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WO2018106641A1 - Pyrazoles pour le traitement de maladies démyélinisantes - Google Patents

Pyrazoles pour le traitement de maladies démyélinisantes Download PDF

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Publication number
WO2018106641A1
WO2018106641A1 PCT/US2017/064627 US2017064627W WO2018106641A1 WO 2018106641 A1 WO2018106641 A1 WO 2018106641A1 US 2017064627 W US2017064627 W US 2017064627W WO 2018106641 A1 WO2018106641 A1 WO 2018106641A1
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Prior art keywords
alkyl
alkylene
oci
independently selected
group
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PCT/US2017/064627
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English (en)
Inventor
Philip N. Collier
Robert J. Davies
Elizabeth DOYLE
James Daniel Frantz
Brian Anthony GOLDMAN
Anne-Laure Grillot
Wenxin Gu
Adrianne Lynne KOLPAK
Raul Eduardo KRAUSS
Sanjay Shivayogi MAGAVI
Emanuele POROLA
Elizabeth Jin-Sun RYU
Joshua Syken
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Vertex Pharmaceuticals Incorporated
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Publication of WO2018106641A1 publication Critical patent/WO2018106641A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • 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
    • 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
    • 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
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

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.
  • 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
  • Axon loss as a result of demyelination is thought to underlie long term disease progression and disability in MS patients (see, Compston, et al., he Lancet, Vol. 359, 1221-1231, 2002 and D.
  • a compound that can promote differentiation and myelination of OPCs should function to restore this regenerative capacity and blunt or reverse the degenerative effects of MS (see, Stangel, M. et al, Progress in Neurobiology, 68, 361-376, 2002, Nairn, F. J. et al, Nature (Letter), published online 20 April 2015, doi: 10.1038/naturel4335).
  • Such an agent could both increase the function of neurons and provide trophic support to enhance their survival (see, Mei, F. et al. Nature Medicine, Vol. 20, No. 8, 954- 961, 2014).
  • 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 periventricular region and leading to severe dysmyelination and demyelination.
  • This pathology has been proposed as the root cause of cerebral palsy, a life-long debilitating CNS disorder characterized by various motor and/or cognitive deficits of variable intensity.
  • a compound promoting differentiation of surviving OPCs and remyelination of damaged areas could be used for the treatment or prevention of cerebral palsy in vulnerable infant populations.
  • Current therapies for MS are immunomodulatory in nature and do not directly promote repair.
  • some of these immunomodulatory agents can leave patients vulnerable to opportunistic infection or neoplasia.
  • compounds, such as those of the present invention that can promote differentiation and myelination of OPCs and lead to the repair of demyelinated axons.
  • Such a compound could also be useful in combination with existing or experimental immunmodulating and other relevant therapies to treat MS and other neurological and demyelinating diseases.
  • 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.
  • a disease or disorder selected from a demyelinating disease, central pontine myelinolysis, a nerve injury disease or disorder, a leukoencephalopathy or a leukodystrophy.
  • R 1 is selected from the group consisting of -NR 4 R 5 , -NR 4 -G°, -G -L -R 6 , -NR'-G ⁇ -L ⁇ R 6 , and G 2 ;
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen and Ci- 4 alkyl
  • G° is a C3- 8 cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- 4 alkyl, Ci -4 haloalkyl, halogen, hydroxyl, oxo, cyano, -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 alkylene-OH
  • G 1 is a 4- to 8-membered monocyclic heterocycle containing a first nitrogen atom and optionally a second heteroatom independently selected from oxygen, nitrogen, and sulfur, and optionally containing one double bond and/or a Ci_ 3 alkylene bridge between two non-adjacent ring atoms, G 1 being connected to the parent molecular moiety through the first nitrogen atom and optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- 4 alkyl, halogen, hydroxyl, and oxo;
  • G 1A 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
  • G 1A being optionally substituted with 1- 4 substituents independently selected from the group consisting of C h alky 1, Ci_ 4 haloalkyl, halogen, hydroxyl, and oxo;
  • L 1 is a bond, -Ci -3 alkylene-, -C(O)-, -0-, or -NR 7 -, wherein R 7 is hydrogen or Ci- 4 alkyl;
  • 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 Cs-gcycloalkyl 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 5- to 12-membered heterocycle containing a first nitrogen atom and optionally 1-3 additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, G 2 being connected to the parent molecular moiety through the first nitrogen atom and optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- 4 alkyl, Ci -4 haloalkyl, halogen, hydroxyl, oxo, cyano, -Ci-ealkylene-cyano, -C(0)Ci -4 alkyl, -C(0)-Ci -6 alkylene-OCi -4 alkyl, -C(0)-Ci_ 6 alkylene-OH, -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)
  • R 2 is selected from the group consisting of Ci -4 alkyl, Ci -4 haloalkyl, and - L 2 -G 3 , R 2 being connected to the parent molecular moiety through a carbon atom;
  • L 2 is a bond or -Ci -3 alkylene-
  • G 3 is selected from the group consisting of phenyl, 5- to 8-membered monocyclic heterocyclyl, C5- 6 cycloalkenyl, and Cs-gcycloalkyl, the 5- to 8-membered monocyclic heterocyclyl optionally containing one double bond, and the 5- to 8- membered monocyclic heterocyclyl and Cs-gcycloalkyl each optionally containing a Ci- 3 alkylene bridge between two non-adjacent ring atoms, G 3 being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- 4 alkyl, Ci -4 haloalkyl, halogen, hydroxyl, oxo, cyano, -C(0)Ci -4 alkyl, -C(0)C3_ ecycloalkyl, -C(0)OCi -4 alkyl, -C(0)OCi -4 haloalkyl, -C(0)NH 2 , -C(0)
  • G 10 being a C3- 6 cycloalkyl or a 4- to 8-membered monocyclic heterocycle containing 1 to 2 heteroatoms independently selected from nitrogen and oxygen, G 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 3 is selected from the group consisting of hydrogen, halogen, Ci- 4 alkyl, and Ci -4 haloalkyl;
  • R 8 is selected from the group consisting of C h alky 1, Ci- 6 haloalkyl, and - L 3 -G 4 ;
  • G 4 is selected from the group consisting of phenyl, 5- to 6-membered monocyclic heteroaryl, 5- to 8-membered monocyclic heterocyclyl, C5- 6 cycloalkenyl, and C3- 8 cycloalkyl, the 5- to 8-membered monocyclic heterocyclyl optionally containing one double bond, and the 5- to 8-membered monocyclic heterocyclyl and C3- 8 cycloalkyl each optionally containing a bridge between two non- adjacent ring atoms, G 4 being optionally substituted with 1-4 substituents
  • Ci- 4 alkyl Ci -4 haloalkyl, halogen, hydroxyl, oxo, cyano, -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)Ci -4 haloalkyl, -OCi -4 alkyl, -OCi -4 haloalkyl, -NH(Ci -4 alkyl), -N(Ci -4 alkyl)(Ci.
