WO2015066697A1 - Morpholinopyrimidines fusionnées et procédés d'utilisation de ces dernières - Google Patents

Morpholinopyrimidines fusionnées et procédés d'utilisation de ces dernières Download PDF

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Publication number
WO2015066697A1
WO2015066697A1 PCT/US2014/063884 US2014063884W WO2015066697A1 WO 2015066697 A1 WO2015066697 A1 WO 2015066697A1 US 2014063884 W US2014063884 W US 2014063884W WO 2015066697 A1 WO2015066697 A1 WO 2015066697A1
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phenyl
amine
pyrimido
oxazin
dihydro
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PCT/US2014/063884
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English (en)
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Duane A. Burnett
Matthew Gregory Bursavich
Andrew J. Mcriner
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Forum Pharmaceuticals Inc.
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Publication of WO2015066697A1 publication Critical patent/WO2015066697A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • This application relates generally to fused morpholinopyrimidine compounds. More specifically, the application relates to the use of the fused morpholinopyrimidine compounds for the treatment of neurological disease.
  • AD Alzheimer's disease
  • ⁇ -amyloid peptide ⁇
  • APP amyloid precursor protein
  • APP is initially processed by ⁇ -secretase forming a secreted peptide and a membrane bound C99 fragment.
  • the C99 fragment is subsequently processed by the proteolytic activity of ⁇ -secretase. Multiple sites of proteolysis on the C99 fragment lead to the production of a range of smaller peptides ( ⁇ 37-42 amino acids).
  • N-terminal truncations can also be found e.g., ⁇ (4-42).
  • notations ⁇ 40 and ⁇ 42, as used herein, include these N-terminal truncated peptides.
  • the ⁇ peptides Upon secretion, the ⁇ peptides initially form soluble aggregates which ultimately lead to the formation of insoluble deposits and plaques.
  • ⁇ 42 is believed to be the most neurotoxic; the shorter peptides have less propensity to aggregate and form plaques.
  • ⁇ plaques in the brain are also associated with cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, multi infarct dementia, dementia pugilistisca and Down's Syndrome.
  • ⁇ -secretase is an association of four proteins: Aphl, nicastrin, presenilin and Pen- 2 (review De Strooper, Neuron 38:9-12 (2003)). Subjects carrying particular mutations in one of these components, presenilin, show increased ⁇ 42/ ⁇ 40 ratio. These mutations are correlated with early onset familial AD. Inhibition of ⁇ -secretase resulting in the lowering of ⁇ 42 has been investigated by the pharmaceutical community, and numerous inhibitors have been found. See, e.g., Thompson et al. ⁇ Bioorg. Med. Chem. Lett. 2006, 16, 2357-63), Shaw et al. ⁇ Bioorg. Med. Chem. Lett.
  • NSAIDs nonsteroidal, anti-inflammatory drugs
  • Flurbiprofen for example Flurbiprofen
  • Other publications that disclose agents said to reduce ⁇ 42 through the modulation of ⁇ -secretase include: WO 2004/074232, WO
  • a compound of Formula (I), Formula ( ⁇ ) or a pharmaceutically acceptable salt thereof (also referred to herein as a "Fused Morpholinopyrimidine”) is useful for treating, preventing or ameliorating symptoms of a neurodegenerative disease.
  • the invention provides a compound of Formula (I)
  • R is phenyl, -C1-C4 alkylene-phenyl, tetrahydro-2H-pyranyl, -C1-C4 alkylene-tetrahydro-2H- pyranyl, -Ci-C 6 alkyl, -C3-C8 monocyclic cycloalkyl, 3- to 7-membered monocyclic heterocycle, -C1-C4 alkylene-nitrogen containing 3- to 7-membered monocyclic heterocycle , -C1-C4 alkylene- C3-C8 monocyclic cycloalkyl or -C1-C4 alkylene-nitrogen containing 3- to 7-membered monocyclic heterocycle, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -CN, -NH 2 , oxo, -C1-C4 alkyl, halo-substituted C1-
  • R is phenyl, -C1-C4 alkylene-phenyl, tetrahydro-2H- pyranyl,
  • -C1-C4 alkylene-tetrahydro-2H-pyranyl or halo-substituted C1-C4 alkyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, oxo, -C1-C4 alkyl, C 3 -Cg monocyclic cycloalkyl, -0-C 3 -Cg
  • Y is phenyl or pyridinyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo and -C 1 -C 4 alkoxy.
  • Z is pyridinyl, imidazolyl, pyrimidinyl or pyridazinyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, - C 1 -C 4 alkyl and -C 1 -C 4 alkoxy.
  • R is phenyl, -C 1 -C 4 alkylene -phenyl, tetrahydro-2H- pyranyl,
  • Y is phenyl or pyridinyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo and -C 1 -C 4 alkoxy; and Z is pyridinyl, imidazolyl, pyrimidinyl or pyridazinyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C 1 -C 4 alkoxy; and Z is pyridinyl, imidazolyl, pyrimidinyl or pyridazinyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consist
  • R is phenyl, -C 1 -C 4 alkylene -phenyl or halo-substituted Ci- C 4 alkyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C 1 -C 4 alkyl, C 3 -Cg monocyclic cycloalkyl, -0-C 3 -Cg monocyclic cycloalkyl, -CF 3 and -OCF 3 ; Y is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo and -C 1 -C 4 alkoxy; and Z is pyridinyl or imidazolyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C 1 -C 4 alkyl and -
  • R is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C 1 -C 4 alkyl, C 3 -Cg monocyclic cycloalkyl, -CF 3 and -OCF 3 ;
  • Y is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo and -C 1 -C 4 alkoxy;
  • Z is pyridinyl or imidazolyl, each of which is unsubstituted or substituted with one or more substituents independently selected from -halo and -C 1 -C 4 alkyl.
  • R is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C 1 -C 4 alkyl, C 3 -C 8 monocyclic cycloalkyl, -CF 3 and -OCF 3 .
  • R is phenyl substituted with -CI or -F. [0017] In some embodiments, R is phenyl substituted with -halo and -CF 3 .
  • R is phenyl substituted with -halo and -OCF 3 .
  • R is phenyl substituted with -halo and -C 1 -C 4 alkyl.
  • R is phenyl substituted with -halo and C 3 -C 8 monocyclic cycloalkyl.
  • -C 1 -C 4 alkyl is methyl.
  • R is phenyl substituted with one methyl.
  • Ris tetrahydro-2H-pyranyl [0027] In some embodiments, Ris tetrahydro-2H-pyranyl.
  • Ris -CH 2 -tetrahydro-2H-pyranyl are examples of substituents.
  • R is -CH 2 -phenyl.
  • R is -CH 2 CH 2 -phenyl.
  • R is -CH 2 -phenyl substituted with -halo or -C 1 -C 4 alkyl.
  • R is -CH 2 CF 3 .
  • Y is phenyl which is unsubstituted or substituted with one to three substituents independently selected from the group consisting of -halo and -C 1 -C 4 alkoxy.
  • Y is phenyl substituted with one to three -F.
  • Y is phenyl substituted with one -F.
  • Y is phenyl substituted with one methoxy.
  • Z is pyridinyl, which is unsubstituted or substituted with one to three substituents independently selected from the group consisting of -halo, -C 1 -C 4 alkyl and
  • Z is pyridinyl substituted with one to three -CI.
  • Z is pyridinyl substituted with one -CI.
  • Z is pyridinyl substituted with one methyl.
  • Z is pyridinyl substituted with one methoxy.
  • Z is imidazolyl, which is unsubstituted or substituted with one to three substituents independently selected from the group consisting of -halo and -Ci-
  • Z is imidazolyl substituted with one to three -CI.
