WO2013148851A1 - Composés permettant de traiter les maladies neurodégénératives - Google Patents

Composés permettant de traiter les maladies neurodégénératives Download PDF

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WO2013148851A1
WO2013148851A1 PCT/US2013/034129 US2013034129W WO2013148851A1 WO 2013148851 A1 WO2013148851 A1 WO 2013148851A1 US 2013034129 W US2013034129 W US 2013034129W WO 2013148851 A1 WO2013148851 A1 WO 2013148851A1
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mmol
spiro
compound
xanthen
amino
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PCT/US2013/034129
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English (en)
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Erik James Hicken
Kevin W. Hunt
Martha E. Rodriguez
Tony P. Tang
Michael Siu
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Array Biopharma Inc.
Genentech, Inc.
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Publication of WO2013148851A1 publication Critical patent/WO2013148851A1/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
    • C07D498/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/10—Spiro-condensed systems

Definitions

  • the present invention relates to organic compounds useful for inhibition of ⁇ - secretase enzymatic activity and the therapy and/or prophylaxis of neurodegenerative diseases associated therewith. More particularly, certain tricyclic compounds useful in the treatment and prevention of neurodegenerative diseases, such as Alzheimer's disease, are provided herein.
  • AD Alzheimer's disease
  • amyloid precursor protein APP
  • PSI presenilin I and II
  • ⁇ 1-42 fragment has a particularly high propensity of forming aggregates due to two very hydrophobic amino acid residues at its C-terminus.
  • ⁇ 1-42 fragment is believed to be mainly responsible for the initiation of neuritic amyloid plaque formation in AD and is therefore actively being pursued as a therapeutic target.
  • Anti- ⁇ antibodies have been shown to reverse the histologic and cognitive impairments in mice which overexpress ⁇ and are currently being tested in human clinical trials. Effective treatment requires anti- ⁇ antibodies to cross the blood-brain barrier ("BBB”), however, antibodies typically cross the BBB very poorly and accumulate in the brain in low concentration.
  • BBB blood-brain barrier
  • APP Different forms of APP range in size from 695-770 amino acids, localize to the cell surface, and have a single C-terminal transmembrane domain.
  • ⁇ is derived from a region of APP adjacent to and containing a portion of the transmembrane domain.
  • processing of APP by a-secretase cleaves the midregion of the ⁇ sequence adjacent to the membrane and releases a soluble, extracellular domain fragment of APP from the cell surface referred to as APP-a.
  • APP-a is not thought to contribute to AD.
  • Processing at the ⁇ - and ⁇ -secretase sites can occur in both the endoplasmic reticulum and in the endosomal/lysosomal pathway after reinternalization of cell surface APP.
  • Dysregulation of intracellular pathways for proteolytic processing may be central to the pathophysiology of AD.
  • mutations in APP, PS1 or PS2 consistently alter the proteolytic processing of APP so as to enhance ⁇ 1-42 formation.
  • N-APP apoptotic death receptor 6
  • DR6 apoptotic death receptor 6
  • the aging process can lead to a reduction in the levels of growth factors in certain areas of the brain and/or the ability to sense growth factors. This in turn would lead to the release of N-APP fragment by cleavage of APP on neuronal surfaces, activating nearby DR6 receptors to initiate the axonal shrinkage and neuronal degeneration of Alzheimer's.
  • BACE-1 inhibitors include WO 201 1/072064, WO 201 1/123674 and WO
  • ⁇ -secretase cleavage of APP is essential for both amyloid plaque formation and DR6-mediated apoptosis, it is a key target in the search for therapeutic agents for treating AD.
  • compositions comprising compounds of Formula I, II, III, IV, V, VI, VII, VIII, IX and X and a pharmaceutically acceptable carrier, diluent or excipient.
  • a method of inhibiting cleavage of APP by ⁇ -secretase in a mammal comprising administering to said mammal an effective amount of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX and X.
  • a method for treating a disease or condition mediated by the cleavage of APP by ⁇ -secretase in a mammal comprising administering to said mammal an effective amount of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX and X.
  • Formula I, II, III, IV, V, VI, VII, VIII, IX and X in the manufacture of a medicament for the treatment of neurodegenerative diseases, such as Alzheimer's disease.
  • Formula I, II, III, IV, V, VI, VII, VIII, IX and X in the treatment of neurodegenerative diseases, such as Alzheimer's disease.
  • Another aspect includes processes for preparing, methods of separation, and methods of purification of the compounds described herein.
  • alkyl includes linear or branched-chain radicals of carbon atoms.
  • alkyl moieties have been abbreviated, for example, methyl (“Me”), ethyl (“Et”), propyl (“Pr”) and butyl (“Bu”), and further abbreviations are used to designate specific isomers of compounds, for example, 1 -propyl or n-propyl (“n-Pr”), 2-propyl or isopropyl (“i-Pr”), 1 -butyl or n-butyl (“n-Bu”), 2 -methyl- 1 -propyl or isobutyl (“i-Bu”), 1-mefhylpropyl or s-butyl (“s-Bu”), 1,1-dimethylethyl or t-butyl (“t-Bu”) and the like.
  • the abbreviations are sometimes used in conjunction with elemental abbreviations and chemical structures, for example, methanol (“MeOH”) or ethanol (“EtOH”).
  • Additional abbreviations used throughout the application may include, for example, benzyl (“Bn”), phenyl (“Ph”) and acetate (“Ac”).
  • alkenyl and alkynyl also include linear or branched-chain radicals of carbon atoms.
  • alkoxy means the group -O(alkyl), wherein the alkyl is linear or branched-chain.
  • the alkyl may be substituted by the same substituents as the "substituted alkyl" group.
  • Q-C6 alkoxy means -0(C!-C alkyl).
  • heterocycle and heterocyclic include four to seven membered rings containing one, two or three heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. In certain instances, these terms may be specifically further limited, such as, “five to six membered heterocyclic” only including five and six membered rings.
  • heteroaryl includes five to six membered aromatic rings containing one, two or three heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. In certain instances, these terms may be specifically further limited, such as, five to six membered heteroaryl, wherein the heteroaryl contains one or two nitrogen heteroatoms.
  • an optionally substituted group may be unsubstituted or substituted by one or more (e.g., 0, 1, 2, 3 or 4) of the substituents listed for that group in which said substituents may be the same or different.
  • an optionally substituted group has 1 substituent.
  • an optionally substituted group has 2 substituents.
  • an optionally substituted group has 3 substituents.
  • an optionally substituted group has 0 to 3 substituents.
  • an optionally substituted group has 0 to 2 substituents.
  • an optionally substituted group has 1 to 3 substituents.
  • an optionally substituted group has 1 to 2 substituents.
  • treat refers to therapeutic, prophylactic, palliative or preventative measures.
  • Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • Those in need of treatment include those already with the condition or disorder, as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.
  • phrases "therapeutically effective amount” or “effective amount” mean an amount of a compound described herein that, when administered to a mammal in need of such treatment, sufficient to (i) treat or prevent the particular disease, condition, or disorder, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
  • the amount of a compound that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the mammal in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
  • phrases "pharmaceutically acceptable” indicates that the substance or composition is compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
  • pharmaceutically acceptable salt refers to pharmaceutically acceptable organic or inorganic salts of a compound described herein.
  • the compounds described herein also include other salts of such compounds that are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds described herein and/or for separating enantiomers of compounds described herein.
  • mammal means a warm-blooded animal that has or is at risk of developing a disease described herein and includes, but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters, and primates, including humans.
  • W is a bond or CH 2 ;
  • Y is O, S or NR a ;
  • Xi is selected from O, S, S(O), S0 2 , NR b and CHR b ;
  • X 2 is selected from CR 6 and N;
  • R 1' and R 2 are independently selected from hydrogen and Q-Q alkyl
  • R is selected from hydrogen and C ! -C 3 alkyl
  • R 4 is selected from hydrogen, halogen, CN, Q-C6 alkyl, Ci-C 6 alkoxy, C 3 -C 6 cycloalkyl, a 3 to 6 membered heterocyclyl, phenyl, a 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, phenyl and heteroaryl are optionally substituted with halogen;
  • R 5 is selected from Q-C6 alkyl, C 3 -C 6 cycloalkyl, a 3 to 6 membered heterocyclyl, phenyl, a 5 to 6 membered heteroaryl, a 9 to 10 membered bicyclic heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, phenyl and heteroaryls are optionally substituted with one or more groups selected from halogen, hydroxyl, C]-C 6 alkyl optionally substituted with halogen, C 3 -C 6 cyclopropyl and Cj-C 6 alkoxy optionally substituted with one or more R c groups;
  • R 6 is selected from hydrogen, halogen, C C 6 alkyl and C]-C6 alkoxy;
  • R a is C 1 -C3 alkyl
  • R b is selected from hydrogen, halogen and Q-Q alkyl
  • R c is selected from oxo and phenyl.
  • W is a bond
  • Y is O or S
  • Z is CH 2 ;
  • X 2 is CR 6 ;
  • R and R are hydrogen
  • R is selected from hydrogen and C!-C 3 alkyl
  • R 4 is selected from hydrogen, halogen, CN, Cj-C 6 alkyl, C C 6 alkoxy, C 3 -C 6 cycloalkyl, a 3 to 6 membered heterocyclyl, phenyl, a 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, phenyl and heteroaryl are optionally substituted with halogen;
  • R 5 is selected from C!-C 6 alkyl, C 3 -C cycloalkyl, a 3 to 6 membered heterocyclyl, phenyl, a 5 to 6 membered heteroaryl, a 9 to 10 membered bicyclic heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, phenyl and heteroaryls are optionally substituted with one or more groups selected from halogen, hydroxyl, C C 6 alkyl optionally substituted with halogen, C 3 -C 6 cyclopropyl and C C 6 alkoxy optionally substituted with one or more R c groups;
  • R 6 is selected from hydrogen and CrC 6 alkoxy
  • R c is selected from oxo and phenyl.