  • G 20 being a C3- 6 cycloalkyl or a 4- to 8-membered monocyclic heterocycle containing 1 to 2 heteroatoms independently selected from nitrogen and oxygen, G 20 being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci -4 alkyl, Ci -4 haloalkyl, halogen, hydroxyl, and oxo;
  • L 2 is -Ci -3 alkylene- when R 1 is G 2 , R 2 is -L 2 -G 3 , G 2 is optionally substituted piperazinyl, G 3 is optionally substituted phenyl and R 8 is Ci_ 6 alkyl; and provided that when R 1 is -G ⁇ L ⁇ R 6 , R 2 is -L 2 -G 3 , G 1 is optionally substituted azetidinyl, L 1 is a bond, and G 3 is optionally substituted phenyl, then R 6 is (a).
  • the present invention provides compounds of formula (I).
  • compositions comprising a pharmaceutically acceptable carrier and therapeutically effective amounts of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • the invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, which promote remyelination of demyelinated axons.
  • the invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, which differentiate endogenous
  • 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 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 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 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 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 a pharmaceutically acceptable salt thereof
  • the invention provides compounds of formula (I), 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 I. DETAILED DESCRIPTION OF THE INVENTION
  • 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.
  • the 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, pyrazolidinyl, o
  • 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. l]heptanyl, 2-azabicyclo[2.2. l]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).
  • CM isopropyl
  • 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.
  • the structures also include zwitterioinc forms of the compounds or salts of formula I where appropriate.
  • G° is a C3- 8 cycloalkyl optionally substituted with 1- 4 substituents independently selected from the group consisting of C h alky 1, Ci_ 4 haloalkyl, halogen, hydroxyl, -OCi- 4 alkyl, oxo, cyano, -C(0)Ci- 4 alkyl, -C(0)OCi_ 4 alkyl, -C(0)NH 2 , -C(0)NH(Ci -4 alkyl), -C(0)N(Ci -4 alkyl)(Ci -4 alkyl), -NHC(0)(Ci_ 4 alkyl), -N(Ci -4 alkyl)C(0)(Ci -4 alkyl), -NH 2 , -NH(Ci -4 alkyl), and -N(Ci -4 alkyl)(Ci. 4 alkyl);
  • G 1 is a 4- to 8-membered monocyclic heterocycle containing a first nitrogen atom and optionally a second heteroatom independently selected from oxygen and nitrogen, G 1 being connected to the parent molecular moiety through the first nitrogen atom and optionally substituted with 1-4 substituents independently selected from the group consisting of Ci -4 alkyl, Ci -4 haloalkyl, halogen, hydroxyl, and oxo;
  • G is a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen and nitrogen, G 1A being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- 4 alkyl, Ci- 4 haloalkyl, halogen, hydroxyl, and oxo;
  • L 1 is a bond, or -C(O)-;
  • R 6 is
  • heterocycle 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, halogen, hydroxyl, oxo, and - OCi -4 alkyl; or
  • G 2 is a 5- to 12-membered heterocycle containing a first nitrogen atom and optionally 1-3 additional heteroatoms independently selected from oxygen and nitrogen, G 2 being connected to the parent molecular moiety through the first nitrogen atom and optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- 4 alkyl, Ci- 4 haloalkyl, halogen, hydroxyl, oxo, cyano, -Ci- 6 alkylene- cyano, -C(0)Ci -4 alkyl, -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), -NH(-Ci- 6 alkylene-OCi- 4 alkyl), - NiCi ⁇ alky i-Ci-ealkylene-OCi ⁇ alky ⁇ NH
  • G 3 is selected from the group consisting of phenyl and C3- 8 cycloalkyl, G 3 being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- 4 alkyl, halogen, hydroxyl, oxo, and -OCi- 4 alkyl;
  • G 4 is selected from the group consisting of phenyl, 5- to 6-membered monocyclic heteroaryl, 5- to 8-membered monocyclic heterocyclyl, C5-6cycloalkenyl, and C3- gcycloalkyl, the Cs-gcycloalkyl optionally containing a bridge between two non-adjacent ring atoms, G 4 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 1 is -NR 4 R 5 (i.e., formula (II)).
  • R 4 and R 5 are each independently Ci- 4 alkyl (e.g., methyl).
  • R 2 is Ci_ 4 haloalkyl.
  • R 3 is hydrogen.
  • R is -L -G 4 , L 3 is a bond, and G is optionally substituted Cs-gcycloalkyl.
  • R 2 is Ci_ 4 haloalkyl.
  • R is hydrogen
  • R is -V-G V is a bond
  • G is C3- 8 cycloalkyl.
  • R 1 is -NR 4 -G° (i.e., formula (III)).
  • R 4 is hydrogen.
  • G° is a C5- 7 cycloalkyl (e.g., cyclohexyl) optionally substituted with -N(Ci- 4 alkyl)(Ci- 4 alkyl) (e.g., -N(CH 3 ) 2 ).
  • G° is 4-dimethylaminocyclohexyl.
  • R 2 is -L 2 -G 3 , L 2 is a bond, and G 3 is optionally substituted C3- 8 cycloalkyl (e.g., cyclopropyl).
  • R 3 is halogen (e.g., fluoro).
  • R is -L -G 4 , L 3 is a bond, and G is optionally substituted Cs-gcycloalkyl.
  • R 2 is -L 2 -
  • G L is a bond
  • G is optionally substituted Cs.gcycloalkyl
  • R is halogen
  • R is -L - G 4
  • L 3 is a bond
  • G 4 is Cs-gcycloalkyl.
  • R 1 is -G -L -R 6 (i.e., formula (IV)), wherein G 1 , L 1 , and R 6 are as defined herein.
  • G 1 is a 4- to 8-membered monocyclic heterocycle containing a first nitrogen atom and optionally a second heteroatom independently selected from oxygen, nitrogen, and sulfur, and optionally containing one double bond and/or a Ci_ 3 alkylene bridge between two non-adjacent ring atoms, G 1 being connected to the parent molecular moiety (i.e., at the pyrimidine 6 position) through the first nitrogen atom and 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, halogen, hydroxyl, and oxo.
  • 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.
  • G 1 contains two nitrogen atoms.
  • the heterocycles at G 1 may be unsubstituted or substituted.
  • G 1 may be piperazinyl,
  • the piperazinyl, homopiperazinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-dihydro-lH-pyrrolyl, morpholino, 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.
  • 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[2.2.1]heptanyl).
  • G 1 is without a Ci- 3 alkylene bridge between two non-adjacent ring atoms.
  • G 1 examples include piperazin-l-yl, 2-oxo-piperazin-l-yl, homopiperazin-l-yl, azetidin-l-yl, piperidin-l-yl, and 2,5-diazabicyclo[2.2.1]heptan-2-yl.
  • G 1 is a 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 1 being connected to the parent molecular moiety through the first nitrogen atom.
  • G 1 is piperazinyl, azetidinyl, morpholinyl, or piperidinyl.
  • R 1 is -NR 4 -G 1A -L -R 6 (i.e., formula V).