  • Z is imidazolyl substituted with one -CI.
  • Z is imidazolyl substituted with one methyl.
  • Z is pyrimidinyl which is unsubstituted or substituted with one to three -C 1 -C4 alkyl.
  • Z is pyrimidinyl substituted with one methyl.
  • Z is pyridazinyl
  • the compound of Formula (I) is N-(2-aminoethyl)-2-aminoethyl
  • the compound of Formula (I) is N-(3-methoxy-4-(2- methylpyridin-4-yl)phenyl)-8-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][l,4]oxazin-2-amine;
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier or vehicle and an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention provides a method for treating a neurodegenerative disease, comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable salt of a compound of Formula (I).
  • the invention provides a method for treating Alzheimer's disease, comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable salt of a compound of Formula (I).
  • the invention provides a method for improving an impaired cognitive function, comprising administering to a subject having impaired cognitive function an effective amount of a compound or a pharmaceutically acceptable salt of a compound of Formula (I).
  • the subject has impaired cognitive function relative to a healthy subject, for example a healthy subject of the same age.
  • the invention provides a method for ameliorating a symptom of Alzheimer's disease, comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable salt of a compound of Formula (I).
  • the symptom of Alzheimer's disease is progressive loss of memory, progressive loss of cognition, progressive loss of reasoning and/or progressive loss of judgment.
  • Alzheimer's disease is early onset Alzheimer's disease.
  • the subject is a human.
  • Exemplary neurodegenerative disease include Alzheimer's disease, early onset Alzheimer's disease, panic disorder, obsessive compulsive disorder, delusional disorder, drug-induced psychosis, post-traumatic stress disorder, age-related cognitive decline, attention deficit/hyperactivity disorder, personality disorder of the paranoid type, personality disorder of the schizoid type, dyskinesia, choreiform condition, psychosis associated with Parkinson's disease, psychotic symptoms associated with Alzheimer's disease, mood disorder, dementia, cognitive impairment, myclonus, seizures, Parkinsonism, extrapyramidal signs (EPS), apraxia, dystonia, dementia with Lewy bodies (DLB), aphasia, visual agnosia, and ataxia.
  • EPS extrapyramidal signs
  • the cognitive function impaired is one or more of attention, learning, delayed memory, working memory, visual learning, speed of processing, vigilance, verbal learning, visual motor function, social cognition, long term memory or executive function.
  • the subject is 65 years old or older. In other embodiments, the subject is 55 years old or older. In still other embodiments, the subject is 55 years old or younger, or 50 years old or younger.
  • a pharmaceutical composition comprising an effective amount of a Fused Morpholinopyrimidine of Formula (I) and a pharmaceutically acceptable carrier or vehicle is useful for treating or preventing a neurodegenerative disease.
  • the invention provides a compound of Formula ( ⁇ )
  • R is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -CN, -NH 2 , -C 1 -C4 alkyl, halo- substituted C 1 -C4 alkyl, amino-substituted C r C 4 alkyl, -NH-C C 4 alkyl, -NHC(0)-C C 4 alkyl,
  • R is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C 1 -C 4 alkyl, C3-C 8 monocyclic cycloalkyl, -CF 3 and -OCF 3 ; or a pharmaceutically acceptable salt thereof.
  • Y is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo and -C 1 -C 4 alkoxy.
  • Z is pyridinyl or imidazolyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of
  • R is phenyl which is unsubstituted; Y is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo and -C 1 -C 4 alkoxy; Z is pyridinyl or imidazolyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -C 1 -C 4 alkyl and -C 1 -C 4 alkoxy; and each R 1 is independently -H or -Ci- C 6 alkyl; and each R 2 is independendently -H or -Ci-C 6 alkyl.
  • R is phenyl which is unsubstituted; Y is phenyl which is substituted with one or more substituents independently selected from the group consisting of -halo and -C 1 -C 4 alkoxy; Z is pyridinyl or imidazolyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -C 1 -C 4 alkyl and -C 1 -C 4 alkoxy; and each R 1 is independently -H or -Ci-C 6 alkyl; and each R 2 is independently -H or -Ci-C 6 alkyl.
  • R is phenyl which is unsubstituted; Y is phenyl which is substituted with one or more substituents independently selected from the group consisting of -halo and -C 1 -C 4 alkoxy; Z is pyridinyl or imidazolyl, each of which is substituted with one or more substituents independently selected from the group consisting of -C 1 -C 4 alkyl and - C 1 -C 4 alkoxy; and each R 1 is independently -H or -Ci-C 6 alkyl; and each R 2 is independently -H or -Ci-C 6 alkyl.
  • R is phenyl which is unsubstituted; Y is phenyl which is substituted with one or more substituents independently selected from the group consisting of -halo and -C 1 -C 4 alkoxy; Z is pyridinyl which is substituted with one or more -C 1 -C 4 alkoxy; and each R 1 is independently -H or -Ci-C 6 alkyl; and each R 2 is independently -H or -Ci-C 6 alkyl.
  • R is phenyl which is unsubstituted; Y is phenyl which is substituted with one or more substituents independently selected from the group consisting of -halo and -C 1 -C 4 alkoxy; Z is imidazolyl, each of which is substituted with one or more -Ci- C 4 alkyl; and each R 1 is independently -H or -Ci-C 6 alkyl; and each R 2 is independently -H or -Ci-C 6 alkyl.
  • R is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C 1 -C 4 alkyl, C3-C8 monocyclic cycloalkyl, -CF 3 and -OCF 3 .
  • R is phenyl which is substituted with one or more substituents independently selected from the group consisting of -halo, -C 1 -C 4 alkyl, C 3 -Cg monocyclic cycloalkyl, -CF 3 and -OCF 3 .
  • R is phenyl which is unsubstituted.
  • -C 1 -C 4 alkyl is methyl.
  • -C 1 -C 4 alkoxy is methoxy
  • Y is phenyl which is unsubstituted or substituted with one to three substituents independently selected from the group consisting of -halo and -C 1 -C 4 alkoxy.
  • Y is phenyl substituted with one to three -F.
  • Y is phenyl substituted with one -F.
  • Y is phenyl substituted with one methoxy.
  • Z is pyridinyl, which is unsubstituted or substituted with one to three substituents independently selected from the group consisting of -halo, -C 1 -C 4 alkyl and
  • Z is pyridinyl substituted with one methoxy.
  • Z is imidazolyl, which is unsubstituted or substituted with one to three substituents independently selected from the group consisting of -halo and -Ci- C 4 alkyl.
  • Z is imidazolyl substituted with one methyl.
  • each R 1 is -H. In some embodiments, one R 1 is -H.
  • each R 2 is -H. In some embodiments, one R 2 is -H.
  • each of R 1 and R 2 is independently -Ci-C 6 alkyl.
  • each R 1 is independently -Ci-C 6 alkyl and each R 2 is -H.
  • each R 2 is independently -Ci-C 6 alkyl and each R 1 is -H.
  • one R 1 is -H and the other R 1 is -Ci-C 6 alkyl and each R 2 is -H.
  • one R 2 is -H and the other R 2 is -Ci-C 6 alkyl and each R 1 is -H. [0092] In some embodiments, each R 1 is methyl. In some embodiments, each R 2 is methyl.
  • the compound of Formula ( ⁇ ) is selected from the group consisting of:
  • the compound of Formula ( ⁇ ) is selected from the group consisting of:
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier or vehicle and an effective amount of a compound of Formula ( ⁇ ) or a pharmaceutically acceptable salt thereof.
  • the invention provides a method for treating a neurodegenerative disease, comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable salt of a compound of Formula ( ⁇ ).