  • compounds of the invention have the stereochemical orientation represented by Formula II:
  • compounds of the invention have the stereochemical orientation represented by Formula IV:
  • compounds of the invention have the stereochemical orientation represented by Formula V:
  • compounds of the invention have the stereochemical orientation represented by Formula VI:
  • compounds of the invention have the stereochemical orientation represented by Formula VII:
  • compounds of the invention have the stereochemical orientation represented by Formula VIII:
  • compounds of the invention have the stereochemical orientation represented by Formula IX:
  • Y is S, Z is CH 2 and W is a bond;
  • Y is O, Z is
  • Y is O or S, Z is CH 2 and W is a bond. In certain embodiments, Y is O, Z is CH 2 and W is a bond. In certain embodiments, Y is S, Z is CH 2 and W is a bond.
  • Y is NR a
  • W is a bond.
  • W is a bond.
  • Formula I have the structure of Formula X:
  • Xi is selected from O, S, S(O), S0 2 , NR b and CHR b . In certain embodiments, is O.
  • X 2 is selected from CR 6 and N. In certain embodiments,
  • X 2 is CR 6 . In certain embodiments, X 2 is N. In certain embodiments, R 6 is selected from hydrogen, halogen, C C 6 alkyl and C C alkoxy. In certain embodiments, R 6 is selected from hydrogen and Ci-C 6 alkoxy. In certain embodiments, R 6 is selected from hydrogen and methoxy. In certain embodiments, R 6 is hydrogen. In certain embodiments, R 6 is methoxy.
  • R 1 and R 2 are independently selected from hydrogen and
  • R 1 and R 2 are independently selected from hydrogen and
  • R and R are hydrogen. In certain embodiments, R and R are methyl. In certain embodiments, R 1 is selected from hydrogen and methyl. In certain embodiments, R is selected from hydrogen and methyl.
  • R 3 is selected from hydrogen and C C 3 alkyl. In certain embodiments, R is selected from hydrogen and methyl. In certain embodiments, R is hydrogen. In certain embodiments, R is methyl.
  • R 4 is selected from hydrogen, halogen, CN, C C 6 alkyl,
  • R 4 is selected from hydrogen, halogen, CN, CpC 6 alkyl, Ci-Ce alkoxy optionally substituted with halogen, C 3 -C 6 cycloalkyl, a 3 to 6 membered heterocyclyl, phenyl optionally substituted with halogen, and a 5 to 6 membered heteroaryl optionally substituted with halogen.
  • R 4 is a heteroaryl optionally substituted with halogen, wherein the heteroaryl contains one, two or three heteroatoms selected from O, N and S.
  • R 4 is a heteroaryl optionally substituted with halogen, wherein the heteroaryl contains one or two N heteroatoms.
  • R 4 is a heteroaryl optionally substituted with halogen, wherein the heteroaryl is selected from pyridine and pyrimidine.
  • R 4 is selected from hydrogen, Br, CN, ethyl, isopropyl, trifluoromethoxy, cyclopropyl, cyclopentyl, cyclohexyl, tetrahydropyran-4-yl, 3-chloro-5-fluorophenyl, pyrimidin-5-yl, 5-fluoropyridin-3-yl and 5- chloropyridin-3-yl.
  • R 5 is selected from C ! -C 6 alkyl, C 3 -C 6 cycloalkyl, a 3 to
  • R 5 is selected from Q-C 6 alkyl, C 3 -C 6 cycloalkyl, a 3 to 6 membered heterocyclyl, phenyl, a 5 to 6 membered heteroaryl, a 9 to 10 membered bicyclic heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, phenyl and heteroaryls are optionally substituted with one or two groups selected from halogen, hydroxyl, C)-C6 alkyl optionally substituted with halogen, C 3 -C 6 cyclopropyl and C C 6 alkoxy optionally substituted with one R c group.
  • R c is selected from oxo and phenyl.
  • R 5 is a 3 to 6 membered heterocyclyl, wherein the heterocyclyl contains one or two heteroatoms selected from O, N and S. In certain embodiments, R 5 is a 3 to 6 membered heterocyclyl, wherein the heterocyclyl contains one heteroatom selected from O and N. In certain embodiments, R 5 is a 3 to 6 membered heterocyclyl, wherein the heterocyclyl is selected from oxetane, THP and pyrrolidine. In certain embodiments, R 5 is a 5 to 6 membered heteroaryl, wherein the heteroaryl contains one, two or three heteroatoms selected from O, N and S.
  • R 5 is a 5 to 6 membered heteroaryl, wherein the heteroaryl contains one or two heteroatoms selected from O, N and S. In certain embodiments, R 5 is a 5 to 6 membered heteroaryl, wherein the heteroaryl is selected from oxazole, isoxazole, imidazole, pyridine, pyrazine, pyrimidine and thiazole. In certain embodiments, R 5 is a 9 to 10 membered bicyclic heteroaryl, wherein the heteroaryl contains one, two or three heteroatoms selected from O, N and S. In certain embodiments, R 5 is a 9 to 10 membered bicyclic heteroaryl, wherein the heteroaryl contains one N heteroatom.
  • R 5 is a 9 to 10 membered bicyclic heteroaryl, wherein the heteroaryl is indole.
  • R 5 is selected from methyl, tert-butyl, neopentyl, 2- fluoropropan-2-yl, 1 ,1-difluoroethyl, 2-hydroxypropan-2-yl, l ,l ,l-trifluoro-2-methylpropan-2- yl, 1 -hydroxy-2-methylpropan-2-yl, difluoromethyl, cyclopropylmethyl, 2-methoxyethyl, methoxymethyl, (benzyloxy)methyl, methylacetate, 1-methylcyclopropyl, 1- (trifluoromethyl)cyclopropyl, 3-methyloxetan-3-yl, tetrahydropyran-4-yl, 2-methylpyrrolidin-2- yl, phenyl, 4-(difiuoromethyl
  • R 5 is Ci-C 6 alkyl optionally substituted with R d , C 3 -C 6 cycloalkyl optionally substituted with R e , a 3 to 6 membered heterocyclyl optionally substituted with R f , phenyl optionally substituted with R g , a 5 to 6 membered heteroaryl optionally substituted with R h , a 9 to 10 membered bicyclic heteroaryl optionally substituted with R 1 .
  • R d is selected from halogen, hydroxyl, C3-C6 cycloalkyl, Cj-C 6 alkoxy optionally substituted with R°.
  • R d is selected from halogen, hydroxyl, cyclopropyl, methoxy, benzyloxy and acetate. In certain embodiments, R d is selected from halogen, hydroxyl, cyclopropyl, methoxy, benzyloxy and acetate. In certain embodiments, R e is selected from hydroxyl and C ⁇ -C alkyl optionally substituted with halogen. In certain embodiments, R e is selected from methyl, CF3 and hydroxyl. In certain embodiments, R f is Q- C 6 alkyl. In certain embodiments, R f is methyl.
  • R 8 is selected from halogen, Ci-C 6 alkyl optionally substituted with halogen and Ci-C ⁇ alkoxy. In certain embodiments, R 8 is selected from CI, CF 2 H, methoxy and ethoxy. In certain embodiments, R h is selected from halogen, C1-C6 alkyl optionally substituted with halogen, and C C 6 alkoxy. In certain embodiments, R h is selected from CI, F, methyl, CF 3 and methoxy. In certain embodiments, R 1 is halogen. In certain embodiments, R 1 is F.
  • R a is Ci-C 3 alkyl. In certain embodiments, R a is methyl.
  • R b is selected from hydrogen, halogen and C]-C 6 alkyl.
  • R b is selected from hydrogen, halogen and C]-C 6 alkyl.
  • Compounds described herein may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein.
  • the starting materials are generally available from commercial sources such as Sigma-Aldrich (St. Louis, MO), Alfa Aesar (Ward Hill, MA), or TCI (Portland, OR), or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-23, New York: Wiley 1967-2006 ed. (also available via the Wiley InterScience® website), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer- Verlag, Berlin, including supplements (also available via the Beilstein online database)).
  • Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butyloxycarbonyl ("Boc”), benzyloxycarbonyl ("CBz”) and 9- fluorenylmethyleneoxycarbonyl ("Fmoc”).
  • Boc trifluoroacetyl
  • CBz benzyloxycarbonyl
  • Fmoc 9- fluorenylmethyleneoxycarbonyl
  • reaction products from one another and/or from starting materials.
  • the desired products of each step or series of steps is separated and/or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art.
  • separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography.
  • Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed (SMB) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.
  • SMB simulated moving bed
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound ⁇ e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting ⁇ e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers.
  • Enantiomers can also be separated by use of a chiral HPLC column.
  • a single stereoisomer e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, C. H., et al. "Chromatographic resolution of enantiomers: Selective review.” J. Chromatogr., 113(3) (1975): pp. 283-302).
  • Racemic mixtures of chiral compounds described herein may be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral denvatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. See: Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.
  • diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, cc-methyl- ⁇ - phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid.
  • the diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography.
  • the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994, p. 322).
  • Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the pure or enriched enantiomer.
  • a method of determining optical purity involves making chiral esters, such as a menthyl ester, e.g., (-) menthyl chloroformate in the presence of base, or Mosher ester, a-methoxy-a- (trifluoromethyl)phenyl acetate (Jacob III, Peyton. "Resolution of ( ⁇ )-5-Bromonornicotine. Synthesis of (R)- and (S)-Nornicotine of High Enantiomeric Purity.” J. Org. Chem. Vol. 47, No. 21 (1982): pp.
  • chiral esters such as a menthyl ester, e.g., (-) menthyl chloroformate in the presence of base, or Mosher ester, a-methoxy-a- (trifluoromethyl)phenyl acetate (Jacob III, Peyton. "Resolution of ( ⁇ )-5-Bromonornicotine. Synthesis of (R)- and
  • Stable diastereomers of atropisomeric compounds can be separated and isolated by normal- and reverse-phase chromatography following methods for separation of atropisomeric naphthyl-isoquinolines (WO 96/15111).
  • a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase (Lough, W.J., Ed. Chiral Liquid Chromatography. New York: Chapman and Hall, 1989; Okamoto, Yoshio, et al. "Optical resolution of dihydropyridine enantiomers by high-performance liquid chromatography using phenylcarbamates of polysaccharides as a chiral stationary phase.” J. of Chromatogr. Vol. 513 (1990): pp. 375-378).
  • Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.
  • the compounds described herein may be administered by any convenient route appropriate to the condition to be treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary and intranasal.
  • the compounds may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc.
  • Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents. If parenteral administration is desired, the compositions will be sterile and in a solution or suspension form suitable for injection or infusion.