  • R 4 is hydrogen
  • G 1A 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 1A being optionally substituted with 1- 4 substituents independently selected from the group consisting of C h alky 1, Ci_ 4 haloalkyl, halogen, hydroxyl, and oxo.
  • G 1A 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 1A 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 1A contains one nitrogen atom.
  • G 1A contains two nitrogen atoms.
  • G 1A is a 6-membered monocyclic heterocycle containing 1 or 2 nitrogen atoms.
  • G 1A is appended to NR 4 by a carbon ring atom of G 1A .
  • the heterocycles at G 1A may be unsubstituted or substituted.
  • G 1A 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, morpholino, 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.
  • pyrrolidinyl and/or piperidinyl is optionally substituted with halogen, 1 hydroxyl, or 1 oxo and the piperazinyl is optionally substituted with oxo.
  • G may have a bridge between two non-adjacent ring atoms (e.g., 2,5-diazabicyclo[2.2. l]heptanyl).
  • G 1A is without a bridge between two non-adjacent ring atoms.
  • G 1A examples include azetidin-3-yl, pyrrolidin- 3-yl, 3-hydroxy-pyrrolidin-3-yl, 3-fluoro-pyrrolidin-3-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-difluoropiperidin-4-yl, azepan-3-yl, 2,5-dihydro-lH-pyrrol- 3-yl, or l,2,3,6-tetrahydropyridin-4-yl.
  • G 1A is a 4- to 6-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen and nitrogen, and optionally containing one double bond and/or a bridge between two non-adjacent ring atoms.
  • G 1A is piperidinyl.
  • 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 -C h alky lene-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
  • Ci- 4 alkyl 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 -C h alky lene-OH.
  • R 6 is a 4- to 6-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen and nitrogen sulfur, the heterocycle optionally containing one double bond and/or a Ci- 3 alkylene bridge between two non-adjacent ring atoms and 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, tetrahydropyranyl, morpholinyl, pyrrolidinyl, or thietanyl each being optionally substituted with 1 -4 substituents independently selected from Ci- 4 alkyl and oxo.
  • tetrahydrofuranyl tetrahydropyranyl
  • morpholinyl pyrrolidinyl
  • thietanyl thietanyl
  • piperazinyl and azetidinyl
  • 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. In other embodiments, R 6 is a 4-membered monocyclic heterocycle containing 1 oxygen atom and optionally substituted with Ci- 4 alkyl. In other embodiments, R 6 is a 4- to 8-membered monocyclic heterocycle containing 1 sulfur atom (e.g., thietanyl,
  • 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., at L 1 ) at any substitutable carbon atom or nitrogen atom of R 6 .
  • the oxygen-containing heterocycle is oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, or tetrahydropyran-4-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. l]heptan-5-yl, 6-oxa-3-azabicyclo[3.1.
  • 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-4alkyl, Ci_ 4haloalkyl, halogen, hydroxyl, oxo, and -OCi-4alkyl.
  • 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 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 optionally substituted with 1-4 substituents independently selected from the group consisting of Ci-4alkyl, Ci_ 4haloalkyl, halogen, hydroxyl, and oxo.
  • the spirocyclic R 6 is optionally substituted with 1-4 substituents independently selected from the group consisting of Ci-4alkyl, -CH 2 S(0)2phenyl, halogen, hydroxyl, oxo, - OCi-4alkyl, -Ci- 6 alkylene-OCi-4alkyl, and -Ci- 6 alkylene-OH.
  • 1-4 substituents independently selected from the group consisting of Ci-4alkyl, -CH 2 S(0)2phenyl, halogen, hydroxyl, oxo, - OCi-4alkyl, -Ci- 6 alkylene-OCi-4alkyl, 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 L 1 through any substitutable carbon or nitrogen atom.
  • the first ring is attached to L 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 (e.g., 2-oxa-5- azabicyclo[4.1.0]heptan-5-yl) 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_ 4haloalkyl, halogen, hydroxyl, and oxo.
  • a 7- to 12-membered fused bicyclic heterocycle e.g., 2-oxa-5- azabicyclo[4.1.0]heptan-5-yl
  • 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_ 4haloalkyl, 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_
  • 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 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 -Ci- 6 alkylene-OH.
  • R 6 is cyclopropyl, cyclobutyl, or cyclopentyl, each being optionally substituted with -C(0)OCi-4alkyl, - C(0)OH, hydroxyl or 1-2 halogen.
  • R 6 is cyclopropyl.
  • R 6 is cyclobutyl. In other embodiments, R 6 is 3,3- difluorocyclobutyl. In other embodiments, R 6 is a cyclobutane carboxylic acid.
  • R may be represented by the following formulas, wherein R 6a 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 1 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 may be represented by the following formulas, wherein R l is the optional G 1A substituent and m is an integer from 0-4:
  • L 1 may be a bond, - Ci -3 alkylene- (e.g., CH 2 ), or -C(O)-.
  • G ⁇ R 6 may also be represented by the following formulas when L 1 is a bond, wherein R l , R 6a , R 6b , m and s are as defined herein:
  • L 1 may be -Ci_ 3alkylene- (e.g., CH 2 ).
  • G ⁇ I ⁇ -R 6 may also be represented by the following fo ned herein:
  • L 1 may be -C(O)-.
  • G ⁇ I ⁇ -R 6 may also be represented by the following formula when L 1 a C(O), wherein R l , R 6a , m and s are as defined herein.
  • -G -L -R 6 together may be 4-(oxetan-3-yl)piperazin-l-yl, 4-(3- methyloxetan-3-yl)piperazin-l -yl, 4-(tetrahydrofuran-3-yl)piperazin-l -yl, 4-(2- methyltetrahydrofuran-3-yl)piperazin-l-yl, 4-(tetrahydro-2H-pyran-3-yl)piperazin-l- yl, 4-(tetrahydro-2H-pyran-4-yl)piperazin-l-yl, 4-((3-methyloxetan-3- yl)methyl)piperazin-l-yl, 4-(oxetan-3-yl)-2-oxo-piperazin-l-yl, 4-(oxetan-3- y l)piperidin- 1 -y 1, 4-(2-oxopy r
  • -G ⁇ R 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; 4-(3,3-difluorocyclobutyl)piperazin-l-yl; or 5-cyclopropyl-2,5- diazabicyclo[2.2. l]heptan-2-yl.
  • R 3 is hydrogen, halogen (e.g., fluoro), or Ci- 4 alkyl.
  • R 8 is Ci- 6 alkyl, Ci- 6 haloalkyl (e.g., CF 3 ), -L 3 - G 4 , L 3 is a bond, and G 4 is optionally substituted phenyl, 5- to 6-membered monocyclic heteroaryl (pyridinyl), 5- to 8-membered monocyclic heterocyclyl (e.g., tetrahydropyranyl), or Cs-gcycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or bicyclo[2.2. l]heptan-2-yl).