  • the invention provides a method for treating Alzheimer's disease, comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable salt of a compound of Formula ( ⁇ ).
  • the invention provides a method for improving an impaired cognitive function, comprising administering to a subject having impaired cognitive function an effective amount of a compound or a pharmaceutically acceptable salt of a compound of Formula ( ⁇ ).
  • the subject has impaired cognitive function relative to a healthy subject, for example a healthy subject of the same age.
  • the invention provides a method for ameliorating a symptom of Alzheimer's disease, comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable salt of a compound of Formula ( ⁇ ).
  • the symptom of Alzheimer's disease is progressive loss of memory, progressive loss of cognition, progressive loss of reasoning and/or progressive loss of judgment.
  • Alzheimer's disease is early onset Alzheimer's disease.
  • the subject is a human.
  • Exemplary neurodegenerative disease include Alzheimer's disease, early onset Alzheimer's disease, panic disorder, obsessive compulsive disorder, delusional disorder, drug-induced psychosis, post-traumatic stress disorder, age-related cognitive decline, attention deficit/hyperactivity disorder, personality disorder of the paranoid type, personality disorder of the schizoid type, dyskinesia, choreiform condition, psychosis associated with Parkinson's disease, psychotic symptoms associated with Alzheimer's disease, mood disorder, dementia, cognitive impairment, myclonus, seizures, Parkinsonism, extrapyramidal signs (EPS), apraxia, dystonia, dementia with Lewy bodies (DLB), aphasia, visual agnosia, and ataxia.
  • EPS extrapyramidal signs
  • the cognitive function impaired is one or more of attention, learning, delayed memory, working memory, visual learning, speed of processing, vigilance, verbal learning, visual motor function, social cognition, long term memory or executive function.
  • the subject is 65 years old or older. In other embodiments, the subject is 55 years old or older. In still other embodiments, the subject is 55 years old or younger, or 50 years old or younger.
  • a pharmaceutical composition comprising an effective amount of a Fused Morpholinopyrimidine of Formula ( ⁇ ) and a pharmaceutically acceptable carrier or vehicle is useful for treating or preventing a neurodegenerative disease.
  • -C 1 -C 4 alkyl refers to a straight chain or branched non-cyclic hydrocarbon having from 1 to 4 carbon atoms, wherein one of the hydrocarbon's hydrogen atoms has been replaced by a single bond.
  • Representative straight chain -C 1 -C 4 alkyls include -methyl, -ethyl, -n-propyl and -n-butyl.
  • Representative branched -C 1 -C 4 alkyls include
  • the -C 1 -C 4 alkyl is substituted.
  • -Ci-C 6 alkyl refers to a straight chain or branched non- cyclic hydrocarbon having from 1 to 6 carbon atoms, wherein one of the hydrocarbon's hydrogen atoms has been replaced by a single bond.
  • Representative straight chain -Ci-C 6 alkyls include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl and -n-hexyl.
  • -Ci-C 6 alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, -1-methylbutyl, -isohexyl, -neohexyl, -2-methylbutyl, -3-methylbutyl, -1,1-dimethylpropyl and
  • -Ci-C 6 alkyl is substituted.
  • -C 3 -C 8 monocyclic cycloalkyl refers to a saturated cyclic hydrocarbon having from
  • Representative -C 3 -C 8 monocyclic cycloalkyls include -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl and -cyclooctyl. In one embodiment, the -C3-C8 monocyclic cycloalkyl is substituted.
  • C 1 -C 4 alkylene refers to a straight or branched chain saturated hydrocarbon containing 1-4 carbon atoms, wherein two of the hydrocarbon's hydrogen atoms have been replaced by a single a bond.
  • Representative C 1 -C 4 alkylene groups include, methylene, ethylene, n-propylene, isopropylene, n-butylene and isobutylene.
  • C 1 -C 4 alkoxy is a C 1 -C 4 alkyl-O- group wherein the C 1 -C 4 alkyl is as defined above.
  • Examples of C 1 -C 4 alkoxy include, but are not limited to, methoxy, trifluoromethoxy, ethoxy, propoxy or butoxy.
  • Halo-substituted C 1 -C 4 alkoxy refers to a C 1 -C 4 alkoxy group, as defined above, wherein one or more of the C 1 -C 4 alkoxy group's hydrogen atoms have been replaced with - F,
  • halo-substituted C 1 -C 4 alkoxy examples include, but are not limited to, -0-CH 2 F, -O-CCI 3 , -O-CF 3 , -0-CH 2 Cl, -0-CH 2 CH 2 Br, -0-CH 2 CH 2 I, -0-CF 2 CF 3 , -O- CH 2 CH 2 CH 2 F, -0-CH 2 CH 2 CH 2 Cl, -0-CH 2 CH 2 CH 2 CH 2 Br, -0-CH 2 CH 2 CH 2 CH 2 I, -O- CH 2 CH(Br)CH 3 , -0-CH 2 CH(Cl)CH 2 CH 3 , -0-CH(F)CH 2 CH 3 and -0-C(CH 3 ) 2 (CH 2 Cl).
  • amino-substituted C 1 -C 4 alkoxy refers to a C 1 -C 4 alkoxy group, as defined above, wherein one or more of the C 1 -C 4 alkoxy group's hydrogen atoms have been replaced with
  • amino-substituted C 1 -C 4 alkoxy examples include, but are not limited to, -O- CH 2 NH 2 , -0-CH 2 CH 2 NH 2 , -0-CH(NH 2 )CH 3 , -0-CH 2 CH 2 CH 2 NH 2 , -O- CH 2 CH 2 CH 2 CH 2 NH 2 , -0-CH 2 CH(NH 2 )CH 3 , -0-CH(NH 2 )CH 2 CH 3 and -O- C(CH 3 ) 2 (CH 2 NH 2 ).
  • a "nitrogen containing 3- to 7-membered monocyclic heterocycle” refers to a monocyclic 3- to 7-membered aromatic or non-aromatic monocyclic cycloalkyl group in which one of the cycloalkyl group's ring carbon atoms has been replaced with a nitrogen atom and 0-4 of the cycloalkyl group's remaining ring carbon atoms are independently replaced with a N, O or S atom.
  • the nitrogen-containing 3- to 7-membered monocyclic heterocycles can be attached via a nitrogen or carbon atom.
  • nitrogen-containing 3- to 7-membered monocyclic heterocycles include, but are not limited to, piperidinyl, piperazinyl, pyrrolyl, piperidonyl, oxazinyl, thiazinyl, diazinyl, triazinyl, tetrazinyl, imidazolyl, tetrazolyl, pyrrolidinyl, isoxazolyl, pyridinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, pyrimidinyl, morpholinyl, furuzanyl, pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, pyrazolidinyl and thiomorpholinyl.
  • the nitrogen-containing 3- to 7-membered monocyclic heterocycle is fully saturated or partially saturated.
  • the nitrogen-containing 3- to 7-membered monocyclic heterocycle is substituted with one or more of -halo, -CF 3 , -CN, -OH, -C 1 -C 4 alkyl, -C 1 -C 4 alkoxy or -OCF 3 . Unless otherwise indicated, the nitrogen-containing 3- to 7-membered monocyclic heterocycle is unsubstituted.
  • a "3- to 7-membered monocyclic heterocycle” refers to a monocyclic 3- to 7- membered aromatic or non-aromatic monocyclic cycloalkyl in which 1-4 of the ring carbon atoms have been independently replaced with a N, O or S atom.
  • the 3- to 7- membered monocyclic heterocycles can be attached via a nitrogen or carbon atom.