  • Compounds of the invention may be administered prior to, concomitantly with, or following administration of other therapeutic compounds. Sequential administration of each agent may be close in time or remote in time.
  • the other therapeutic agents may be anti- neurodegenerative with a mechanism of action that is the same as compounds of the invention, i.e., inhibit beta-secretase cleavage of APP, or a different mechanism of action, e.g., anti- ⁇ antibodies.
  • the compounds may be administered together in a unitary pharmaceutical composition or separately and, when administered separately this may occur simultaneously or sequentially in any order. Such sequential administration may be close in time or remote in time.
  • a typical formulation is prepared by mixing a compound described herein and a carrier or excipient.
  • Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C, et ah, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005.
  • the formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug ⁇ i.e., a compound described herein or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
  • buffers stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug ⁇ i.e., a compound described herein or pharmaceutical composition thereof) or aid in the manufacturing
  • One embodiment includes a pharmaceutical composition comprising a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX and X, or a stereoisomer or pharmaceutically acceptable salt thereof.
  • a further embodiment provides a pharmaceutical composition comprising a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX and X, or a stereoisomer or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.
  • the compounds of the invention inhibit the cleavage of amyloid precursor protein by ⁇ -secretase which is implicated in diseases, in particular, neurodegenerative diseases such as Alzheimer's disease.
  • AD processing of APP by ⁇ -secretase produces soluble N-APP, which activates extrinsic apoptotic pathways by binding to death receptor 6.
  • APP that is processed by ⁇ -secretase is subsequently cleaved by ⁇ -secretase, thereby producing amyloid beta peptides, such as ⁇ 1-42 that form amyloid plaques, which contribute to nerve cell death.
  • Compounds of the invention inhibit enzymatic cleavage of APP by ⁇ -secretase.
  • a method of inhibiting cleavage of APP by ⁇ -secretase in a mammal comprising administering to said mammal an effective amount of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX and X.
  • a method for treating a disease or condition mediated by the cleavage of APP by ⁇ -secretase in a mammal comprising administering to said mammal an effective amount of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX and X.
  • the neurodegenerative disease is Alzheimer's disease.
  • the neurodegenerative disease is Alzheimer's disease.
  • the BACE inhibition properties of the compounds of the invention may be determined by the following in vitro cellular Amyloidp 1-40 production assay.
  • Inhibition of Amyloidp 1 -40 production was determined by incubating cells with compound for 48 hours and quantifying the level of Amyloidp 1-40 using an homogeneous time-resolved fluorescence ("HTRF”) immunoassay.
  • HTRF time-resolved fluorescence
  • HEK-293 cells stably transfected with a DNA construct containing the coding sequence for the wild type APP695 sequence were grown in Dulbecco's Modified Eagle Medium ("DMEM") supplemented with 10% fetal bovine serum, penicillin/streptomycin and 150 ⁇ g/mL G418. Cells were plated in 96-well plates at 35,000 cells/well and allowed to attach for 8-12 hours. Media was changed to DMEM supplemented with 10% fetal bovine serum, penicillin/streptomycin 15 minutes prior to compound addition. Diluted compounds were then added at a final concentration of 0.5% DMSO.
  • DMEM Dulbecco's Modified Eagle Medium
  • HTRF reagents were obtained from the CisBio Amyloidp 1-40 peptide assay kit (Cat# 62B40PEC) and were prepared as follows anti- peptide ⁇ (l-40)-Cryptate and anti-peptide ⁇ (l-40)-XL655 were stored in 2 plate aliquots at - 80°C. Diluent and Reconstitution buffer were stored at 4°C. Aliquots of the two antibodies were diluted 1 : 100 with Reconstitution buffer, and this mixture was diluted 1 :2 with Diluent.
  • Step A A solution of 1 ,4-cyclohexanedione monoethylene ketal (50 g, 320 mmol), morpholine (30.7 mL, 352 mmol), and 4-methylbenzenesulfonic acid-monohydrate (1.22 g, 6.40 mmol) in toluene (320 mL, 1M) in a 500 mL round bottom flask was fitted with a Dean-Stark trap and a condensor, and then the reaction mixture was heated at 132°C (bath temperature) for 12 hours.
  • Step B A solution 4-(l ,4-dioxaspiro[4.5]dec-7-en-8-yl)morpholine (70 g, 261 mmol), 5-bromo-2-hydroxybenzaldehyde (52 g, 261 mmol) in toluene (131 mL, 261 mmol) was stirred at room temperature for 24 hours. A solid precipitated after 10 minutes of reaction. After 1 day, the mixture was filtered and washed with a minimal amount of toluene. The solid was dried in a vacuum oven at 50°C overnight.
  • Step C A solution of 7'-bromo-4a , -morpholino-l ',3',4 , ,4a , ,9',9a'- hexahydrospiro[[l ,3]dioxolane-2,2'-xanthen]-9'-ol (50 g, 1 17 mmol) in DCM (586 mL, 1 17 mmol) was cooled to 0°C, and Dess-Martin reagent (59.7 g, 141 mmol) was added. The mixture was stirred at room temperature for 2 hours, monitoring by TLC. The reaction mixture was diluted with DCM (1 L) and then slowly quenched with 2N NaOH.
  • Step D A solution of 7'-bromo-3',4'-dihydrospiro[[l ,3]dioxolane-2,2'-xanthen]-
  • Step E Tebbe reagent (36 mL, 18 mmol) was added to a solution of 7'-bromo- l',4',4a',9a'-tetrahydrospiro[[l ,3]dioxolane-2,2'-xanthen]-9'(3 , H)-one (5.5 g, 16 mmol) in THF (162 mL, 16 mmol) at 0°C, and the resulting mixture was stirred at 0°C for 1 hour, warming to room temperature and stirring for an additional 1 hour. The reaction mixture was cooled to 0°C, and methanol was slowly added until bubbling slowed down.
  • Step F Iodine (18.8 g, 74.1 mmol) was added to a suspension of thiocyanatosilver (14.8 g, 89.0 mmol) in acetonitrile (30 mL) and tetrahydrofuran (30 mL) at 0°C, and the resulting mixture was stirred for 1 minute.
  • Step G A solution of (4a'5,9'ai?)-7'-bromo-3',4 , ,4 , a,9 , a-tetrahydro-l 'H,2"H- dispiro[l,3-dioxolane-2,2'-xanthene-9',3"-[l ,4]thiazole]-5"-amine (7.5 g, 18.2 mmol) in 4N HC1 (aqueous, 91.2 mL, 182 mmol) and acetone (91.2 mL, 18.2 mmol) was heated at 60°C overnight. The reaction mixture was concentrated and washed with ether.
  • Step H A suspension of (4a'S,9a' ⁇ )-2-amino-7'-bromo-l , ,4',4a , ,9a , -tetrahydro- 5H-spiro[thiazole-4,9'-xanthen]-2'(3'H)-one (2.17 g, 5.91 mmol) in DCM (59 niL) was treated with TEA (1.24 niL, 8.86 mmol), followed by Boc 2 0 (1.93 g, 8.86 mmol) at 60°C overnight. The reaction mixture was washed with brine, and the organic layer was dried and concentrated.
  • Step I tert-Butyl (4a'S,9a'i?)-7'-bromo-2'-oxo-l',2',3',4',4a',9a'-hexahydro-5H- spiro[thiazole-4,9'-xanthene]-2-ylcarbamate (0.500 g, 1.07 mmol) and ammonium acetate (1.24 g, 16.0 mmol) in MeOH (21 niL) was heated at 60°C for 1 hour. The reaction mixture was cooled to room temperature, and sodium cyanoborohydride (0.101 g, 1.60 mmol) was added and stirred at room temperature overnight.
  • Step J TEA (0.0312 mL, 0.224 mmol) was added to a solution of tert-butyl (4a ,9a'i?)-2'-amino-7'-bromo-1 ⁇ 2 ⁇ 3 ⁇ 4 ⁇ 4a ⁇ 9a'-hexahydro-5H-spiro[thiazole-4,9 , -xanthene]-2- ylcarbamate (0.100 g, 0.213 mmol) in DCM (2.13 ml) at room temperature, followed by the addition of pivaloyl chloride (0.029 mL, 0.235 mmol).
  • Step K A solution of rt-butyl (4a'S,9a'/?)-7'-bromo-2'-pivalamido- l , ,2 , ,3 , ,4',4a',9a'-hexahydro-5H-spiro[thiazole-4,9'-xanthene]-2-ylcarbamate (23 mg, 0.042 mmol), pyrimidin-5-ylboronic acid (5.42 mg, 0.044 mmol), Pd(PPh 3 ) 4 (2.41 mg, 0.002 mmol), Na 2 C0 3 (2M aqueous) in dioxane (208 ⁇ , 0.042 mmol) was degassed with nitrogen for 5 minutes, sealed in a vial and stirred at 80°C for 1 day.
  • reaction mixture was filtered through glass microfibre filter ("GF/F") paper, washing with methanol. The filtrate was concentrated. Boc deprotection: The residue was dissolved in DCM and treated with TFA (0.5 mL). After stirring at room temperature for 4 hours, the reaction mixture was concentrated and then purified by C18 semi-preparative HPLC eluting with 5-95% ACN/H 2 0 + 0.1% TFA.
  • Step A A mixture of rt-butyl (4a ,9a , i?)-2'-amino-7'-bromo-l',2',3 , ,4',4a , ,9a'- hexahydro-5H-spiro[thiazole-4,9'-xanthene]-2-ylcarbamate, 2-fluoro-2-methylpropanoic acid (0.0322 g, 0.303 mmol), and triethylamine (0.106 mL, 0.758 mmol) in CH 2 C1 2 (10 mL) at room temperature was treated with BOP-C1 (0.0353 g, 0.379 mmol).
  • Step A N-((4a'S,9a'/?)-2-Amino-7'-bromo-l , ,2 , ,3 , ,4 * ,4a',9a , -hexahydro-5H- spiro[thiazole-4,9'-xanthene]-2'-yl)-2,2-difluoropropanamide (9 mg, 0.019 mmol, 17%) was prepared using a procedure analogous to Example 3, Step A, substituting 2,2-difluoropropanoic acid for 2-fluoro-2-methylpropanoic acid, then deprotection of the Boc group as in Example 1 , Step K.