  • Ci- 6 alkyl Ci- 6 haloalkyl
  • -L 3 - G 4 L 3 is a bond
  • G 4 is optionally substituted phenyl, 5- to 6-membered monocyclic heteroaryl (pyridinyl), 5- to 8-membered monocyclic heterocyclyl (e
  • R 2 is Ci-4alkyl, or -L 2 -G 3 , L 2 is a bond, and G 3 is optionally substituted C3- gcycloalkyl;
  • R 3 is hydrogen, halogen, or Ci-4alkyl;
  • R 8 is Ci- 6 alkyl, Ci- 6 haloalkyl, -L 3 - G 4 , L 3 is a bond, and G 4 is optionally substituted phenyl, 5- to 6-membered monocyclic heteroaryl, 5- to 8-membered monocyclic heterocyclyl, or Cs-gcycloalkyl.
  • G -L -R 6 is still further embodiments in combination with the foregoing, m is 0.
  • v or
  • L 1 may be -Ci_ 3alkylene- (e.g., CH2).
  • G ⁇ -L ⁇ R 6 may also be represented by the following formula when L 1 is a CH 2 , wherein R gl , R 6a , m and s are as defined herein:
  • R 1 is G 2 (i.e., formula (VI)), provided that L 2 is Ci- 3 alkylene- when G 2 is optionally substituted piperazin-l-yl, G 3 is optionally substituted phenyl, and R 8 is Ci- 6 alkyl.
  • G 2 is a 5- to 12-membered heterocycle containing a first nitrogen atom and optionally 1-3 additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, G 2 being connected to the parent molecular moiety (i.e., at the pyrimidine 6 position) through the first nitrogen atom and optionally substituted as described herein.
  • G 2 may be substituted or unsubstituted.
  • Optional G 2 substituents include 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)OCi -4 alkyl (e.g., -C(0)OCH 3 , -C(0)OCH 2 CH 3 , - C(0)OC(CH 3 ) 3 ), -C(0)OCi -4 haloalky
  • G 2 is optionally substituted with Ci- 4 alkyl, Ci_ 4 haloalkyl, halogen, hydroxyl, -N(Ci- 4 alkyl)(-Ci- 6 alkylene-OH), -Ci- 6 alkylene-OCi- 4 alkyl, -Ci- 4 alkylene-C(0)OCi- 4 alkyl, -N(Ci- 4 alkyl)(Ci- 4 alkyl), or a -Ci -6 alkylene substituted by 2 groups independently selected from hydroxyl and -OCi-4alkyl.
  • the 5- to 12-membered heterocycle at G 2 may be a 5- to 8-membered monocyclic heterocycle containing a first nitrogen atom and optionally 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, G 2 being connected to the parent molecular moiety through the first nitrogen atom and optionally substituted as described herein.
  • the 5- to 8-membered monocyclic heterocycle at 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).
  • the 5- to 8-membered monocyclic heterocycle at G 2 is without a Ci_ 3 alkylene bridge between two non-adjacent ring atoms.
  • the heterocycles of G 2 are appended to the parent molecule by a nitrogen atom in G 2 (e.g., morpholin-4-yl, homomorpholin-4-yl, thiomorpholin-4-yl, 4-thiomorpholine 1,1 -dioxide, piperazin-1- yl, homopiperazin-l-yl, pyrrolidin-l-yl, piperidin-l-yl, azepan-l-yl, 2,5- diazabicyclo[2.2. l]heptan-2-yl, 6-oxa-3-azabicyclo[3.1.
  • a nitrogen atom in G 2 e.g., morpholin-4-yl, homomorpholin-4-yl, thiomorpholin-4-yl, 4-thiomorpholine 1,1 -dioxide, piperazin-1- yl, homopiperazin-l-yl, pyrrolidin-l-yl, piperidin-l-yl, aze
  • G 2 is a pyrrolidin-l-yl, piperidin-l-yl, morpholin- 4-yl, thiomo holin-4-yl, piperazin-l-yl, azepan-l-yl, azocan-l-yl, l,4-oxazepan-4-yl, 1,4-diazepan-l-yl, 1,5-diazocan-l-yl, l,5-oxazocan-5-yl, each optionally containing one double bond and/or a bridge between two non-adjacent ring atoms, G 2 being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- 4 alkyl, Ci -4 haloalkyl, halogen, hydroxyl, oxo, cyano, -Ci_ 6 alkylene-cyano, -C(0)Ci -4 alkyl, -C(0)-Ci_ 6
  • the optionally substituted G 2 may be piperidin-l-yl, 3- fluoropiperidin-l-yl, 4-fluoropiperidin-l-yl, 3 -methoxy piperidin-l-yl, 3- (methoxymethyl)piperidin-l-yl, 4-(methoxymethyl)piperidin-l-yl, 4-methylpiperidin- 1-yl, 4-hydroxy-4-methylpiperidin-l-yl, l-acetylpiperidin-3-yl, 4- (ethoxycarbonyl)piperidin-l -yl, 4-(tert-butoxycarbonyl)piperidin-l -yl, 3- cyanopiperidin-l-yl, 4-cyanopiperidin-l-yl, 3-hydroxypiperidin-l-yl, 4- hydroxypiperidin-l-yl, 3-(hydroxymethyl)piperidin-l-yl, 4-(2- methoxyethyl)piperidin-l-yl,
  • 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 5- 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 the first nitrogen atom and optionally 1-3 additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, G 2 being connected to the parent molecular moiety through the first nitrogen atom, 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, halogen, hydroxy 1, and oxo.
  • 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.
  • the first ring is a 4- to 6-membered monocyclic heterocycle containing 1 -2 nitrogen atoms.
  • the first ring is 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 C3-8cycloalkyl, 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-d
  • 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]
  • G 2 is selected from the group consisting of 2,6-diazaspiro[3.3]heptan-2-yl, 2-oxa-6-azaspiro[3.4]octan-6-yl, and 2- oxa-8-azaspiro[4.5]decan-8-yl.
  • the 5- to 12-membered heterocycle at G 2 is a 7- to 12-membered fused bi cyclic heterocycle containing a first nitrogen atom and optionally 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, G 2 being connected to the parent molecular moiety through the first nitrogen atom and optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- 4 alkyl, halogen, hydroxyl, -OCi- 4 alkyl, and oxo.
  • the fused bicyclic heterocycle is a 7-12-membered ring system having a monocyclic heterocycle, as defined herein, fused to another monocyclic heterocyclic ring.
  • the fused bicyclic heterocycle is a 7-12-membered ring system having a monocyclic heterocycle, as defined herein, fused to another monocyclic heterocyclic ring.
  • C h alky 1 e.g., C h alky 1
  • G 2 may be substituted with one substituent selected from the
  • G z is
  • R 2 is -L 2 -G 3
  • L 2 is a bond or and G 3 is optionally substituted phenyl or C3- gcycloalkyl (e.g., cyclopropyl).
  • G 3 is optionally substituted phenyl or C3- gcycloalkyl (e.g., cyclopropyl).
  • R 3 is hydrogen or halogen (e.g., fluoro).
  • R 8 is Ci- 6 alkyl or -L -G 4 , L 3 is a bond, and G 4 is optionally substituted C3- 8 cycloalkyl.
