxone®).
  • the additional therapeutic agent is an antibody or fragment thereof against alpha-4 integrin (e.g., natalizumab (Tysabri®)).
  • the additional therapeutic agent is an
  • anthracenedione molecule such as mitoxantrone (Novantrone®).
  • the additional therapeutic agent is a sphingosine 1- phosphate receptor modulator such as fingolimod (Gilenya®) and those described in
  • the additional therapeutic agent is a dimethyl fumarate such as an oral dimethyl fumarate (Tecfidera®).
  • the additional therapeutic agent is an antibody to the alpha subunit of the IL-2 receptor of T cells such as daclizumab (Zenapax®).
  • the additional therapeutic agent is an antibody against CD52 such as alemtuzumab (Lemtrada®).
  • the additional therapeutic agent is an inhibitor of a dihydroorotate dehydrogenase such as teriflunomide (Aubagio®).
  • the additional therapeutic agent is an antibody to CD20 such as ocrelizumab, rituximab or ofatumumab.
  • the additional therapeutic agent is a corticosteroid such as, but not limited to methylprednisolone, Depo-Medrol®, Solu-Medrol®, Deltasone®, Delta-Cortef®, Medrol®, Decadron® or Acthar®.
  • a corticosteroid such as, but not limited to methylprednisolone, Depo-Medrol®, Solu-Medrol®, Deltasone®, Delta-Cortef®, Medrol®, Decadron® or Acthar®.
  • the additional therapeutic agent is one or more compounds useful for treating symptoms of the disease such as bladder problems (e.g., Botox®, DDAVP Nasal Spray®, Detrol®, Ditropan®, Ditropan XL®, Enablex®, Flomax®, Hytrin®, Minipress®, Oxytrol®, Pro-Banthine®, Sanctura®, Tofranil®, Vesicare®); infections (Bactrim®, Septra®, Cipro®, Macrodantin®, Hiprex®, Pyridium®); bowel dysfunction (Colace®, Dulcolax®, Enemeez®, Fleet enema, Mineral oil, Metamucil®, Milk of Magnesia®, glycerin suppositories);
  • bladder problems e.g., Botox®, DDAVP Nasal Spray®, Detrol®, Ditropan®, Ditropan XL®, Enablex®, Flomax®, Hytrin®, Minipress®, Ox
  • kits of the present invention are drawn to kits wherein the compounds or the pharmaceutical compositions of the present invention and the one or more additional therapeutic agent(s) are in separate containers.
  • kits of the present invention are drawn to kits wherein the compounds or the pharmaceutical compositions of the present invention and the one or more additional therapeutic agent(s) are in the same container.
  • the container is a bottle, vial, or blister pack, or combination thereof.
  • the compounds of the invention may be readily prepared by known methods and by using the following methods, schemes and examples. Illustrated below in Scheme A through Scheme Q are general methods for preparing the compounds of the present invention. Compounds were named using either IUPAC nomenclature or the nomenclature used in ChemBioDraw Ultra (Version 12.0.2.1076, CambridgeSoft®).
  • UPLC method A Mobile phase A: water (0.1 % trifluoroacetic acid).
  • Mobile phase B acetonitrile (0.1 % trifluoroacetic acid).
  • UPLC method B Mobile phase A: water (0.1 % trifluoroacetic acid). Mobile phase B: acetonitrile (0.1 % trifluoroacetic acid).
  • UPLC method D Mobile Phase A: 95 % water [50 mM ammonium formate pH 9] : 5% acetonitrile.
  • Mobile Phase B acetonitrile.
  • Column: Waters Acquity BEH C8, 2.1 x 50 mm, 1.7 ⁇ particle size. Flow rate 0.6ml/min ; Injection Volume: 2 ⁇ L.
  • UPLC method E Mobile Phase A: water (0.1 % trifluoroacetic acid).
  • Mobile phase B acetonitrile (0.1 % trifluoroacetic acid);
  • HPLC method F Mobile phase A: water (0.1 % trifluoroacetic acid).
  • Mobile phase B acetonitrile (0.1 % trifluoroacetic acid).
  • Reagents and conditions (a) Pd 2 (dba) 3 , RuPhos, CS2CO 3 , 90 °C, morpholine, 1,4- dioxane (b) 10% Pd/C (wet), EtOH, H 2 (c) ⁇ -BuXPhos Palladacycle, NaOtBu, 1,4- dioxane, 90 °C.
  • Tris(dibenzylideneacetone)dipalladium(0) (80 mg, 0.09 mmol) was added and nitrogen purge continued for 5 minutes, then the vial was sealed and heated at 90 °C for 18 hours. The mixture was cooled, diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, filtered through a plug of Florisil, and concentrated. Flash chromatography on silica gel (40 g column) eluting with 0-20% ethyl acetate/heptane afforded 4-(3-methyl-5-nitrophenyl)morpholine (447 mg, 46%) as an off-white solid.

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Abstract

L'invention concerne des composés hétérocycliques de formule (I) et (IV) ou des sels pharmaceutiquement acceptables de ceux-ci, utiles en tant que modulateurs de maladies de démyélinisation. L'invention concerne également des compositions pharmaceutiquement acceptables comprenant lesdits composés, ainsi que des méthodes d'utilisation des compositions et des trousses de ces dernières dans le traitement de diverses maladies de démyélinisation et neurodégénératives, y compris la sclérose en plaques.
PCT/US2017/064629 2016-12-06 2017-12-05 Azoles hétérocycliques pour le traitement de maladies de démyélinisation WO2018106643A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2018231910A1 (fr) * 2017-06-13 2018-12-20 National Health Research Institutes Composés aminothiazoles utilisés comme inhibiteurs de protéine kinase
EP4194450A4 (fr) * 2020-08-07 2024-10-30 Pharmablock Sciences Nanjing Inc Inhibiteur de cdk9 et son utilisation

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