  • Step A tert-Butyl (4a ,9a' ?)-2'-amino-7'-(5-chloropyridin-3-yl)-l',2',3',4',4a',9a'- hexahydro-5H-spiro[thiazole-4,9'-xanthene]-2-ylcarbamate (70 mg, 0.112 mmol, 52%) was prepared using a procedure analogous to Example 1 , Step K (no deprotection), substituting tert- butyl (4a ,9a' ?)-7'-bromo-2'-oxo-l',2 , ,3',4',4a , ,9a , -hexahydro-5H-spiro[thiazole-4,9 , -xanthene]- 2-ylcarbamate (Example 1, Step ⁇ ) and 5-chloropyridn-3-yl boronic acid.
  • Step B /ert-Butyl (4a'5,9a'7?)-7'-(5-chloropyridin-3-yl)-2'-(2-methyloxazole-4- carboxamido)- ,2 , ,3 l ,4',4a',9a'-hexahydro-5H-spiro[thiazole-4,9'-xanthene]-2-ylcarbamate (15 mg, 0.025 mmol, 36%) was prepared using a procedure analogous to Example 3, Step A, substituting 2-methyloxazole-4-carboxylic acid.
  • Step C N-((4a , S,9a'i?)-2-Amino-7'-(5-chloropyridin-3-yl)-l',2 , ,3 , ,4',4a , ,9a'- hexahydro-5H-spiro[thiazole-4,9'-xanthen]-2'-yl)-2-methyloxazole-4-carboxamide
  • Step A N-((2' 1 S,45,4a ,9a'J?)-2-Amino-7'-bromo-l * ,2 , ,3 , ,4 , ,4a',9a , -hexahydro-5H- spiro[thiazole-4,9'-xanthene]-2'-yl)-l -methylcyclopropanecarboxamide (10 mg, 0.018 mmol, 17%) was prepared using a procedure analogous to Example 3, Step A, substituting 1- methylcyclopropanecarboxylic acid.
  • Step A (4a ,9a'i?)-2-Amino-7'-(3-chloro-5-fluorophenyl)-r,4 * ,4a',9a'-tetrahydro- 5H-spiro[thiazole-4,9'-xanthen]-2'(3'H)-one (77 mg, 0.185 mmol, 68%) was prepared from the product of Example 1, Step G, and 3-chloro-5-phenylboronic acid using the procedure in Example 1, Step K.
  • Step B rt-Butyl (4S,4a'S,9a'i?)-7 , -(3-chloro-5-iluorophenyl)-2 , -oxo- r,2',3',4',4a',9a'-hexahydro-5H-spiro[thiazole-4,9'-xanthene]-2-ylcarbamate (106 mg, 0.205 mmol, >99%) was prepared using an analogous procedure to Example 1 , Step H.
  • Step C tert-Butyl (45,4a ,9a'i?)-2'-amino-7'-(3-chloro-5-fluorophenyl)- l',2 , ,3',4',4a',9a'-hexahydro-5H-spiro[thiazole-4,9'-xanthene]-2-ylcarbamate (79 mg, 0.015 mmol, 74%) was prepared using an analogous procedure to Example 1 , Step I.
  • Step D N-((2'S,4a'S,9a ⁇ )-2-Amino-7'-(3-chloro-5-fluorophenyl)-
  • Step A In a 20-dram vial, a solution of iodine (1.66 g, 6.52 mmol) in THF (3.26 mL, 3.26 mmol) was added to a suspension of silver cyanate (1.96 g, 13.0 mmol) in acetonitrile (3.26 mL, 3.26 mmol). The resulting mixture was shaken for 60 seconds.
  • Step B A solution of (4'aS,9'ai?)-7'-bromo-3',4',4'a,9'a-tetrahydro-l'H,2 ,, H- dispiro[l ,3-dioxolane-2,2'-xanthene-9',3"-[l,4]oxazole]-5"-amine (1.20 g, 3.04 mmol) in 2N HC1 (8.0 mL) and acetone (15 mL, 3.04 mmol) was heated at 55°C overnight. The mixture was basified with NaOH until a pH of greater than 10, and the mixture was extracted with ethyl acetate (3 X). The combined organic layers were dried and concentrated.
  • Step C A suspension of (4a'S,9a'7?)-2-amino-7'-bromo-l',4',4a',9a'-tetrahydro- 5H-spiro[oxazole-4,9'-xanthen]-2'(3'H)-one (1.00 g, 2.85 mmol) in DCM (29 mL) at room temperature was treated with TEA (0.60 mL, 4.27 mmol), followed by Boc 2 0 (0.932 g, 4.27 mmol).
  • Step D rt-Butyl (4S,4a'S',9a , i?)-2 , -amino-7'-bromo-l',2 , ,3 , ,4',4a',9a , -hexahydro- 5H-spiro[oxazole-4,9'-xanthene]-2-ylcarbamate (1.4 g, 3.10 mmol, >99%) was prepared using an analogous procedure to Example 1 , Step I.
  • Step E N-((4a'S,9a' ⁇ )-2-Amino-7 , -bromo-l',2',3 , ,4 , ,4a',9a , -hexahydro-5H- spiro[oxazole-4,9'-xanthene]-2'-yl)pivalamide was prepared using an analogous procedure to Example 1, Step J, and Boc deprotection from Example 1, Step (99 mg, 0.19 mmol, 86%).
  • N-((2'S,4a ,9a'7?)-2-Amino-7'- ⁇ yrimidin-5-yl)-l 2 3',4 , ,4a',9a'-hexahydro-5H- spiro[thiazole-4,9'-xanthen]-2'-yl)pivalamide trifluoroacetic acid salt 22 mg, 0.049 mmol, 56%; racemic, unknown thiazole stereochemistry
  • N-((2 ,4a'S,9a , i?)-2-Amino-7'-bromo- 1 ' ⁇ ' ⁇ ' ⁇ ' ⁇ a' ⁇ a'-hexahydro-SH- spiro[thiazole-4,9'-xanthen]-2'-yl)-l-(trifluoromethyl) cyclopropanecarboxamide trifluoroacetic acid salt (5 mg, 0.008, 8%; racemic, unknown thiazole stereochemistry) was prepared using the procedure from Example 3, Step A, substituting l-(trifluoromethyl)cyclopropanecarboxylic acid, followed by Boc deprotection from Example 1, Step K.
  • m/z (APCI-pos) M+l 504.0 (100%), 506.0 (100%).
  • Step A Oxalyl Chloride in DCM (2M) (52.90 mL, 105.8 mmol) was added to a mixture of 2-fluoro-4-methoxybenzoic acid (15.0 g, 88.16 mmol) in DCM (293.9 mL, 88.16 mmol) at 0°C. A few drops of DMF were added.
  • Step B A mixture of 7-(2-fluoro-4-methoxybenzoyl)-l ,4-dioxaspiro[4.5]decan-8- one (16.6 g, 53.84 mmol) and K 2 C0 3 (14.88 g, 107.7 mmol) in DMF (150 mL, 53.84 mmol) was stirred at room temperature for 2 hours. This was then worked up with EtOAc and water. The organics were extracted twice, washed with brine and dried with Na 2 S0 4 .
  • Step C L-Selectride® (55.82 mL, 55.82 mmol) was added to a mixture of 6'- methoxy-3',4'-dihydrospiro[[l ,3]dioxolane-2,2'-xanthen]-9'(rH)-one (14.63 g, 50.75 mmol) in DCM (169.2 mL, 50.75 mmol) at -78°C. This was stirred for 45 minutes. 0.5N Rochelle's salt solution was poured into the reaction. The mixture was then allowed to come to room temperature overnight. This was worked up with EtOAc and water.
  • Step D Tebbe reagent (9.09 mL, 4.55 mmol) was added to a mixture of (4a ,9a , 5)-6'-methoxy-1 ⁇ 4 ⁇ 4a ⁇ 9a'-tetrahydrospiro[[l ,3]dioxolane-2,2'-xanthen]-9X3'H)-one (1.1 g, 3.79 mmol) in THF (18.9 mL, 3.79 mmol) at 0°C. This was then stirred overnight at room temperature. The mixture was quenched with MeOH and then 2N NaOH was added, and this was stirred for 1 hour.
  • Step E I 2 (0.726 g, 2.86 mmol) was added to a mixture of silver cyanate (1.17 g, 7.80 mmol) and (4a'S,9a'i?)-6'-methoxy-9'-methylene-l ',3',4',4a , ,9 , ,9a'- hexahydrospiro[[l,3]dioxolane-2,2'-xanthene] (0.75 g, 2.60 mmol) in THF (10.4 mL, 2.60 mmol) and some ACN. This was stirred at 0°C overnight. The mixture was filtered through GF/F paper.
  • Step F A mixture of the product of Step E (0.752 g, 2.17 mmol) and HC1 (10.9 mL, 21.7 mmol) in acetone (15 mL, 2.17 mmol) was refluxed overnight. The mixture was worked up with DCM and water. The organics were extracted with DCM twice, washed with brine and dried with Na 2 S0 4 .
  • Step G A mixture of (4a ,9a * ⁇ )-2-amino-6'-methoxy-l , ,4',4a',9a'-tetrahydro-5H- spiro[oxazole-4,9'-xanthen]-2'(3'H)-one (0.462 g, 1.53 mmol) and N3 ⁇ 4OAc (1.77 g, 22.9 mmol) in MeOH (10.2 mL, 1.53 mmol; d. 0.791) was stirred at 60°C for 3 hours. This was then cooled to 0°C, and NaCNBH 3 (0.144 g, 2.29 mmol) was added. The mixture was stirred at room temperature overnight.
  • Step H A mixture of (2 , S,4a , S,9a'i?)-6'-methoxy-l , ,2 , ,3',4',4a',9a'-hexahydro-5H- spiro[oxazole-4,9'-xanthene]-2,2'-diamine (0.150 g, 0.494 mmol), 5-chloropicolinic acid (0.195 g, 1.24 mmol), EDCI (0.237 g, 1.24 mmol) and HOBT (0.100 g, 0.742 mmol) in DMF (4.94 mL, 0.494 mmol) was stirred at room temperature for 3 hours.
  • Step A A solution of l,4-dioxaspiro[4.5]decan-8-one (100.0 g, 641 mmol), morpholine (61.4 g, 705 mmol), and 4-methylbenzenesulfonic acid-monohydrate (2.9 g, 15 mmol) in toluene (1000 mL) in a 2000 mL round bottom flask was fitted with a Dean-Stark trap and a condenser. The reaction mixture was stirred at 135°C for 16 hours.