  • R is -L 2 -G 3 , L 2 is a bond or -Ci- 3 alkylene-, G 3 is optionally substituted phenyl or C3- 8 cycloalkyl, R 3 is hydrogen or halogen, R is -L -G 4 , L 3 is a bond, and G 4 is C3- 8 cycloalkyl.
  • R 2 is selected from the group consisting of Ci- 4 alkyl, Ci- 4 haloalkyl, and - L 2 -G 3 , R 2 being connected to the parent molecular moiety through a carbon atom.
  • R 2 is Ci- 4 alkyl (e.g., methyl, ethyl, isopropyl) or
  • R 2 is Ci- 4 haloalkyl (e.g., CF 3 ). In some embodiments,
  • R is -V-G 1 is a bond or -Ci- 3 alkylene-
  • G is selected from the group consisting of phenyl, 5- to 8-membered monocyclic heterocyclyl, C5- 6 cycloalkenyl, and Cs-gcycloalkyl, the 5- to 8-membered monocyclic heterocyclyl optionally containing one double bond, and the 5- to 8-membered monocyclic heterocyclyl and C3- 8 cycloalkyl each optionally containing a Ci- 3 alkylene bridge between two non-adjacent ring atoms, G 3 being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- 4 alkyl, Ci_ 4 haloalkyl, halogen, hydroxyl, oxo, cyano, -C(0)Ci- 4 alkyl, -C(0)C3- 6 cycloalkyl, - C(0)OCi -4 alkyl, -C
  • L 2 is a bond or -Ci_ 3 alkylene-
  • G 3 is phenyl or Cs-gcycloalkyl (e.g., cyclopropyl, cyclohexyl) optionally substituted with 1-4 halogen.
  • L 2 is a bond or -Ci_ 3 alkylene-
  • G 3 is phenyl optionally substituted with 1-4 halogen.
  • L 2 is a bond and G 3 is Cs-gcycloalkyl.
  • R 8 is selected from the group consisting of Ci- 6 alkyl, Ci- 6 haloalkyl, and - L -G 4 .
  • R 8 is Ci- 6 alkyl (e.g., methyl, ethyl, isopropyl, isobutyl, tert-butyl, neopentyl). In other embodiments, R 8 is Ci-6haloalkyl (e.g., CF3).
  • R is -L -G 4
  • L 3 is a bond or and G 4 is selected from the group consisting of phenyl, 5- to 6-membered monocyclic heteroaryl, 5- to 8- membered monocyclic heterocyclyl, C5- 6 cycloalkenyl, and Cs-gcycloalkyl, the 5- to 8- membered monocyclic heterocyclyl optionally containing one double bond, and the 5- to 8-membered monocyclic heterocyclyl and Cs-gcycloalkyl each optionally containing a C h alky lene bridge between two non-adjacent ring atoms, G 4 being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- 4 alkyl, Ci -4 haloalkyl, halogen, hydroxyl, oxo, cyano, -C(0)Ci- 4 alkyl, -C(0)C 3 - 6 cycloalkyl, -C(0)
  • G 4 is selected from the group consisting of phenyl, 5- to 6-membered monocyclic heteroaryl, 5- to 8-membered monocyclic heterocyclyl, and C3- 8 cycloalkyl, each optionally substituted.
  • G 4 is phenyl.
  • G 4 is pyridinyl (e.g., pyridin-2-yl).
  • G 4 is a 4- to 8-membered monocyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, optionally containing one double bond and/or a bridge between two non- adjacent ring atoms, wherein G 4 is attached at a ring carbon ring atom of G 4 or G B , and optionally substituted as described herein.
  • G 4 is tetrahydropyranyl (e.g., tetrhydropyran-4-yl).
  • L is a bond.
  • L is a bond and G 4 is C3- 8 cycloalkyl optionally containing a C h alky lene bridge between two non-adjacent ring atoms, G 4 being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- 4 alkyl, and halogen.
  • G 4 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or bicyclo[2.2.1]heptan-2-yl, G 4 being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- 4 alkyl and halogen.
  • the compounds of the present invention are selected from 2-cyclopropyl-5-fluoro-N-(5-((lr,3r)-3-fluorocyclobutyl)-lH-pyrazol-3- yl)-6-(4-(oxetan-3-yl)piperazin-l-yl)pyrimidin-4-amine; 2-cyclopropyl-5-fluoro-N-(5- ((ls,3s)-3-fluorocyclobutyl)-lH-pyrazol-3-yl)-6-(4-(oxetan-3-yl)piperazin-l- yl)pyrimidin-4-amine; N-(5-(bicyclo[2.2.1]heptan-2-yl)-lH-pyrazol-3-yl)-2- cyclopropyl-5-fluoro-6-(4-(oxetan-3-yl)piperazin-l-yl)pyrirni
  • the compounds of formula I include isotope- labelled forms thereof.
  • An isotope-labelled form of a compound of formula I 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 by well-known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example 2 H, H, 1 C, 14 C, 15 N, 18 0, 17 0, 1 P, 2P, 5 S, 18 F and 6 C1, respectively.
  • a compound of formula I or a pharmaceutically acceptable salt thereof which contains one or more of the above-mentioned isotopes and/or other isotopes of other atoms is intended to be part of the present invention.
  • the present invention features a compound of formula I and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.
  • an isotope-labelled compound of formula I can be used in a number of beneficial ways.
  • an isotope-labelled compound of formula I 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 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 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 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.
  • a compound of formula I 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 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
  • the invention features a compound of formula I, wherein the compound or a pharmaceutically acceptable salt thereof, is selected from Table 1 below.
  • Salts Compositions. Uses. Formulation. Administration and Additional Agents
  • the compounds of formula 1 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.
  • said compounds of formula 1 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
  • 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 injur ⁇ ', stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital hypomyelination, 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 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, Marchiafava-Bignami syndrome, metachromatic
  • HTLV- 1 human T-lvmphotropic virus 1
  • the compounds of formula I of th e 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 auditor ⁇ - impairment, optic neuritis, decreased visual acuity, diplopia, nystagmus, ocular dysmetria, intemuclear 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, para
  • 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 quaternization 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 and one or more
  • 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 a composition thereof.
  • a method of the present invention comprises promoting oligodendrocyte proliferation, differentiation or survival. In another embodiment, a method of the present invention comprises promoting oligodendrocyte proliferation, differentiation or survival with a compound of formula I or a composition thereof. In another embodiment, 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 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 a composition thereof.
  • a method of the present invention comprises promoting survival of cells of the nervous system. In another embodiment, 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.
  • 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 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 t pe of multiple sclerosis is primary 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 embodi ment, the type of multiple sclerosis is progressive relapsing multiple sclerosis.
  • 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 T 1 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 f unctional readout such as ambulators 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 acuity 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 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.