  • 3- to 7-membered monocyclic heterocycle group include, but are not limited to, nitrogen-containing 3- to 7-membered monocyclic heterocycles discussed above, tetrahydrofuranyl, dihydrofuranyl, pyranyl, dihydropyranyl, tetrahydropyranyl, thiopyranyl, dihydrothiopyranyl, tetrahydrothiopyranyl, dioxanyl, dithianyl, trithianyl, dioxolanyl, furanyl and thiophenyl.
  • the 3- to 7-membered monocyclic heterocycle is a nitrogen-containing 3- to 7-membered monocyclic heterocycle.
  • the 3- to 7-membered monocyclic heterocycle is saturated or partially saturated.
  • halogen or halo refer to chlorine, bromine, fluorine or iodine.
  • Halo-substituted C 1 -C 4 alkyl refers to a C 1 -C 4 alkyl group, as defined above, wherein one or more of the C 1 -C 4 alkyl group's hydrogen atoms have been replaced with -F, - CI, -Br or -I.
  • Examples of a halo-substituted C 1 -C 4 alkyl include, but are not limited to, -CH 2 F, -CCI 3 , -CF 3 , -CH 2 CI, -CH 2 CH 2 Br, -CH 2 CH 2 I, -CF 2 CF 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CH 2 C1, -CH 2 CH 2 CH 2 CH 2 Br, -CH 2 CH 2 CH 2 CH 2 I, -CH 2 CH(Br)CH 3 , -CH 2 CH(C1)CH 2 CH 3 , - CH(F)CH 2 CH 3 and -C(CH 3 ) 2 (CH 2 C1).
  • amino-substituted C 1 -C 4 alkyl refers to a C 1 -C 4 alkyl group, as defined above, wherein one or more of the C 1 -C 4 alkyl group's hydrogen atoms have been replaced with - NH 2 .
  • Examples of amino-substituted C 1 -C 4 alkyl include, but are not
  • Halo-substituted phenyl refers to a phenyl group, wherein one or more of the phenyl group's hydrogen atoms have been replaced with -F, -Cl,-Br or -I. The one or more -
  • F, -Cl,-Br or -I can be in ortho, meta and/or para position.
  • Representative examples of halo- substituted phenyl include, but are not limited to, -CeH 4 F, -C 6 H 3 CIF, -CH 3 CI 2 , -C 6 H 2 F 3 , -C 6 HC1 4 , -C 6 H 2 FC1I and -C 6 F 5 .
  • Ci-C 4 alkylene -phenyl refers to a Ci-C 4 alkyl group, as defined above, wherein one of the Ci-C 4 alkyl group's hydrogen atoms has been replaced with phenyl.
  • Ci-C 4 alkyl refers to a Ci-C 4 alkyl group, as defined above, wherein one or more of the Ci-C 4 alkyl group's hydrogen atoms have been replaced with - OH.
  • Representative examples of a hydroxy-substituted Ci-C 4 alkyl include, but are not limited to,
  • any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.
  • phrases "pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the Fused Morpholinopyrimidine from one organ, or portion of the body, to another organ, or portion of the body.
  • a pharmaceutically acceptable material, composition or vehicle such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the Fused Morpholinopyrimidine from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject.
  • materials which can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn 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 as butylene glycol; polyols, such as glycerin, sorbitol, mannitol and 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'
  • carrier denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application.
  • the components of the pharmaceutical compositions also are capable of being comingled with the compounds described herein, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficiency.
  • the compounds described herein may form salts which are also within the scope of this invention. Reference to a compound described herein is understood to include reference to salts thereof, unless otherwise indicated.
  • salt(s) denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases.
  • a compound described herein contains both a basic moiety, such as, but not limited to, amine, pyridine or imidazole and an acidic moiety, such as, but not limited to, a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein.
  • Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g., in isolation or purification steps which may be employed during preparation.
  • Salts of the compounds described herein may be formed, for example, by reacting a compound with an amount of acid or base, such as an equivalent amount, in a medium, such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • the compounds described herein which contain a basic moiety may form salts with a variety of organic and inorganic acids.
  • Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides
  • 2-naphthalenesulfonates 2-naphthalenesulfonates
  • nicotinates nitrates
  • oxalates nitrates
  • pectinates nitrates
  • persulfates nitrates
  • phenylpropionates e.g., 3-phenylpropionates
  • phosphates picrates, pivalates, propionates
  • salicylates succinates
  • sulfates such as those formed with sulfuric acid
  • sulfonates tartrates
  • thiocyanates toluenesulfonates, such as tosylates, undecanoates and the like.
  • the compounds described herein which contain an acidic moiety such as, but not limited to, a carboxylic acid, may form salts with a variety of organic and inorganic bases.
  • Exemplary basic salts include ammonium salts, alkali metal salts, such as sodium, lithium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases (for example, organic amines), such as benzathines, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl) ethylenediamine), N-methyl-D- glucamines, N-methyl-D-glycamides, t-butyl amines and salts with amino acids, such as arginine, lysine and the like.
  • organic bases for example, organic amines
  • organic amines such as benzathines, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl) ethylenediamine), N-methyl-D- glucamines, N-methyl-D-glycamides, t-butyl amines
  • Basic nitrogen-containing groups may be quaternized with agents, such as lower alkyl halides (e.g., methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.
  • agents such as lower alkyl halides (e.g., methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl and diamyl sulfates),
  • Prodrugs and solvates of the compounds described herein are also contemplated herein.
  • the term "prodrug” as employed herein denotes a compound that, upon
  • Solvates of the compounds described herein include, for example, hydrates.
  • compositions described herein are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 97%, equal to or greater than 98%, or equal to or greater than 99% of the compounds
  • All stereoisomers of the present compounds are contemplated within the scope of this invention.
  • Individual stereoisomers of the compounds described herein may, for example, be substantially free of other isomers (e.g., as a pure or substantially pure optical isomer having a specified activity), or may be admixed, for example, as racemates or with all other, or other selected,
  • the chiral centers of the compounds described herein may have the S or R configuration as defined by the International Union of Pure and Applied Chemistry (IUPAC) 1974 Recommendations.
  • the racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography.
  • the individual optical isomers can be obtained from the racemates by any suitable method, including without limitation, conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.
  • a particular enantiomer of a compound described herein may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
  • Isomeric mixtures containing any of a variety of isomer ratios may be utilized in accordance with the present invention. For example, where only two isomers are combined, mixtures containing 50:50, 60:40, 70:30, 80:20, 90: 10, 95:5, 96:4, 97:3, 98:2, 99: 1, or 100:0 isomer ratios are all contemplated by the present invention. Those of ordinary skill in the art will readily appreciate that analogous ratios are contemplated for more complex isomer mixtures.
  • the present invention also includes isotopically labeled compounds, which are identical to the compounds disclosed herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, U C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F and 36 C1, respectively.
  • isotopically labeled compounds can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • an effective amount refers to any amount that is necessary or sufficient for achieving or promoting a desired outcome, e.g., for treating, preventing, or ameliorating a symptom of a neurodegenerative disease. In some instances an effective amount is a therapeutically effective amount.
  • a therapeutically effective amount is any amount that is necessary or sufficient for promoting or achieving a desired biological response in a subject. The effective amount for any particular application can vary depending on such factors as the disease or condition being treated, the particular agent being administered, the size of the subject, or the severity of the disease or condition.
  • treat or “treating” includes reducing a symptom of a
  • neurodegenerative disease for example, improving cognitive function.
  • the term "subject" refers to a vertebrate animal.
  • the subject is a mammal.
  • the subject is a human.
  • the subject is a non-human vertebrate animal, including, without limitation, non-human primates, laboratory animals, livestock, domesticated animals and non- domesticated animals.