  • Step B A solution of 4-(1,4 ⁇ 38 ⁇ [4.5 ⁇ 6 ⁇ -7-6 ⁇ -8 ⁇ 1 ⁇ ⁇ 1 ⁇ (144.0 g, crude), 5-bromo-2-hydroxylbenzaldehyde (128.2 g, 641 mmol) in toluene (300 mL) was stirred at room temperature for 24 hours. The mixture was filtered and washed with a minimal amount of toluene.
  • Step C A solution of 7'-bromo-4a'-morpholino-l',3',4 , ,4a',9',9a'- hexahydrospiro[[l,3]dioxolane-2,2'-xanthen]-9'-ol (80.0 g, crude) in DCM (800 mL) was cooled to 0°C, and Dess-Martin reagent (95.4 g, 225 mmol) was added in portions. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM (1L), then slowly quenched with 2N NaOH. The mixture was poured into a separatory funnel, rinsing the flask with DCM and water.
  • Step D A solution of 7'-bromo-3',4'-dihydrospiro[[l,3]dioxolane-2,2'-xanthen]- 9'(l'H)-one (50 g, 149 mmol) in THF (800 mL) was cooled to -70°C, and L-Selectride® (1.0M in THF, 223 mL, 223 mmol) was added dropwise. The reaction was stirred at -70°C for 2 hours, then quenched at -70°C with saturated NH4CI (800 mL). The suspension was stirred vigorously while warming to room temperature.
  • reaction mixture was diluted with ethyl acetate (800 mL) and water (800 mL) with constant stirring. The mixture was transferred to a separatory funnel, and the aqueous layer was extracted with ethyl acetate (3 X 1L). The combined organic layers were dried and concentrated to afford the crude product which was purified by silica gel (hexanes:EtOAc, 15: 1 to 5:1) to give compound (4a'S 7'-bromo-l',4',4a',9a'- tetrahydrospiro[[l,3]dioxolane-2,2'-xanthen]-9'(3'H)-one (27.0 g, 54.0%) as a solid.
  • Step E Tebbe reagent (0.60M in toluene, 274 mL, 164 mmol) was slowly added at 0°C to a solution of (4a'S)-7'-bromo- ,4',4a , ,9a'-tetrahydrospiro[[l,3]dioxolane-2,2'-xanthen]- 9'(3'H)-one (37.0 g, 109 mmol) in THF (600 mL). The reaction mixture was stirred at room temperature for 1 hour. The mixture was quenched by 2N NaOH, to this stirring mixture was added Na 2 S0 4 , and the reaction mixture was filtered. The filtrate was concentrated.
  • Step F A solution of iodine (9.2 g, 36 mmol) in EtOAc (120 mL) was added dropwise to a suspension of AgSCN (7.0 g, 42 mmol) and (4a'S',9a'i?)-7'-bromo-9'-methylene- ,3',4',4a',9',9a'-hexahydrospiro[[l,3]dioxolane-2,2'-xanthene] (10 g, 30 mmol) in acetonitrile (60 mL) and EtOAc (60 mL) at 0°C. After 3 hours, the reaction mixture was filtered through Celite®, washed with EtOAc.
  • Step G A solution of the product of Step F (1 1.2 g, 27 mmol) in 3N HC1 (150 raL), acetone (400 mL) and THF (50 mL) was heated at 60°C for 16 hours. The mixture was basified with NaOH until pH greater than 10, and the mixture was extracted with EtOAc (3 X 500 mL).
  • Step H DMAP (2.7 g, 22.3 mmol) and Boc 2 0 (24.3 g, 1 1 1.5 mmol) were added to a solution of (4a'5,9a'J?)-2-amino-7'-bromo-l',4',4a , ,9a'-tetrahydro-5H-spiro[thiazole-4,9'- xanthen]-2'(3'H)-one (8.2 g, 22.3 mmol) in DCM (100 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. The solvent was removed.
  • Step I Ammonium acetate (15.9 g, 206 mmol) was added to a solution of the product of Step H (7.3 g, 12.9 mmol) in MeOH (100 mL). The reaction mixture was stirred at 60°C for 1 hour. After cooling to room temperature, NaBH 3 CN (1.3 g, 20.6 mmol) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The mixture was poured into water, and extracted with DCM (3 X 200 mL). The solvent was removed under reduced pressure to give a crude product (7.0 g) that was used without further purification.
  • Step L To a solution of -((43 ⁇ ,93 ⁇ )-2 ⁇ -7' ⁇ -1 2 ⁇ 3 ⁇ 4',43',9 ⁇ - hexahydro-5H-spiro[thiazole-4,9'-xanthen]-2'-yl)pivalamide (250 mg, 0.55 mmol) in DMAc were added Zn(CN) 2 (45 mg, 0.39 mmol), dppf (60 mg, 0.1 mmol), Zn(CHO) 2 -2H 2 0 (45 mg, 0.2 mmol) and Pd/C (25 mg). The reaction was stirred at 140°C for 24 hours.
  • N-((2'S,4R 'S,9a'R)-2- amino-7'-cyano-r,2',3',4',4a',9a'-hexahydro-5H-spiro[thiazole-4,9'-xanthen]-2'-yl)pivalamide 29.6 mg
  • N-((2 , i?,4i?,4a ,9a'J?)-2-amino-7 , -cyano-l',2',3',4 , ,4a',9a , -hexahydro-5H- spiro[thiazole-4,9'-xanthen]-2'-yl)pivalamide (1 1.5 mg) as a solid.
  • Step A Pd(PPh 3 ) 2 Cl 2 (84 mg, 0.13 mmol) and Na 2 C0 3 (318 mg, 3.0 mmol) were added to a solution of tert-butyl ((4a'5',9a'i?)-7'-bromo-2'-pivalamido-l',2 , ,3',4',4a , ,9a'-hexahydro- 5H-spiro[thiazole-4,9'-xanthen]-2-yl)carbamate (350 mg, 0.6 mmol), 2-isopropenyl-4,4,5,5- tetramethyl-[l ,3,2]dioxaborolane (218 mg, 1.3 mmol) in dioxane (8 mL) and water (2 mL).
  • Step B 10% Pd/C (50 mg) was added to a solution of rt-butyl ((4a ,9a'i?)-2'- pivalamido-7'-( rop-l -en-2-yl)-r,2 , ,3',4',4a',9a'-hexahydro-5H-spiro[thiazole-4,9 , -xanthen]-2- yl)carbamate (250 mg, 0.49 mmol) in MeOH (10 mL). The mixture was stirred at room temperature under H 2 atmosphere for 2 hours.
  • Step C A solution of tert-butyl ((4a'S,9a'/?)-7 , -isopropyl-2'-pivalamido- r,2',3',4 , ,4a',9a , -hexahydro-5H-spiro[thiazole-4,9 , -xanthen]-2-yl)carbamate (200 mg, 0.39 mmol) in 4N HCl/MeOH (10 mL) was stirred at room temperature overnight.
  • N-((2 ,4i ⁇ ,4a ,9a , ⁇ )-2-amino-7'-isopropyl-1 ⁇ 2 ⁇ 3 ⁇ 4 ⁇ 4a 9a'-hexahydro-5H-spiro[thiazole- 4,9'-xanthen]-2'-yl)pivalamide (34.4 mg) and N-((2'/?,4 ?,4a'S,9a' ⁇ )-2-amino-7'-isopropyl- r,2',3',4',4a',9a'-hexahydro-5H-spiro[thiazole-4,9'-xanthen]-2'-yl)pivalamide (14.5 mg) as a solid.
  • Step A Pd(PPh 3 ) 2 Cl 2 (116 mg, 0.17 mmol) and Na 2 C0 3 (350 mg, 3.3 mmol) were added to a solution of tert-butyl ((4a'5',9a' ⁇ )-7'-bromo-2'-pivalamido-r,2 , ,3 , ,4',4a',9a'- hexahydro-5H-spiro[thiazole-4,9'-xanthen]-2-yl)carbamate (600 mg, 1.1 mmol), potassium vinyl trifluoroborate (221 mg, 1.7 mmol) in dioxane (8 mL) and water (2 mL).
  • reaction mixture was heated at 60°C under N 2 for 2 hours.
  • Step B 10% Pd/C (50 mg) was added to a solution of rt-butyl ((4a'S,9a'i?)-2'- pivalamido-7'-vinyl- ,2 , ,3',4',4a',9a'-hexahydro-5H-spiro[thiazole-4,9'-xanthen]-2-yl)carbamate (250 mg, 0.49 mmol) in MeOH (10 mL). The mixture was stirred at room temperature under H 2 atmosphere for 2 hours.
  • Step C A solution of rt-butyl ((4a ,9a' ⁇ )-7'-ethyl-2'-pivalamido- l',2',3',4 , ,4a',9a , -hexahydro-5H-spiro[thiazole-4,9'-xanthen]-2-yl)carbamate (170 mg, 0.34 mmol) in 4N HCl/MeOH (10 mL) was stirred at room temperature overnight.
  • N-((2 ,4a ,9a ⁇ )-2-amino-7 , -ethyl-l',2 , ,3',4 , ,4a',9a , -hexahydro-5H-spiro[thiazole-4,9'- xanthen]-2'-yl)pivalamide (33.9 mg) and N-((2 , i?,4a'S,9a , i?)-2-amino-7'-ethyl-r,2',3 , ,4',4a',9a'- hexahydro-5H-spiro[thiazole-4,9'-xanthen]-2'-yl)pivalamide (13.6 mg).
  • Step A Potassium cyclopropyl-l-trifluoroborate (4.0 g, 26.9 mmol), Pd(OAc) 2 (605 mg, 2.7 mmol), RuPhos (2.5 g, 5.4 mmol) and K 3 P0 4 (11.4 g, 54.0 mmol) were added to a solution of (4a'S,9a'i?)-7'-bromo-9'-methylene-l',3',4',4a',9',9a , -hexahydrospiro[[l,3]dioxolane- 2,2'-xanthene] (6.0 g, 17.9 mmol) in toluene (60 mL) and H 2 0 (6 mL).