  • the compounds of formula I of the present invention and the methods, compositions and kits disclosed herein are useful for promoting myelin regeneration in progressive demyelinating diseases. In one embodiment, the compounds of formula I of the present invention and the methods, compositions and kits disclosed herein are useful for promoting myelin regeneration in primary progressive multiple sclerosis. In another embodiment, the compounds of formula I 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 of the present invention and the methods, compositions and kits disclosed herein are useful for promoting myelin regeneration in relapsing-remitting multiple sclerosis. In another embodiment, the compounds of formula I 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 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 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 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 of the present invention and the methods, compositions and kits disclosed herein are useful for promoting
  • oligodendrocyte cells thereby treating demyelinating diseases or disorders.
  • the compounds of formula I 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.
  • 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
  • encephalomyelitis central pontine myelolysis, hypoxic demyelination, ischemic demyelination.
  • neuromyelitis optics adrenoleukodystrophy, Alexander's disease, Niemann-Pick disease, Pelizaeus Merzbacher disease, periventricular leukomalatia, globoid cell ieucodystrophy ( 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, 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 B12 deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornz eig syndrome, Leber's hereditary optic atrophy Leber congenital amaurosis. M arch i afa v a- B i gn ami syndrome, metachromatic
  • the present invention provides a method of 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, paraesthesia, anaesthesia, neuralgia, neuropathic and neurogenic pain, L'hermitte's, proprioceptive dysfunction, trigeminal neuralgia, ataxia, intentio tremor, dysmetria, vestibular ataxia, vertigo, speech ataxia, dystonia, disability progression,
  • bladder spasticity, flaccid bladder, detrusor- sphincter dyssynergia, erectile dysfunction or anorgasmy comprisin administering an effective amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula I.
  • the present invention provides a method of treating or lessening the severity of, in a subject, a disease or disorder selected from a demyelinatin 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 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 demyelinatin disease, central pontine myelinolysis, a nerve injury disease or disorder, a leukoencephalopathy or a leukodystrophy
  • the present invention provides a method of treating or lessening the severity of, in a subject, a disease or disorder selected from spinal cord injur ⁇ ', stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital hypomyelination, 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, Tax -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, Marchiafava-Bignami syndrome, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia.
  • Bell's palsy schizophrenia, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraparesis uman 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 with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound or pharmaceutical composition.
  • HTLV-1 T-lymphotropic virus 1
  • the present invention provides a method of treating or lessening the severity of, in a subject, a type of multiple sclerosis selected from primary progressive multiple sclerosis, relapsing-remitting multiple sclerosis, secondaiy progressive multiple sclerosis or progressive relapsing multiple sclerosis.
  • a type of multiple sclerosis selected from primary progressive multiple sclerosis, relapsing-remitting multiple sclerosis, secondaiy progressive multiple sclerosis or progressive relapsing multiple sclerosis.
  • the type of multiple sclerosis is primary progressive multiple sclerosis.
  • the t pe of multiple sclerosis is relapsing-remittin multiple sclerosis.
  • the type 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 impairment, optic neuritis, decreased visual acuity, diplopia, nystagmus, ocular dysmetria.
  • intemiiclear 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, paresthesia, anaesthesia, neuralgia, neuropathic and neurogenic pain, L'hermitte's, proprioceptive dysfunction, trigeminal neuralgia, ataxia, intention tremor, dysmetria, vestibular ataxia, vertigo, speech ataxia, dy stonia, disability progression,
  • d sdi adoch ok i ties i a. frequent micturation, bladder spasticit ', 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 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 hypomyelination, 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 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, Marchiafava-Bignami syndrome, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, schizophrenia, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic parapares i s uman T-lymphotropic virus 1 (HTLV- 1 ) associated myelopathy, essential tremor or osmotic hyponatremia.
  • HTLV- 1 T-lymphotropic virus 1
  • 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, intern uclear ophthalmoplegia, movement and sound phosphenes.
  • afferent pupillar - 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, pallesthesia, anaesthesia, neuralgia, neuropathic and neurogenic pain, L'hermitte's, proprioceptive dy sfunction, trigeminal neuralgia, ataxia, intention tremor, dysmetria, vestibular ataxia, vertigo, speech ataxia, dystonia, disability progression, dysdiadochokinesia, frequent micturation, bladder spasticity, flaccid bladder, detrusor
  • 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 concurrentl 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 demy elinating disease, central pontine myelinolysis, a nerve injury disease or disorder or a leukoeiicephalopathy 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 demy elinating disease, central pontine myelinolysis, a nerve injury disease or disorder or a leukoeiicephalopathy 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 congenital hypomyelination, encephalomyelitis, acute disseminated encephalomy elitis, central pontine my eloly sis, hypoxic demy elination.
  • ischemic demyelination neuromyelitis optics, adrenoleukodystrophy, Alexander's disease, Niemann-Pick disease, Pelizaeus Merzbacher disease, periventricular leukomalatia. globoid cell leucody strophy (Krabbe's disease).
  • Wallerian degeneration optic neuritis, transverse myelitis, amy otrophic 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 injur ', post radiation injury, 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.
  • the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treatin or lessening the seventy of, in a subject, a t pe 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 t pe of multiple sclerosis is relapsing-remitting multiple sclerosis.
  • the type of multiple sclerosis is secondar ' 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, iiitemuclear ophthalmoplegia, movement and sound phosphenes, afferent pupillary defect, paresis, monoparesis, paraparesis, hemiparesis, quadraparesis, piegia, paraplegia, hemiplegia, tetraplegia, quadraplegia, spasticity, dysarthria, motor dysfunction, walking impairment, muscle atrophy, spasms, cramps, hypotonia, clonus, myoclonus, myokymia, restless le syndrome, gait disturbances, footdrop.
  • another neurodegenerative disease selected from auditory impairment,
  • 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 [00153]
  • the pharmaceutically acceptable 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, corn, 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.
  • delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle.
  • Injectable depot forms are made by forming
  • 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 alcohol
  • 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.
  • buffering agents 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.
  • 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 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
  • 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.
  • 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
  • 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,
  • 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,
  • 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 US 8894999 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 US 8894999 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
  • the additional therapeutic agent is a Toll-Like Receptor-2 (TLR-2) inhibitor.
  • TLR-2 Toll-Like Receptor-2
  • the additional therapeutic agent is a TLR-2 (TLR-2) inhibitor.
  • 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 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, subcutaneously or intramuscularly.
  • the IFN- ⁇ 1 molecule is administered at 20-45 microgram once a week by intramuscular injection.
  • the IFN- ⁇ 1 molecule is administered at 20-30 microgram three times a week by intramuscular injection.
  • 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 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 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 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.
  • 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 ⁇ ⁇ . Gradient 5-95% phase B over 1.4 minutes.
  • Normal phase silica gel flash chromatography was performed using pre-packed Isco RediSepRf regular or high performance (Isco Gold) columns as well as specialty capped silicagel columns such as Isco Gold Amine, Isco Gold Diol, Isco Gold Cyano as specified in the Examples.
  • Reverse phase chromatography was performed using pre-packed Isco RediSepRf reverse phase columns such as Isco C18 and Isco Gold C18Aq.