  • Non-limiting examples of subject include a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, and non-human primate, such as a monkey, chimpanzee, baboon or rhesus.
  • the subject is a human.
  • tautomeric forms for example, as an amide or imino ether.
  • the scope of this disclosure is meant to include all such tautomeric forms.
  • a tetrazole may exist in two tautomeric forms, 1-H tetrazole and a 2-H tetrazole. This is depicted in the figure below. This example is not meant to be limiting in the scope of tautomeric forms.
  • Fused Morpholinopyrimidines i.e., compounds according to Formula (I), Formula ( ⁇ ), and pharmaceutically acceptable salts thereof, as well as methods for preparing the compounds and using the compounds to treat one or more
  • GSMs gamma secretase modulators
  • the compounds alter the relative levels of ⁇ peptides produced by ⁇ -secretase, for example the level of ⁇ 42 peptide, without significantly changing the total level of ⁇ peptides produced.
  • R, Y and Z are as defined above for the compounds of Formula (I).
  • R is phenyl, -C 1 -C 4 alkylene-phenyl, tetrahydro-2H- pyranyl,
  • -C 1 -C 4 alkylene-tetrahydro-2H-pyranyl or halo-substituted C 1 -C 4 alkyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, oxo, -C 1 -C 4 alkyl, C 3 -C 8 monocyclic cycloalkyl, -O-C 3 -C 8 monocyclic cycloalkyl, -CF 3 and -OCF 3 .
  • Y is phenyl or pyridinyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo and -C 1 -C 4 alkoxy.
  • Z is pyridinyl, imidazolyl, pyrimidinyl or pyridazinyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, - C 1 -C 4 alkyl and -C 1 -C 4 alkoxy.
  • R is phenyl, -C 1 -C 4 alkylene -phenyl, tetrahydro-2H- pyranyl,
  • Y is phenyl or pyridinyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo and -C 1 -C 4 alkoxy; and Z is pyridinyl, imidazolyl, pyrimidinyl or pyridazinyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C 1 -C 4 alkoxy; and Z is pyridinyl, imidazolyl, pyrimidinyl or pyridazinyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consist
  • R is phenyl, -C 1 -C 4 alkylene -phenyl or halo-substituted Ci- C 4 alkyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C 1 -C 4 alkyl, C 3 -Cg monocyclic cycloalkyl, -0-C 3 -Cg monocyclic cycloalkyl, -CF 3 and -OCF 3 ; Y is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo and -C 1 -C 4 alkoxy; and Z is pyridinyl or imidazolyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C 1 -C 4 alkyl and -
  • R is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C 1 -C 4 alkyl, C 3 -Cg monocyclic cycloalkyl, -CF 3 and -OCF 3 ;
  • Y is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo and -C 1 -C 4 alkoxy;
  • Z is pyridinyl or imidazolyl, each of which is unsubstituted or substituted with one or more substituents independently selected from -halo and -C 1 -C 4 alkyl.
  • R is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C 1 -C 4 alkyl, C 3 -Cg monocyclic cycloalkyl, -CF 3 and -OCF 3 .
  • R is phenyl substituted with -CI or -F.
  • R is phenyl substituted with -halo and -CF 3 .
  • R is phenyl substituted with -halo and -OCF 3 .
  • R is phenyl substituted with -halo and -C 1 -C 4 alkyl.
  • R is phenyl substituted with -halo and C 3 -Cg monocyclic cycloalkyl.
  • Y is phenyl substituted with one to three -F.
  • Y is phenyl substituted with one -F.
  • Y is phenyl substituted with one methoxy.
  • Z is pyridinyl, which is unsubstituted or substituted with one to three substituents independently selected from the group consisting of -halo, -C 1 -C 4 alkyl and
  • Z is pyridinyl substituted with one to three -CI.
  • Z is pyridinyl substituted with one -CI.
  • Z is pyridinyl substituted with one methyl.
  • Z is pyridinyl substituted with one methoxy.
  • Z is imidazolyl, which is unsubstituted or substituted with one to three substituents independently selected from the group consisting of -halo and -Ci-
  • Z is imidazolyl substituted with one to three -CI.
  • Z is imidazolyl substituted with one -CI.
  • Z is imidazolyl substituted with one methyl.
  • Z is pyrimidinyl which is unsubstituted or substituted with one to three -C 1 -C4 alkyl. [0188] In some embodiments, Z is pyrimidinyl substituted with one methyl.
  • Z is pyridazinyl
  • Z is attached to Y at the 4 position of Y. In some embodiments, Z is attached to Y at the 4 position of Z. In some embodiments, Z is attached to Y at the 1 position of Z.
  • the compound of Formula (I) is a compound selected from the compounds in Table I.
  • the invention provides a compound of Formula ( ⁇ )
  • R is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -CN, -NH 2j -C 1 -C 4 alkyl, halo- substituted C1-C4 alkyl, amino-substituted C1-C4 alkyl, -NH-C1-C4 alkyl, -NHC(0)-Ci-C 4 alkyl,
  • R is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C 1 -C 4 alkyl, C 3 -C 8 monocyclic cycloalkyl, -CF 3 and -OCF 3 ; or a pharmaceutically acceptable salt thereof.
  • Y is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo and -C 1 -C 4 alkoxy.
  • Z is pyridinyl or imidazolyl, each of which is
  • R is phenyl which is unsubstituted; Y is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo and -C 1 -C 4 alkoxy; Z is pyridinyl or imidazolyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -C 1 -C 4 alkyl and -C 1 -C 4 alkoxy; and each R 1 is independendently -H or -Ci-C 6 alkyl; and each R 2 is independendently -H or -Ci-C 6 alkyl.
  • R is phenyl which is unsubstituted; Y is phenyl which is substituted with one or more substituents independently selected from the group consisting of -halo and -C 1 -C 4 alkoxy; Z is pyridinyl or imidazolyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -C 1 -C 4 alkyl and -C 1 -C 4 alkoxy; and each R 1 is independendently -H or -Ci-C 6 alkyl; and each R 2 is independendently -H or -Ci-C 6 alkyl.
  • R is phenyl which is unsubstituted; Y is phenyl which is substituted with one or more substituents independently selected from the group consisting of -halo and -C 1 -C 4 alkoxy; Z is pyridinyl or imidazolyl, each of which is substituted with one or more substituents independently selected from the group consisting of -C 1 -C 4 alkyl and - C 1 -C 4 alkoxy; and each R 1 is independendently -H or -Ci-C 6 alkyl; and each R 2 is
  • R is phenyl which is unsubstituted; Y is phenyl which is substituted with one or more substituents independently selected from the group consisting of -halo and -C 1 -C 4 alkoxy; Z is pyridinyl which is substituted with one or more -C 1 -C 4 alkoxy; and each R 1 is independendently -H or -Ci-C 6 alkyl; and each R 2 is independendently -H or -Ci-C 6 alkyl.
  • R is phenyl which is unsubstituted; Y is phenyl which is substituted with one or more substituents independently selected from the group consisting of -halo and -C 1 -C 4 alkoxy; Z is imidazolyl, each of which is substituted with one or more -Ci- C 4 alkyl; and each R 1 is independendently -H or -Ci-C 6 alkyl; and each R 2 is
  • R is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, -C 1 -C 4 alkyl, C3-C8 monocyclic cycloalkyl, -CF 3 and -OCF 3 .
  • R is phenyl which is substituted with one or more substituents independently selected from the group consisting of -halo, -C 1 -C 4 alkyl, C 3 -C 8 monocyclic cycloalkyl, -CF 3 and -OCF 3 .
  • R is phenyl which is unsubstituted.