  • Step B A solution of iodine (1.0 g, 4.0 mmol) in EtOAc (15 mL) was added dropwise to a suspension of AgSCN (840 mg ,5.1 mmol) and (4a'S,9a'i?)-7'-cyclopropyl-9'- methylene-r,3',4 , ,4a',9',9a'-hexahydrospiro[[l,3]dioxolane-2,2'-xanthene] (1.0 g, 3.4 mmol) in acetonitrile (15 mL) and EtOAc(15 mL) at 0°C.
  • reaction mixture was filtered through Celite® and washed with EtOAc. The solvent was removed under reduced pressure. The residue was dissolved in THF (50 mL), and NH 4 OH (15 mL, 25% w/w) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and saturated NaHC0 3 , and the aqueous layer was extracted with EtOAc (3 X 50 mL). The combined organic layers were dried and concentrated to afford a solid (0.9 g, crude) that was used without further purification.
  • Step C A solution of the crude product of Step (900 mg) in 3N HC1 (25 mL) and THF (50 mL) was heated at 60°C for 16 hours. The mixture was basified with saturated NaHC0 3 until the pH was greater than 10, and the mixture was extracted with EtOAc (3 X 100 mL).
  • Step D DMAP (279 mg, 2.3 mmol) and Boc 2 0 (1.5 g, 6.9 mmol) were added to a solution of (4a'5',9a , i?)-2-amino-7'-cyclopropyl- 1 ',4',4a',9a'-tetrahydro-5H-spiro[thiazole-4,9'- xanthen]-2'(3'H)-one (750 mg, crude) in DCM (10 mL) at room temperature. The mixture was stirred at room temperature for 2 hours.
  • Step E Ammonium acetate (2.1 g, 28.0 mmol) was added to a solution of tert- butyl ((4a ,9a'i?)-7'-cyclopropyl-2'-oxo-l',2',3',4',4a',9a , -hexahydro-5H-spiro[thiazole-4,9'- xanthen]-2-yl)carbamate (750 mg, crude) in MeOH (10 mL). The reaction mixture was stirred at 60°C for 1 hour. After cooling to room temperature, NaBH 3 CN (180 mg, 2.8 mmol) was added to the mixture. The reaction mixture was stirred at room temperature overnight.
  • tert- butyl ((4a ,9a'i?)-7'-cyclopropyl-2'-oxo-l',2',3',4',4a',9a , -hexahydro-5H-spiro[thiazole-4,
  • Step F 2,2-Dimethyl-propionyl chloride (180 mg, 1.5 mmol) was added dropwise at 0°C to a solution of tert-butyl ((4a'5',9a'i?)-2 , -amino-7'-cyclopropyl-l',2',3',4',4a',9a'- hexahydro-5H-spiro[thiazole-4,9'-xanthen]-2-yl)carbamate (530 mg, crude) and Et 3 N (370 mg, 3.7 mmol) in DCM (10 mL). The mixture was stirred at room temperature for 2 hours.
  • tert-butyl ((4a'5',9a'i?)-2 , -amino-7'-cyclopropyl-l',2',3',4',4a',9a'- hexahydro-5H-spiro[thiazole-4,9'-xanthen]-2-y
  • Step G A solution of tert-butyl ((4a'S,9a'i?)-7'-cyclopropyl-2'-pivalamido- ,2',3',4',4a',9a'-hexahydro-5H-spiro[thiazole-4,9'-xanthen]-2-yl)carbamate (350 mg, crude) in 4N HCl/MeOH (40 mL) was stirred at room temperature overnight. The solvent was removed under reduce pressure to give the crude product, which was purified by pre-HPLC (HCl) to give N-((2 ,4a ,9a ?)-2-amino-7'-cyclopropyl-1 ⁇ 2 ⁇
  • Step A A solution of iodine (1.0 g, 4.0 mmol) in EtOAc (30 mL) was added dropwise to a suspension of AgOCN (705 mg, 4.7 mmol ) and (4a'S,9a'7?)-7'-cyclopropyl-9'- methylene-r,3',4',4a',9',9a'-hexahydrospiro[[l,3]dioxolane-2,2'-xanthene] (1.0 g, 3.4 mmol) in acetonitrile (15 mL) and EtOAc (15 mL) at 0°C.
  • reaction mixture was filtered through Celite® and washed with EtOAc. The solvent was removed under reduced pressure. The residue was dissolved in THF (50 mL), and NH 4 OH (10 ml, 25% w/w) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between EtOAc and saturated NaHC0 3 , and the aqueous layer was extracted with EtOAc (3 X 50 mL). The combined organic layers were dried and concentrated to give a solid (1.0 g, crude, mixture of two diastereomers) that was used without further purification.
  • Step B A solution of the product of Step A (1.0 g, crude) in 3N HC1 (30 mL), acetone (80 mL) and THF (10 mL) was heated at 60°C for 16 hours. The mixture was basified with saturated NaHC0 3 until a pH greater than 10, and the mixture was extracted with EtOAc (3 X 50mL).
  • Step C DMAP (330 mg, 2.7 mmol) and Boc 2 0 (1.8 g, 8.16 mmol) were added to a solution of (4a ,9a'/?)-2-amino-7'-cyclopropyl-l',4',4a',9a'-tetrahydro-5H-spiro[oxazole-4,9'- xanthen]-2'(3'H)-one (850 mg, crude) in DCM (100 mL) at room temperature. The mixture was stirred at room temperature for 2 hours.
  • Step D Ammonium acetate (772 mg, 10 mmol) to a solution of tert-butyl ((45,4a , 5,9a , i ⁇ )-7'-cyclopropyl-2'-oxo-l',2 , ,3',4 , ,4a',9a , -hexahydro-5H-spiro[oxazole-4,9 , - xanthen]-2-yl)carbamate (270 mg, crude) in MeOH (10 mL). The reaction mixture was stirred at 60°C for 1 hour. After cooling to room temperature, NaBH 3 CN (63 mg, 1.0 mmol) was added to the mixture.
  • tert-butyl ((45,4a , 5,9a , i ⁇ )-7'-cyclopropyl-2'-oxo-l',2 , ,3',4 , ,4a',9a , -hexahydro-5H-s
  • Step E 2,2-Dimethyl-propionyl chloride (1 10 mg, 0.9 mmol) was added dropwise at 0°C to a solution of tert-butyl ((4S,4a ,9a'i?)-2'-amino-7'-cyclopropyl- r,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2-yl)carbamate (250 mg, 0.6, crude) and Et 3 N (184 mg, 1.8 mmol) in DCM (10 mL). The mixture was stirred at room temperature for 2 hours.
  • tert-butyl ((4S,4a ,9a'i?)-2'-amino-7'-cyclopropyl- r,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2
  • Step F A solution of fert-butyl ((4S,4a , S,9a' J R)-7'-cyclopropyl-2'-pivalamido- r,2 , ,3 , ,4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2-yl)carbamate (250 mg, crude) in 4N HCl/MeOH (20 mL) was stirred at room temperature overnight.
  • Step A to a solution of tert-butyl ((45,4a' i S,9a'i?)-7'-cyclopropyl-2'-oxo- r,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2-yl)carbamate (560 mg, crude) in MeOH (15 mL) was added ammonium acetate (1.7 g, 22 mmol). The reaction mixture was stirred at 60°C for 1 hour. After cooling to room temperature, NaBH 3 CN (140 mg, 2.2 mmol) was added to the mixture. The reaction mixture was stirred at room temperature overnight.
  • tert-butyl ((45,4a' i S,9a'i?)-7'-cyclopropyl-2'-oxo- r,2',3',4',4a',9a'-hexahydro-5H-spiro[
  • Step B 2,2-Dimethyl-propionyl chloride (220 mg, 1.8 mmol) was added dropwise at 0°C to a solution of tert-butyl ((4S,4a'S,9a ?)-2'-amino-7'-cyclopropyl- r,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2-yl)carbamate (480 mg, crude) and Et 3 N (350 mg, 3.5 mmol) in DCM (10 mL). The mixture was stirred at room temperature for 2 hours.
  • tert-butyl ((4S,4a'S,9a ?)-2'-amino-7'-cyclopropyl- r,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2-yl
  • Step C A solution of rt-butyl ((45',4a'S , ,9a'i?)-7'-cyclopropyl-2'-pivalamido- r,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2-yl)carbamate (450 mg, crude) in 4N HCl/MeOH (20 mL) was stirred at room temperature overnight.
  • Step A A solution of iodine (9.2 g, 36 mmol) in EtOAc (120 mL) was added dropwise to a suspension of AgOCN (6.3 g, 42 mmol) and (4a ,9a'i?)-7'-bromo-9'-methylene- r,3 , ,4',4a',9',9a'-hexahydrospiro[[l,3]dioxolane-2,2'-xanthene] (10 g, 30 mmol) in acetonitrile (60 mL) and EtOAc (60 mL) at 0°C.
  • Step B A solution of the product of Step A (11.0 g, 27 mmol) in 3N HC1 (150 mL), acetone (150 mL) was heated at 60°C for 16 hours. The mixture was basified with NaOH until a pH greater than 10, and the mixture was extracted with EtOAc (3 X 500 mL). The combined organic layers were dried, concentrated, and purified by trituration with PE to give (4a ,9a ⁇ )-2-amino-7'-bromo-1 ⁇ 4 ⁇ 4a ⁇ 9a'-tetrahydro- ⁇
  • Step C DMAP (1.4 g, 11.4 mmol) and Boc 2 0 (5.0 g, 22.8 mmol) was added to a solution of (4a , S,9a'i?)-2-amino-7'-bromo- ,4',4a',9a'-tetrahydro-5H-spiro[oxazole-4,9'- xanthen]-2'(3'H)-one (4.0 g, 11.4 mmol) in DCM (20 mL) at room temperature. The mixture was stirred at room temperature for 2 hours.
  • Step D Ammonium acetate (2.6 g, 33.3 mmol) to a solution of tert-butyl ((4a'5,9a , J /?)-7'-bromo-2'-oxo-l',2',3',4 , ,4a , ,9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2- yl)carbamate (1.0 g, 2.2 mmol) in MeOH (50 mL). The reaction mixture was stirred at 60°C for 1 hour. After cooling to room temperature, NaBH 3 CN (210 mg, 3.33 mmol) was added to the mixture.