  • the crude material was purified by silica gel chromatography (40 g column; 0-100% ethyl acetate/heptane) to give 4- chloro-2-cyclopropyl-5-fluoro-6-[4-(oxetan-3-yl)piperazin-l-yl]pyrimidine (1.49 g, 97%) as a white solid.
  • the reaction was stirred at 70 °C for 1 hour. Ethyl acetate and water were added, the aqueous layer was extracted with ethyl acetate and the combined organic layers were concentrated. The crude material was purified by silica gel chromatography (12g Gold column (ISCO); 0-10% methanol/dichloromethane).
  • the pure trifiuoroacetic acid salt was neutralized by passing through a PL-HCO 3 MP SPE cartridge (100 mg, loading level 1.8 mmol/g) to provide, after concentration, 2-cyclopropyl-N-(5-(3,3- difluorocyclobutyl)-lH-pyrazol-3-yl)-5-fluoro-6-(4-(oxetan-3-yl)piperazin-l- yl)pyrimidin-4-amine (Cmpd 40).
  • the reaction mixture was filtered and purified by reverse phase HPLC using an acetonitrile/water gradient with a trifluoroacetic acid modifier.
  • the pure trifluoroacetic acid salt was neutralized by passing through a PL-HCO 3 MP SPE cartridge (500 mg, loading level 1.8 mmol/g) to provide, after concentration, 2-cyclopropyl-N-[5-(3,3-difluorocyclopentyl)-lH- pyrazol-3-yl]-5-fluoro-6-[4-(oxetan-3-yl)-l-piperidyl]pyrimidin-4-amine, 101 (26.4 mg, 44%).
  • Peak 1 6-chloro-2-cyclopropyl-5-fluoro-N-(5-((lr,3r)-3-fluorocyclobutyl)-lH-pyrazol-3- yl)pyrimidin-4-amine, 86 (106 mg, 8%).
  • Peak 2 6-chloro-2-cyclopropyl-5-fluoro-N-(5-((ls,3s)-3-fluorocyclobut l)- lH-pyrazol-3-yl)pyrimidin-4-amine, 87 (85 mg, 6%).
  • 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 ⁇ ⁇ .
  • mice 24 hours prior to the start of dosing, 6 to 10 mice are switched from cuprizone chow to normal chow (Picolab rodent diet 20 EXT IRR 5053, irradiated) without added cuprizone. These mice are maintained on normal chow throughout the course of dosing.
  • mice per group 6 to 10 mice per group are randomized into new cages such that mice that are housed in one cage during the cuprizone diet are not housed together in one dose group during the study.
  • mice can be dosed with compound in one of two regimens:
  • Regimen A mice are dosed QD or BID for 14 days via oral gavage.
  • Regimen B mice are dosed QD or BID for 14 days via IP injection.
  • other dosing schedules and/or routes of administration may also be used.
  • mice are transcardially perfused with 12 ml of PBS (Sigma, P4417) followed by 20 ml of 3.2% paraformaldehyde in PBS (Electron Microscopy Sciences # 15714-S).
  • PBS Pulsham Standard Eagle's Base
  • the brains are removed via standard dissection techniques and each is postfixed in 3.2% paraformaldehyde (20 ml) for 24- 48 hours at room temperature in sealed scintillation vials.
  • Tissue sections are stained using an automated system for processing blots (hereinafter the "blotinator") (described in WO2011/087646 and US Patent numbers US 8,337,754 and US 8,679,406 each of which is incorporated herein by reference in its entirety). Brain sections are placed in the blotinator plate and bathed in PBS. The blotinator applies primary antibodies (MOG and MBP together) and Hoechst nuclear stain for 12 hours at room temperature with constant shaking.
  • blotinator automated system for processing blots
  • MBP Myelin basic Protein
  • Myelin Oligodendrocyte Glycoprotein (MOG) (R&D systems Cat # AF2439) is diluted at a 1 :250 ratio in blocking buffer.
  • Antibodies are diluted in blocking buffer, which consists of 0.3% Triton X-100 (Sigma Cat # 234729), 0.02% Sodium Azide (Sigma Cat# S2002) and 8% fetal bovine serum in PBS (Sigma Cat# F2442).
  • Alexa 488 donkey anti-rat secondary (Life technologies Cat# A-21208) is diluted at 1 : 1000 in blocking buffer.
  • Alexa 568 donkey anti-goat secondary (Life technologies Cat# A- 11057) is diluted at 1 : 1000 in blocking buffer.
  • Antibodies are also diluted in blocking buffer described above.
  • a custom algorithm developed in house, is used to quantify the amount of new myelin in mice that has been demyelinated with cuprizone and subsequently is treated with compounds.
  • the software subtracts a mature myelin marker from a pan-myelin (young and old myelin) marker, and measures the area of the remaining "new" myelin.
  • Myelin oligodendrocyte glycoprotein (“MOG) is specific to old myelin
  • MBP myelin basic protein
  • This process accounts for the variability inherent in the demyelination process, in which some animals experience more demyelination than others. It more accurately measures myelin generated in response to compound treatment.
  • the MOG channel is loaded and the Definiens "Auto Threshold" function is used to distinguish MOG positive regions from background. Regions of putative white matter with areas ⁇ 50 pixels are returned to the tissue class. Thus, remaining white matter tracts that resist demyelination from cuprizone are excluded from subsequent analyses.
  • the ratio of MBP signal to MOG signal is calculated. This consists of the mean MBP intensity value divided by the mean MOG intensity value over the entirety of the image.
  • This MBP: MOG ratio is used to normalize the intensity between the MBP and MOG channels.
  • the normalized MOG signal multiplied by 0.5 is subtracted from the MBP signal, creating a new image, "MBP-MOG".
  • the "Auto Threshold" function is used on the MBP-MOG image, and the 'new' myelin consisting of pixels with intensities above the threshold is delineated. Regions of putative new myelin with areas ⁇ 2 pixels are returned to the tissue class, and the number of pixels positive for "new" myelin is measured.
  • the algorithm returns the area of the tissue and the MBP positive, MOG negative 'new' myelin. Each section is normalized by area relative to its comparable tissue (e.g., the first). Most anterior sections are normalized relative to other first anterior sections. The 5 normalized MBP+/MOG- areas are summed, yielding a total positive area per sample. This yields a representation of myelin synthesis over the whole extent of the brain, excluding the olfactory bulb and the cerebellum.
  • Compound of the present invention may be tested in the in vivo Mouse Cuprizone assay described above.
  • oligodendrocyte precursor cells oligodendrocyte precursor cells
  • oligodendrocytes oligodendrocytes
  • astrocytes oligodendrocytes
  • microglia The assay quantifies myelination by measuring myelin basic protein (MBP)
  • Tissue from 1-3 pups was collected and placed into 15 ml conical tubes in a total volume of 5 ml of Complete Dissociation Medium.