  • -C 1 -C 4 alkyl is methyl.
  • -C 1 -C 4 alkoxy is methoxy.
  • Y is phenyl which is unsubstituted or substituted with one to three substituents independently selected from the group consisting of -halo and -C 1 -C 4 alkoxy.
  • Y is phenyl substituted with one to three -F.
  • Y is phenyl substituted with one -F.
  • Y is phenyl substituted with one methoxy.
  • Z is pyridinyl, which is unsubstituted or substituted with one to three substituents independently selected from the group consisting of -halo, -C 1 -C 4 alkyl and
  • Z is pyridinyl substituted with one methoxy.
  • Z is imidazolyl, which is unsubstituted or substituted with one to three substituents independently selected from the group consisting of -halo and -Ci- C 4 alkyl.
  • Z is imidazolyl substituted with one methyl.
  • each R 1 is -H. In some embodiments, one R 1 is -H.
  • each R 2 is -H. In some embodiments, one R 2 is -H.
  • each of R 1 and R 2 is independendently -Ci-C 6 alkyl.
  • each R 1 is independendently -Ci-C 6 alkyl and each R 2 is - H.
  • each R 2 is independendently -Ci-C 6 alkyl and each R 1 is - H.
  • one R 1 is -H and the other R 1 is -Ci-C 6 alkyl and each R 2 is -H.
  • one R 2 is -H and the other R 2 is -Ci-C 6 alkyl and each R 1 is -H.
  • each R 1 is methyl. In some embodiments, each R 2 is methyl.
  • Z is attached to Y at the 4 position of Y. In some embodiments, Z is attached to Y at the 4 position of Z. In some embodiments, Z is attached to Y at the 1 position of Z.
  • the compound of Formula ( ⁇ ) is a compound selected from the compounds in Table II. Table II. Exemplary Fused Morpholinopyrimidines
  • Schemes 1-5 are general synthetic schemes for manufacturing Fused
  • Schemes 1-2 describe various methods for the synthesis of intermediates that may be used to prepare compounds described herein. Various modifications to these methods may be envisioned by those skilled in the art to achieve similar results to those provided below. For example, optional protecting groups can be used as described, for example, in Greene et al., Protective Groups in Organic Synthesis (3 rd ed. 1999).
  • a compound of formula 4 can be reacted with the compound of formula 5 under basic conditions to provide a compound of formula 6.
  • the compound of formula 6 can be reduced to provide a compound of formula 3.
  • a compound of formula 7 can be reacted with a compound of formula 8 under basic conditions to provide a compound of formula 9.
  • the compound of formula 9 can then be reacted with BBr 3 to provide a compound of formula 10.
  • the compound of formula 10 can be reacted using, for example, l-bromo-2-chloroethane, to provide a compound of formula 11.
  • the compound of formula 11 can then be reacted with compound of formula 3 to provide a Fused Morpholinopyrimidine of Formula (I).
  • a compound of formula 7 can be reacted with a compound of formula 12 under basic conditions to provide a compound of formula 13.
  • the compound of formula 13 can then be reacted with BBr 3 to provide a compound of formula 14.
  • the compound of formula 14 can then be reacted using, for example, di-tert-butyl dicarbonate, to provide a compound of formula 15.
  • the compound of formula 15 can then be reacted using, for example, triphenylphosphine and diisopropyl azodicarboxylate, to provide a compound of formula 16.
  • the compound of formula 16 can then be reacted with hydrochloric acid to provide a compound of formula 17.
  • the compound of formula 17 can then be reacted with a compound of formula 18 to provide a compound of formula 19.
  • the compound of formula 19 can then be reacted with compound of formula 3 to provide a Fused Morpholinopyrimidine of Formula ( ⁇ ), wherein both R 2 are -H.
  • a compound of formula 10 can be reacted with a compound of formula 20 under basic conditions to provide a compound of formula 21.
  • the compound of formula 21 can then be reacted with BBr 3 to provide a compound of formula 19.
  • the compound of formula 19 can then be reacted with compound of formula 3 to provide a Fused Morpholinopyrimidine of Formula ( ⁇ ), wherein both R 1 are -H.
  • compositions Comprising a Fused Morpholinopyrimidine
  • the present disclosure provides pharmaceutical compositions for treating, preventing, or ameliorating a symptom of a neurodegenerative disease in a subject having a neurodegenerative disease, wherein the pharmaceutical composition comprises a therapeutically effective amount of a Fused Morpholinopyrimidine, and a pharmaceutically acceptable carrier or vehicle.
  • a Fused Morpholinopyrimidine is in the form of a hydrate or a pharmaceutically acceptable salt.
  • Fused Morpholinopyrimidines are provided in the form of pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt refers to the relatively non-toxic, inorganic and organic acid or base addition salts of compounds described herein. These salts can be prepared in situ during the final isolation and purification of the compounds described herein, or by separately reacting a purified compound described herein in its free base or acid form with a suitable organic or inorganic acid or base, and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, laurylsulphonate, ammonium, amine salts and the like.
  • sulfate bisulfate
  • phosphate nitrate
  • acetate valerate
  • oleate palmitate
  • stearate laurate
  • benzoate lactate
  • phosphate tosylate
  • citrate maleate
  • fumarate succinate
  • tartrate napthylate
  • mesylate mesylate
  • glucoheptonate lactobionate
  • laurylsulphonate ammonium,
  • the pharmaceutically acceptable salts of Fused Morpholinopyrimidines include the conventional nontoxic salts or acid salts of the compounds, e.g., from non-toxic organic or inorganic acids.
  • such conventional nontoxic salts include those derived from inorganic acids, such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids, such as acetic, butionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic and the like.
  • Fused Morpholinopyrimidines may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases.
  • pharmaceutically acceptable salts refers to the relatively non-toxic, inorganic and organic base addition salts of compounds described herein. These salts can likewise be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. (See, for example, Berge et al, supra.)
  • a suitable dose of a Fused Morpholinopyrimidine will be in the range of 0.01 to 100 mg per kilogram body weight of the recipient per day, preferably in the range of 0.2 to 10 mg per kilogram body weight per day.
  • the desired dose is preferably presented once daily, but may be dosed as two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day.
  • concentration of compounds included in compositions used in the methods described herein can range from about 1 nM to about 100 ⁇ . Effective doses are believed to range from about 10 picomole/kg to about 100 micromole/kg.
  • a Fused Morpholinopyrimidine can be administered as the sole active agent, or in combination with other known therapeutics to be beneficial in the treatment of
  • the administering physician can provide a method of treatment that is prophylactic or therapeutic by adjusting the amount and timing of drug administration on the basis of observations of one or more symptoms (e.g., motor or cognitive function as measured by standard clinical scales or assessments) of the disease being treated.
  • symptoms e.g., motor or cognitive function as measured by standard clinical scales or assessments
  • compositions described herein may comprise suitable solid or gel phase carriers or excipients.
  • suitable solid or gel phase carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers, such as polyethylene glycols.
  • wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polybutylene oxide copolymer, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the pharmaceutical compositions.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient, which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of 100%, this amount will range from about 1% to about 99% of active ingredient, preferably from about 5% to about 70%, most preferably from about 10% to about 30%.
  • Methods of preparing these formulations or compositions include the step of bringing into association a compound described herein with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound described herein with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • a Fused Morpholinopyrimidines When administered as pharmaceuticals to humans and animals, it can be given per se or as a pharmaceutical composition containing, for example, 0.1% to 99.5% (more preferably, 0.5%> to 90%>) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • the compounds and pharmaceutical compositions described herein can be employed in combination therapies, that is, the compounds and pharmaceutical 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.