  • tert-butyl ((4a'5,9a , J /?)-7'-bromo-2'-oxo-l',2',3',4 , ,4a , ,9a'-hexahydro-5H-spiro[oxazole-4
  • Step E 2,2-Dimethyl-propionyl chloride (400 mg, 3.3 mmol) was added dropwise at 0°C to a solution of tert-butyl ((4a'5,9a'J?)-2 , -amino-7 , -bromo-l',2',3',4 , ,4a',9a'- hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2-yl)carbamate (1.0 g, crude) and Et 3 N (670 mg, 6.6 mmol) in DCM (50 mL). The mixture was stirred at room temperature for 2 hours.
  • tert-butyl ((4a'5,9a'J?)-2 , -amino-7 , -bromo-l',2',3',4 , ,4a',9a'- hexahydro-5H-spiro[oxazole-4,9'-xant
  • Step F 10% Pd/C (50 mg) was added to a solution of tert-butyl ((4a'5,9a'i?)-7'- bromo-2 , -pivalamido-r,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2- yl)carbamate (250 mg, 0.47 mmol) in MeOH (8 mL). The mixture was stirred at room temperature under H 2 atmosphere for 2 hours.
  • Step G A solution of rt-butyl ((4S,4a , 5,9a'/?)-2 , -pivalamido-l',2',3 , ,4 , ,4a',9a'- hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2-yl)carbamate (140 mg, 0.3 mmol) in 4N HCl/MeOH (5 mL) was stirred at room temperature overnight.
  • Step A A solution of /ert-butyl ((4a'S,9a' ?)-7 , -bromo-2'-pivalamido- ,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2-yl)carbamate (2.0 g, 3.7 mmol) in 4N HCl/MeOH (50 mL) was stirred at room temperature overnight.
  • Step B Zn(CN) 2 (45 mg, 0.39 mmol), dppf (60 mg, 0.1 mmol), Zn(CHO) 2 -2H 2 0 (45 mg, 0.2 mmol) and Pd/C (25 mg) were added to a solution of N-((4a'5',9a' ?)-2-amino-7'- bromo-r,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9 , -xanthen]-2'-yl)pivalamide (350 mg, crude) in DM Ac. The reaction was stirred at 140°C for 24 hours.
  • Step A Pd(PPh 3 ) 2 Cl 2 (53 mg, 0.08 mmol) and Na 2 C0 3 (160 mg, 1.5 mmol) were added to a solution of N-((4a'S,9a'i?)-2-amino-7 , -bromo-l , ,2',3',4',4a',9a , -hexahydro-5H- spiro[oxazole-4,9'-xanthen]-2'-yl)pivalamide (235 mg, 0.5 mmol), 4,4,5,5-tetramethyl-2-(prop- l-en-2-yl)-l,3,2-dioxaborolane (126 mg, 0.75 mmol) in dioxane (8 mL) and water (2 mL).
  • Step B 10% Pd/C (50 mg) was added to a solution of N-((4a'5,9a'i?)-2-amino-7'- ( rop-l-en-2-yl)-r,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2'-yl)pivalamide (500 mg, crude) in MeOH (20 mL). The mixture was stirred at room temperature under H 2 atmosphere for 6 hours.
  • Step A Pd(PPh 3 ) 2 Cl 2 (116 mg, 0.17 mmol ) and Na 2 C0 3 (350 mg, 3.3 mmol) were added to a solution of N-((4a'S,9a , ⁇ )-2-amino-7 , -bromo-l',2 , ,3',4',4a',9a'-hexahydro-5H- spiro[oxazole-4,9'-xanthen]-2'-yl)pivalamide (500 mg, 1.1 mmol), 2-(cyclohex-l-en-l-yl)- 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (358 mg, 1.7 mmol) in dioxane (8 mL) and water (2 mL).
  • Step B 10% Pd/C (50 mg) was added to a solution of N-((4a ,9a'i?)-2-amino-7'- (cyclohex- 1 -en- 1 -yl)- 1 ',2',3 ',4',4a',9a'-hexahydro-5H-spiro [oxazole-4,9'-xanthen] -2'- yl)pivalamide (600 mg, crude) in MeOH (20 mL). The mixture was stirred at room temperature under H 2 atmosphere for 6 hours.
  • Step A Pd(PPh 3 ) 2 Cl 2 (116 mg, 0.17 mmol) and Na 2 C0 3 (350 mg, 3.3 mmol) were added to a solution of N-((4a'5 , ,9a'i?)-2-amino-7 , -bromo-l',2',3 , ,4 , ,4a',9a , -hexahydro-5H- spiro[oxazole-4,9'-xanthen]-2'-yl)pivalamide (500 mg, 1.1 mmol), 2-(cyclopent-l-en-l-yl)- 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (330 mg, 1.7 mmol) in dioxane (8 mL) and water (2 mL).
  • Step B 10% Pd/C (50 mg) to a solution of N-((4a'S,9a'i?)-2-amino-7'-(cyclopent- 1 -en- 1 -yl)- 1 * ,2',3 ' ⁇ ' ⁇ a' ⁇ a'-hexahydro-SH-spiro [oxazole-4,9'-xanthen] -2'-yl)pivalamide (600 mg, crude) in MeOH (20 mL). The mixture was stirred at room temperature under H 2 atmosphere for 6 hours.
  • Step A Pd(PPh 3 ) 2 Cl 2 (116 mg, 0.17 mmol) and Na 2 C0 3 (350 mg, 3.3 mmol) to a solution of N-((4a , 1 S,9a'i ⁇ )-2-amino-7'-bromo-l ',2 , ,3 , ,4',4a',9a'-hexahydro-5H-spi ⁇ o[oxazole-4,9 , - xanthen]-2'-yl)pivalamide (500 mg
  • Step B 10% Pd/C (50 mg) was added to a solution of
  • Step A A solution of Intermediate 1 (6.0 g, 15.2 mmol), 4,4,5,5-tetramethyl-2- (prop-l-en-2-yl)-l,3,2-dioxaborolane (3.8 g, 22.8 mmol), Pd(PPh 3 ) 2 Cl 2 (1.1 g, 1.5 mmol) and Na 2 C0 3 (4.8 g, 45.6 mmol) in dioxane/H 2 0 (120/40 mL) was stirred at 100°C for 2.5 hours. Water was added, and the mixture was extracted with EtOAc (3 X 100 mL), the organic layer was dried over Na 2 S0 4 , filtered and concentrated. The residue was purified by column chromatography on silica gel (eluting with 50% ethyl acetate in petroleum ether) to yield the product (3.3 g, 80.0% purity) that was used without fur her purification.
  • Step B A mixture of the product of Step A (3.3 g, 9 mmol) and Pd/C (960 mg) in MeOH (50 ml) was stirred at room temperature under H 2 atmosphere for 2 hours. The catalyst was filtered off, and the filtrate was concentrated to give the product (2.5 g, 75.8%).
  • Step C A solution of the product of Step A (2.5 g, 7.0 mmol) in 3N HC1 (25 mL), acetone/THF (75/25 mL) was heated at 60°C for 16 hours. The mixture was basified with Na 2 C03 until a pH greater than 10, and the mixture was extracted with EtOAc (3 X 60 mL). The combined organic layers were dried, concentrated, and purified by trituration with PE to give (4S,4a , i?,9a'5)-2-amino-7'-isopropyl- ,4',4a , ,9a'-tetrahydro-5H-spiro[oxazole-4,9 ! -xanthen]- 2'(3'H)-one (2.0 g, crude) as a solid that was used without further purification.
  • Step D Ammonium acetate (4.3 g, 56 mmol) was added to a solution of (4S,4a' J /?,9a'S)-2-amino-7'-isopropyl-l , ,4 , ,4a',9a'-tetrahydro-5H-spiro[oxazole-4,9'-xanthen]- 2'(3'H)-one (1.1 g, 3.5 mmol) in MeOH (50 mL). The reaction mixture was stirred at 60°C for 1 hour. After cooling to room temperature, NaBH 3 CN (352 mg, 5.6 mmol) was added to the mixture. The reaction mixture was stirred at room temperature overnight.
  • Step E EDCI (184 mg, 0.96 mmol), HOBT (130 mg, 0.96 mmol) and DIPEA (206 mg, 1.6 mmol) at 0°C were added to a mixture of (2'i?,4S,4a'i?,9a'S)-7'-isopropyl- l , ,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthene]-2,2'-diamine (100 mg, 0.32 mmol) and 5-methylpicolinic acid (108 mg, 0.79 mmol) in DCM (8 mL). The mixture was stirred at room temperature overnight.
  • Step F A mixture of N,N'-((4S,4a , i?,9a , 5)-7 , -isopropyl-l , ,2 , ,3 , ,4 , ,4a',9a'- hexahydro-5H-spiro[oxazole-4,9'-xanthene]-2,2'-diyl)bis(5-methylpicolinamide) (200 mg, 0.36 mmol) and LiOH H 2 0 (151 mg, 3.6 mmol) in MeOH/H 2 0 (3/3 mL) was stirred at reflux for 1.5 hours. Water was added, and the mixture was extracted with EtOAc. The organic layer was concentrated.
  • Step B A mixture of methyl 4-(difluoromethyl)benzoate (1.1 g, 5.9 mmol) and LiOH H 2 0 (1.24 g, 29.5 mmol) in THF/H 2 0 (30/10 mL) was stirred at room temperature for 3 hours. The mixture was acidified by IN HC1 to a pH of 2 and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na 2 S0 4 , filtered and concentrated to give 4-(difluoromethyl)benzoic acid (1.0 g, 98.0% yield).
  • Step C EDCI (184 mg, 0.96 mmol), HOBT (130 mg, 0.96 mmol) and DIPEA (206 mg, 1.6 mmol) were added at 0°C to a mixture of (4S,4a'i?,9a'S)-7'-isopropyl- l , ,2',3 , ,4',4a , ,9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthene]-2,2'-diamine (100 mg, 0.32 mmol) and 4-(difluoromethyl)benzoic acid (136 mg, 0.79 mmol) in DCM (8 mL).
  • Step D A mixture of N ⁇ , -((4S,4a'i?,9a'S)-7 , -isopropyl-l',2 , ,3',4 , ,4a',9a'- hexahydro-5H-spiro[oxazole-4,9'-xanthene]-2,2'-diyl)bis(4-(difluoromethyl)benzamide) (200 mg, 0.32 mmol) and LiOH H 2 0 (134 mg, 3.2 mmol) in MeOH/H 2 0 (5/5 mL) was stirred at reflux for 1.5 hours. Water was added, and the mixture was extracted with EtOAc.