  • Activated papain (3 ml) was added to each 15 ml conical tube and tissue was incubated at 37°C for 30 minutes. After the 30 minute incubation, DNase (Sigma D4527; 75 ⁇ of a 1 mg/ml stock) was added to each tube, followed by mechanical trituration using a 2 ml serological pipette and autopipettor to gently dissociate the tissue. Following trituration, larger tissue pieces were allowed to settle by gravity, and the supernatant containing dissociated cells was transferred to a 50 ml conical tube with 4 ml of trypsin inhibitor.
  • Cells were pelleted by centrifugation, resuspended in myelination medium and filtered through a 40 ⁇ filter. Cells were then seeded in 96-well plates (BD Biosciences, Black, PDL- coated, Cat. No. 356640) or in some cases in 384-well plates at 87,500-95,000 cells/well in a final volume of 200 ⁇ 1 of Myelination Medium in the presence or absence of compound and cultured for 14 days in a humidified 37°C incubator with 5% CO2. Half the medium was removed and replaced with fresh medium containing IX compound on days 6 and 10.
  • the Vertex myelin detection software was used to quantify the amount of myelin wrapping axons in a digital image that was obtained from our in-house microscope.
  • the software identified and traced MBP positive ridge like structures in the image that were indicative of myelinating axons.
  • a confounding factor in the analysis was the large debris fields typically occurring in the images. These fields resulted from the assay conditions required to achieve myelination. Special care was taken to ensure that noise in the image induced by the debris field was appropriately suppressed so that the signal that arose from the myelination could be recovered.
  • the software was written in the Jython programming language and made significant utilization of the Fiji image analysis toolkits (see, Schindelin, J.; Arganda-Carreras, I. & Frise, E. et al, "Fiji: an open-source platform for biological- image analysis", Nature Methods 9(7): 676-682, 2012). There were several steps to the algorithm, each of which are discussed below.
  • Morphological skeletonization was applied to the binary mask and the resulting image was then converted to a graph data structure.
  • Each node of the graph represented a pixel of the image. Owing to the skeletonizaiton process, each node was connected to at most 4 neighboring pixels. Nodes connected to one other node indicated the end of a myelin strand ("end nodes"); nodes connected to exactly two other nodes indicated a pixel contained in a myelin strand (“myelin node”); while nodes connected to 3 or 4 other nodes indicated regions where myelin strands intersect ("join nodes").
  • Neighboring 'myelin nodes' that were adjacent to the same "join node” were merged into longer strands of myelin. This process was done in a greedy fashion. The longest strand of myelin originating from an "end node” in the graph was identified. If this strand terminated in an end node the strand was extracted from the graph. If the strand terminated at a "join node” then it was joined with one of the other myelin strands adjacent to the same join node. The largest angle between the growing strand and all other strands adjacent to the join node was determined. If this angle was greater or equal to 140 degrees, then the growing strand and the strand that made this large angle were merged into one strand.
  • the two strands that were merged were removed from being adjacent to the "join node". If the angle was less than 140 degrees, the growing strand was extracted from the graph and removed as being adjacent to the join node. The entire process was repeated until all strands were removed from the graph.
  • Various geometric properties of the strand such as length and maximum curvature were computed from the number of pixels in the strand and the connectivity of the graph.
  • the strand needed to be of a sufficient length (at least greater than 40 pixels). To ensure the strand was not overly curved, the ratio of the geometric distance between strand endpoints to the length of the strand needed to be greater than or equal to 0.8. Finally, to ensure the strand was not overly thick, the gray scale gradient at each point on the strand in the directions orthogonal to the strand direction needed to decay sufficiently rapidly. Specifically, the gray scale needed to decrease by 25% from the gray scale value of pixel intersected by the orthogonal line and the putative myelin strand. This decrease needed to occur within 5 pixels. If a strand passes all quality checks it was quantified as myelin.
  • lOx Dissociation Media lOx DM was prepared on a 1 liter scale by combining 900 mM Na2S04, 300 mM K2S04, 58 mM MgC12, 2.5 mM CaC12, 10 mM HEPES and 20 mL of a phenol red solution (0.5%). The pH was adjusted with . IN NaOH by eye until orange-red. The solution was then sterilized by Alteration through a 0.2uM filter (prewashed with 100 ml of deionized sterile water which was discarded prior to filtration of the DM media solution.
  • KyMg stock was prepared on a 200 mL scale as follows. To a 250 mL flask was added 190 mL of water, 1 mL of phenol red (Sigma P0290), stock, 1.75 mL of IN NaOH, 378 mg of kynurenic acid, and 2 mL 500 mM HEPES. The mixture was then sonicated to dissolve the kynurenate and then MgC12 (4.1 ml of a 4.9 M solution) was added. The pH was adjusted to 7.4 by adding up to 1 ml of 0.1N NaOH and the mixture sterilized by filtration through a prewashed nylon filter
  • Papain Enzyme Solution (Worthinaton Biochemical. LK003178): A 10 units/mL stock solution was made fresh the day of dissection by adding lmL of lOmM NaOH and Complete Dissociation Medium to one vial of papain (-100 units) to give a 10 units/mL final concentration. The papain was activated at 37 °C for 10- 15 minutes prior to use.
  • Trypsin Inhibitor Solution 9.6mL of Complete Dissociation Medium was added to 100 mg of trypsin inhibitor (type II-O; Sigma T-9253) and the mixture was sonicated. The pH was adjustedto -5.75 using IN NaOH and pH strips. Aliquots (4 mL) were measured out and and stored at -20 °C.
  • DNase I Solution lmg/mL Added 25 mL DMEM/F12 medium (Corning, 10-092-CM) to 20 KU DNAse I (Sigma D4527) and aliquoted into one time use aliquots stored at -20° C.
  • Pen Strep (1 : 100) 10,000 units/mL (Cat # Gibco 15140122)
  • PDGF/FGF 0.3 ng/mL each (3 uL per 100 mL; PeproTech, cat #100-13 A and cat #100-18B
  • Myelination medium was made fresh the day of use from a stock bottle of DMEM containing pencillin/streptomycin and Glutamax, which was stored at 4° C for up to one month. On the day of use, 1 :50 B27, 1% FBS and 0.3ng/mL of PDGF and FGF were added to the DMEM containing pencillin/streptomycin and Glutamax.

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Abstract

L'invention concerne des composés de triazole de formule (I) ou des sels pharmaceutiquement acceptables de ceux-ci, utiles en tant que modulateurs de maladies démyélinisantes. L'invention concerne également des compositions pharmaceutiquement acceptables comprenant les composés de l'invention, des procédés d'utilisation des compositions et des kits associés dans le traitement de diverses maladies démyélinisantes et neurodégénératives, notamment la sclérose en plaques.
PCT/US2017/064627 2016-12-06 2017-12-05 Pyrazoles pour le traitement de maladies démyélinisantes WO2018106641A1 (fr)

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CN114728007A (zh) * 2019-09-12 2022-07-08 达萨玛治疗公司 Sarm1的抑制剂
WO2023097234A1 (fr) * 2021-11-23 2023-06-01 Genentech, Inc. Modulateurs spirocycliques de la biosynthèse du cholestérol et leur utilisation pour favoriser la remyélinisation

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