  • compositions described herein can be administered in a variety of dosage forms including, but not limited to, a solid dosage form, a liquid dosage form, an oral dosage form, a parenteral dosage form, an intranasal dosage form, a suppository, a lozenge, a troche, a buccal dosage form, a controlled release dosage form, a pulsed release dosage form, an immediate release dosage form, an intravenous solution, a suspension or combinations thereof.
  • compositions described herein suitable for oral administration can be in the form of capsules, cachets, pills, tablets, caplet, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in- water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouthwashes and the like, each containing a predetermined amount of a compound described herein as an active ingredient.
  • the dosage can be an oral dosage form that is a controlled release dosage form.
  • a Fused Morpholinopyrimidine may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically acceptable carriers and/or any of the following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, and sodium starch glycolate; solution retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and poly
  • absorbents such as kaolin and bentonite clay
  • lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof
  • coloring agents such as kaolin and bentonite clay
  • talc calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof
  • coloring agents such as kaolin and bentonite clay.
  • compositions may also comprise buffering agents.
  • 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 sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet can be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using a binder (for example, gelatin or hydroxybutylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions described herein may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxybutylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions, which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid diluent, and soft gelatin capsules, wherein the active ingredients is mixed with water or an oil, such as peanut oil, liquid paraffin or olive oil.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • Liquid dosage forms for oral administration of the compounds described herein include 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, isobutyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, butylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • cyclodextrins e.g., hydroxybutyl- -cyclo
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and mixtures thereof.
  • the oral compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • compositions for oral use can be obtained through combination of a Fused Morpholinopyrimidine with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable additional compounds, if desired, to obtain tablets or dragee cores.
  • carbohydrate or protein fillers that include, but are not limited to, sugars, including lactose, sucrose, mannitol, or sorbitol; starch from corn, wheat, rice, potato, or other plants; cellulose, such as methyl cellulose, hydroxypropylmethyl-cellulose or sodium carboxymethylcellulose; and gums including arabic and tragacanth; as well as proteins, such as gelatin and collagen.
  • disintegrating or solubilizing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate.
  • Aqueous suspensions can contain a Fused Morpholinopyrimidine in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose,
  • hydroxypropylmethylcellulose sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents, such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensation product of ethylene oxide with a partial ester derived from fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate).
  • a naturally occurring phosphatide e.g., lecithin
  • the aqueous suspension can also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, aspartame or saccharin.
  • preservatives such as ethyl or n-propyl p-hydroxybenzoate
  • coloring agents such as a coloring agent
  • flavoring agents such as sucrose, aspartame or saccharin
  • sweetening agents such as sucrose, aspartame or saccharin.
  • Formulations can be adjusted for osmolarity.
  • Oil suspensions can be formulated by suspending a Fused Morpholinopyrimidine in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil, such as liquid paraffin; or a mixture of these.
  • the oil suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents can be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose.
  • These formulations can be preserved by the addition of an antioxidant, such as ascorbic acid.
  • an injectable oil vehicle see Minto, J. Pharmacol. Exp. Ther. 281 :93-102, 1997.
  • the pharmaceutical formulations can also be in the form of oil-in- water emulsions.
  • the oily phase can be a vegetable oil or a mineral oil, described above, or a mixture of these.
  • Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum
  • tragacanth naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono-oleate, and
  • the emulsion can also contain sweetening agents and flavoring agents, as in the formulation of syrups and elixirs. Such formulations can also contain a demulcent, a preservative, or a coloring agent.
  • a Fused Morpholinopyrimidine can be administered parenterally, such as intravenous (IV) or intramuscular (IM) administration.
  • IV intravenous
  • IM intramuscular
  • formulations for administration will commonly comprise a solution of a Fused
  • Morpholinopyrimidine dissolved in a pharmaceutically acceptable carrier can be achieved by direct injection of the pharmaceutical composition comprising the Fused Morpholinopyrimidine or by the use of infusion pumps.
  • the pharmaceutical compositions may be formulated in solid form and re-dissolved or suspended immediately prior to use. Lyophilized forms are also included.
  • the injection can be, for example, in the form of a bolus injection or continuous infusion (e.g., using infusion pumps) of pharmaceutical composition.
  • compositions of this invention suitable for parenteral
  • administration comprise one or more compounds described herein in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • the acceptable vehicles and solvents that can be employed for formulation and/or reconstitution are water (e.g., water for injection) and Ringer's solution, an isotonic sodium chloride.
  • sterile fixed oils can conventionally be 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 can likewise be used in the preparation of injectables.
  • These solutions are sterile and generally free of undesirable matter.
  • These formulations may be sterilized by conventional, well known sterilization techniques such as gamma-radiation or electron beam sterilization.
  • the formulations may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions, such as pH adjusting and buffering agents, toxicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like.
  • concentration of a Fused Morpholinopyrimidine in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight, and the like, in accordance with the particular mode of
  • the formulation can be a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
  • This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally-acceptable diluent or solvent, such as a solution of 1, 3-butanediol.
  • a Fused Morpholinopyrimidine can be administered by introduction into the central nervous system of the subject, e.g., into the cerebrospinal fluid of the subject.
  • the formulations for administration will commonly comprise a solution of the Fused Morpholinopyrimidine dissolved in a pharmaceutically acceptable carrier.
  • the Fused Morpholinopyrimidine is introduced intrathecally, e.g., into a cerebral ventricle, the lumbar region, or the cisterna magna.
  • the pharmaceutical composition comprising a Fused Morpholinopyrimidine is administered into a subject intrathecally.
  • intrathecal administration is intended to include delivering a pharmaceutical composition comprising a Fused Morpholinopyrimidine directly into the cerebrospinal fluid of a subject, by techniques including lateral cerebroventricular injection through a borehole or cisternal or lumbar puncture or the like (described in Lazorthes et al. Advances in Drug Delivery
  • the term "lumbar region” is intended to include the area between the third and fourth lumbar (lower back) vertebrae.
  • the term “cisterna magna” is intended to include the area where the skull ends and the spinal cord begins at the back of the head.
  • the term “cerebral ventricle” is intended to include the cavities in the brain that are continuous with the central canal of the spinal cord.
  • the pharmaceutical composition is administered by injection into the cisterna magna, or lumbar area of a subject.
  • a Fused Morpholinopyrimidine can also be formulated as a depot preparation.
  • Such long acting formulations may be administered by implantation or transcutaneous delivery (e.g., subcutaneously or intramuscularly), intramuscular injection or a transdermal patch.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • suitable polymeric or hydrophobic materials e.g., as an emulsion in an acceptable oil
  • ion exchange resins e.g., as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • sparingly soluble derivatives for example, as a sparingly soluble salt.
  • a liquid suspension of crystalline or amorphous material having poor water solubility The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form.
  • delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • One strategy for depot injections includes the use of polyethylene oxide-polybutylene oxide copolymers, wherein the vehicle is fluid at room temperature and solidifies at body temperature.
  • Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers, such as polylactide-polyglycolide.
  • the rate of drug release can be controlled.
  • biodegradable polymers include poly (orthoesters) and poly (anhydrides).
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions, which are compatible with body tissue.
  • the compounds are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base, such as lactose or starch.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art.
  • Other delivery systems can include time-release, delayed release or sustained release delivery systems. Such systems can avoid repeated administrations of the compounds, increasing convenience to the subject and the physician.
  • release delivery systems are available and known to those of ordinary skill in the art. They include polymer base systems such as poly(lactide-glycolide), copolyoxalates, polycaprolactones, polyesteramides, polyorthoesters, polyhydroxybutyric acid and polyanhydrides.
  • Microcapsules of the foregoing polymers containing drugs are described in, for example, U.S. Pat. No. 5,075,109.
  • Delivery systems also include non-polymer systems that are: lipids including sterols, such as cholesterol, cholesterol esters and fatty acids or neutral fats, such as mono-, di- and tri-glycerides; hydrogel release systems; silastic systems; peptide based systems; wax coatings; compressed tablets using conventional binders and excipients;
  • partially fused implants include, but are not limited to: (a) erosional systems in which an agent described herein is contained in a form within a matrix, such as those described in U.S. Pat. Nos. 4,452,775, 4,675,189, and 5,736,152, and (b) diffusional systems in which an active component permeates at a controlled rate from a polymer, such as described in U.S. Pat. Nos. 3,854,480, 5,133,974 and 5,407,686.
  • pump-based hardware delivery systems can be used, some of which are adapted for implantation.
  • a method for treating a neurodegenerative disease comprising administering to a subject an effective amount of the compound or
  • the method for treating a neurodegenerative disease is a method for reducing or ameliorating a symptom of the neurodegenerative disease.
  • a method for reducing or ameliorating a symptom of a neurological disease comprising administering to a subject in need thereof an effective amount of a Fused Morpholinopyrimidine.
  • Ameliorating or reducing the symptoms can be manifested in a variety of ways, for example by improvement in cognitive function.
  • Exemplary symptoms of neurological disease that can be reduced or ameliorated by administration of a Fused Morpholinopyrimidine are loss of memory, loss of cognition, loss of reasoning and/or loss of judgment. The loss of each of memory, cognition, reasoning and/or judgment can be progressive or sudden. Dementia is an exemplary symptom of neurodegenerative disease. Administration of a Fused Morpholinopyrimidine can reduce or improve one or more of these symptoms.
  • Exemplary cognitive functions that can be improved by administration of a Fused Morpholinopyrimidine are attention, learning, delayed memory, working memory, visual learning, speed of processing, vigilance, verbal learning, visual motor function, social cognition, long term memory or executive function.
  • the neurodegenerative disease is Alzheimer's disease. In some embodiments, the neurodegenerative disease is early onset Alzheimer's disease. In some embodiments, the early onset Alzheimer's disease is autosomal dominant early onset Alzheimer's disease.
  • the subject is 65 years or older. In some embodiments, the subject is 55 years old or younger, or 50 years old or younger. In some embodiments, the subject us older than 55 years and younger than 65 years. In some embodiments, the subject is older than 55 years.
  • the neurodegenerative disease is panic disorder, obsessive compulsive disorder, delusional disorder, drug-induced psychosis, post-traumatic stress disorder, age-related cognitive decline, attention deficit/hyperactivity disorder, personality disorder of the paranoid type, personality disorder of the schizoid type, dyskinesia, choreiform condition, psychosis associated with Parkinson's disease, psychotic symptoms associated with Alzheimer's disease, mood disorder, or dementia.
  • the neurodegenerative disease is cognitive impairment, myclonus, seizures, Parkinsonism, extrapyramidal signs (EPS), apraxia, dystonia, dementia with Lewy bodies (DLB), aphasia, visual agnosia, or ataxia.
  • the subject has impaired cognitive function including one or more of attention, learning, delayed memory, working memory, visual learning, speed of processing, vigilance, verbal learning, visual motor function, social cognition, long term memory or executive function.
  • the subject has a mutation in at least one gene selected from PSEN1, PSEN2 and APP.
  • the mutation in PSEN1, PSEN2 or APP is a missense mutation.
  • the invention provides a method for treating or
  • a symptom of neurodegenerative disease e.g., Alzheimer's disease
  • the method comprising administering to a subject in need thereof an effective amount of a Fused Morpholinopyrimidine.
  • the increased level of ⁇ 42 in cerebrospinal fluid can be detected relative to the level of ⁇ 42 in cerebrospinal fluid of a healthy subject.
  • the invention provides a method for lowering ⁇ 42 concentration in a subject, the method comprising administering to a subject in need thereof an effective amount of a Fused Morpholinopyrimidine.
  • the subject has an elevated ⁇ 42 concentration relative to a healthy subject.
  • the invention provides a method for preventing increase of ⁇ 42 concentration in a subject, the method comprising administering to a subject in need thereof an effective amount of a Fused Morpholinopyrimidine.
  • kits that can simplify the administration of an Fused
  • the kit can comprise one or more containers filled with one or more of the ingredients of the pharmaceutical compositions described herein.
  • Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
  • a typical kit comprises a unit dosage form of a Fused Morpholinopyrimidine.
  • the unit dosage form is a container, which can be sterile, containing an effective amount of a Fused Morpholinopyrimidine and a pharmaceutically acceptable carrier or vehicle.
  • the kit can further comprise a label or printed instructions instructing the use of the Fused Morpholinopyrimidine to treat or prevent a neurodegenerative disease.
  • the kit can also further comprise a unit dosage form of another prophylactic or therapeutic agent, for example, a container containing an effective amount of the other prophylactic or therapeutic agent.
  • the kit comprises a container containing an effective amount of a Fused Morpholinopyrimidine and an effective amount of another prophylactic or therapeutic agent. Examples of other prophylactic or therapeutic agents include, but are not limited to, those listed above.
  • LC-MS 248 (M+l); (column; X-Bridge C-18 (50 x 3.0 mm, 3.5 ⁇ ); RT 3.23 min. 0.05% TFA in water: ACN; 0.80 ml/min); UPLC (column; Acquity BEH C-18, 50 x 2.1mm, 1.7 ⁇ ); RT 2.17 min. ACN: 0.025% TFA (Aq); 0.50 ml/min; TLC: 10% MeOH: DCM (R/. 0.6).
  • the mixture was degassed with argon for 15 min and stirred at 120 °C for 16 h in a sealed tube. After completion of reaction (monitored by TLC), the reaction was diluted with water (20 mL) and extracted with 10% MeOH:CH 2 Cl 2 (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography using 2%
  • reaction was diluted with water (20 mL) and extracted with 10% MeOH:CH 2 Cl 2 (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo.
  • reaction was diluted with a saturated sodium bicarbonate solution (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo.

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Abstract

La présente invention concerne des morpholinopyrimidines fusionnées, des compositions pharmaceutiques comprenant une quantité efficace d'une morpholinopyrimidine fusionnée et des procédés d'utilisation d'une morpholinopyrimidine fusionnée dans le traitement d'une maladie neurodégénérative, qui consistent à administrer à un sujet nécessitant un tel traitement, une quantité efficace d'une morpholinopyrimidine fusionnée.
PCT/US2014/063884 2013-11-04 2014-11-04 Morpholinopyrimidines fusionnées et procédés d'utilisation de ces dernières WO2015066697A1 (fr)

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Publication number Priority date Publication date Assignee Title
CN108164548A (zh) * 2016-12-07 2018-06-15 四川大学 嘧啶并吗啉衍生物及其制备方法和用途
CN108164548B (zh) * 2016-12-07 2020-09-08 四川大学 嘧啶并吗啉衍生物及其制备方法和用途
US11926616B2 (en) 2018-03-08 2024-03-12 Incyte Corporation Aminopyrazine diol compounds as PI3K-γ inhibitors
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors
US11649260B2 (en) 2021-06-18 2023-05-16 Hongene Biotech Corporation Functionalized N-acetylgalactosamine nucleosides
US11692001B2 (en) 2021-08-30 2023-07-04 Hongene Biotech Corporation Functionalized n-acetylgalactosamine analogs
US11884691B2 (en) 2021-08-30 2024-01-30 Hongene Biotech Corporation Functionalized n-acetylgalactosamine analogs
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