  • Step A A mixture of 2,3-dichloro-5-(trifluoromethyl)pyridine (2.0 g, 9.3 mmol),
  • Step B A mixture of ethyl 3-chloro-5-(trifluoromethyl)picolinate (500 mg, 2.0 mmol) and LiOH H 2 0 (1.24 g, 29.6 mmol) in THF/H 2 0 (12/4 mL) was stirred at room temperature for 3 hours. The mixture was concentrated, then dissolved in DCM, filtered and the filtrate was concentrated to give 3-chloro-5-(trifluoromethyl)picolinic acid (400 mg, 90% yield).
  • Step C EDCI (184 mg, 0.96 mmol), HOBT (130 mg, 0.96 mmol) and DIPEA (206 mg, 1.6 mmol) were added at 0°C to a mixture of (45',4a' ⁇ ,9a , 5)-7'-isopropyl- l',2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthene]-2,2 , -diamine (100 mg, 0.32 mmol) and 3-chloro-5-(trifluoromethyl)picolinic acid (136 mg, 0.79 mmol) in DCM (8 mL).
  • Step D to a mixture of N,iV-((4-S',4a' ⁇ ,9a , 5)-7'-isopropyl-l',2',3',4',4a',9a , - hexahydro-5H-spiro[oxazole-4,9'-xanthene]-2,2'-diyl)bis(3-chloro-5-
  • Step A EDCI (184 mg, 0.96 mmol), HOBT (130 mg, 0.96 mmol) and DIPEA (206 mg, 1.6 mmol) were added at 0°C to a mixture of (45 , ,4a'i?,9a'5)-7'-isopropyl- r,2',3',4',4a ! ,9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthene]-2,2'-diamine (100 mg, 0.32 mmol) and 5-methoxypicolinic acid (121 mg, 0.79 mmol) in DCM (8 mL). The mixture was stirred at room temperature overnight.
  • Step B A mixture of N V-((4 1 S,4a'i?,9a , S)-7 , -isopropyl-l',2',3',4',4a',9a'- hexahydro-5H-spiro[oxazole-4,9'-xanthene]-2,2'-diyl)bis(5-methoxypicolinamide) (200 mg, 0.32 mmol) and LiOH H 2 0 (134 mg, 3.2 mmol) in MeOH/H 2 0 (5/5 mL) was stirred at reflux for 1.5 hours. Water was added, and the mixture was extracted with EtOAc.
  • Step A A solution of (2'i?,45,4a , i?,9a , S)-7'-isopropyl-l',2 , ,3',4',4a',9a , -hexahydro- 5H-spiro[oxazole-4,9'-xanthene]-2,2'-diamine (100 mg, 0.32 mmol), 5-methylpyrazine-2- carboxylic acid (1 10 mg, 0.79 mmol), HATU (362 mg, 0.96 mmol) and DIPEA (206 mg, 1.6 mmol) in DCM (8 mL) was stirred at room temperature overnight. Water was added and the mixture was extracted with EtOAc.
  • Step B A mixture of N,N'-((2'i ⁇ ,4S,4a , J ? ⁇ ,9a'5)-7'-isopropyl-l',2',3',4 , ,4a',9a , - hexahydro-5H-spiro[oxazole-4,9'-xanthene]-2,2 , -diyl)bis(5-methylpyrazine-2-carboxamide) (200 mg, 0.32 mmol) and LiOH H 2 0 (134 mg, 3.2 mmol) in MeOH/H 2 0 (5/5 mL) was stirred at reflux for 1.5 hours. Water was added, and the mixture was extracted with EtOAc.
  • Step A EDCI (184 mg, 0.96 mmol), HOBT (130 mg, 0.96 mmol) and DIPEA (206 mg, 1.6 mmol) were added at 0°C to a mixture of (4S,4a'i?,9a'5)-7'-isopropyl- l , ,2',3 , ,4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthene]-2,2'-diamine (100 mg, 0.32 mmol) and pyrimidine-4-carboxylic acid (134 mg, 0.79 mmol) in DCM (8 mL). The mixture was stirred at room temperature overnight.
  • Step B A mixture of N,iV-((45,4a'i?,9a'5)-7 , -isopropyl-l',2 , ,3',4',4a',9a'- hexahydro-5H-spiro [oxazole-4,9'-xanthene] -2,2'-diyl)bis(pyrimidine-4-carboxamide) (200 mg, 0.32 mmol) and LiOH H 2 0 (134 mg, 3.2 mmol) in MeOH/H 2 0 (5/5 mL) was stirred at reflux for 1.5 hours. Water was added, and the mixture was extracted with EtOAc.
  • Step A BBr 3 (85.2 g, 341 mmol) was added dropwise at -20°C under N 2 to a solution of 2-methoxy-5-(trifluoromethoxy)benzaldehyde (50.0 g, 227 mmol) in DCM (500 mL). The reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was worked up by adding ice chips, then the mixture was poured into saturated aqueous NaHC0 3 (300 mL), and extracted with DCM (3 X 400 mL).
  • Step B A solution 2-hydroxy-5-(trifluoromethoxy)benzaldehyde (36.6 g, 178 mmol), 4-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)morpholine (40.0 g, 178 mmol) in toluene (70 mL) was stirred at room temperature for 24 hours. The mixture was filtered and washed with a minimal amount of toluene.
  • Step C A solution of 4a , -mo holino-7'-(trifluoromethoxy)-l , ,3',4 , ,4a',9 , ,9a , - hexahydrospiro[[l,3]dioxolane-2,2'-xanthen]-9'-ol (67.2 g, 156 mmol) in DCM (400 mL) was cooled to 0°C and Dess-Martin reagent (79.0 g, 187 mmol) was added in portions. The mixture was stirred at room temperature for overnight. The reaction mixture was diluted with DCM (400 mL), then slowly quenched with 2N NaOH.
  • Step D A solution of compound 5 (52.5 g, 154 mmol) in THF (800 ml) was cooled to -70°C, and L-Selectride® (1.0 M in THF , 230 mL, 230 mmol) was added dropwise.
  • the reaction was stirred at -70°C for 2 hours and then quenched at -70°C with saturated NFL;C1 (10 mL). The suspension was stirred vigorously while warming to room temperature. The reaction mixture was diluted with ethyl acetate (800 mL) and water (800 mL) with constant stirring. The mixture was transferred to a separatory funnel, and the aqueous layer was extracted with ethyl acetate (3 X 800 mL).
  • Step E Tebbe reagent (0.60M in toluene, 200 mL, 120 mmol) was slowly added at 0°C to a solution of (4a'S,9a'S)-7'-(trifluoromethoxy)-l ',4',4a , ,9a'- tetrahydrospiro[[l,3]dioxolane-2,2'-xanthen]-9'(3'H)-one (17.0g ,48mmol) in THF (250 mL). The reaction mixture was stirred at room temperature for 1 hour. The mixture was quenched by 2N NaOH. Na 2 S0 4 was added to this stirring mixture, and the reaction mixture was filtered.
  • Step F A solution of iodine (13.4 g, 52.5 mmol) in EtOAc (150 mL) was added dropwise to a suspension of AgOCN (9.15 g, 61.4 mmol) and 9'-methylene-7'- (trifluoromethoxy)-l',3',4',4a',9',9a'-hexahydrospiro[[l ,3]dioxolane-2,2'-xanthene] (15 g, 43.8 mmol) in acetonitrile (150 mL ) and EtOAc(150 mL) at 0°C.
  • reaction mixture was filtered through Celite® and washed with EtOAc. The solvent was removed under reduced pressure. The residue was dissolved in THF (750 mL), and NH 4 OH (230 mL, 25% w/w) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and saturated NaHC0 3 (300 mL), and the aqueous layer was extracted with EtOAc (3 X 200 mL). The combined organic layers were dried and concentrated to afford the crude product, which was purified by trituration with PE to give the product as a solid (15.6 g, mixture of two diastereomers, 74.3% of yield).
  • Step G A solution of the product of Step F (15.6 g, 39 mmol) in 3N HC1 (150 mL) and acetone (300 mL) was heated at 60°C for 16 hours. The mixture was basified with NaOH until a pH greater than 10, and the mixture was extracted with EtOAc (3 X 500 mL).
  • Step H Ammonium acetate (1.7 g, 22.5 mmol) was added to a solution of (4 ⁇ ,4a ,9a'i?)-2-amino-7'-(trifluoromethoxy)-l',4 , ,4a',9a'-tetrahydro-5H-spiro[oxazole-4,9'- xanthen]-2'(3'H)-one (500 mg, 1.4 mmol) in MeOH (20 mL). The reaction mixture was stirred at 60°C for 1 hour. After cooling to room temperature, NaBH 3 CN (145 mg, 2.3 mmol) was added to the mixture. The reaction mixture was stirred at room temperature overnight.
  • Step I 2,2-Dimethyl-propionyl chloride (150 mg, 1.3 mmol) was added dropwise at 0°C to a solution of (4i?,4a ,9a'i?)-7 , -(trifluoromethoxy)-l , ,2 , ,3',4',4a',9a'-hexahydro-5H- spiro[oxazole-4,9'-xanthene]-2,2'-diamine (150 mg, 0.4 mmol) and Et 3 N (240 mg, 2.5 mmol) in DCM (5 mL). The mixture was stirred at room temperature for 2 hours.
  • Step J LiOH H 2 0 (265 mg, 6.3 mmol) to a solution of TV- ⁇ a'S ⁇ a'/?)-?'- (trifluoromethoxy)- ,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthene]-2,2'- diyl)bis(2,2-dimethylpropanamide) (200 mg, 0.42 mmol) in MeOH (3 mL) and water (3 mL). The reaction mixture was stirred at 100°C for 2 hours. After cooling to room temperature, water was added, and the mixture was extracted with EtOAc. The organic layer was concentrated.
  • Step A N-((2'S.4S.4a'S,9a'i?)-2-amino-7 , -(trifluoromethoxy - ⁇ .2',3 '.4'.4a'.9a'-hexahvdro-5H- spiro [oxazole-4.9'-xanthen] -2'-yl)-5 -chloropicolinamide
  • Step A EDCI (270 mg, 1.4 mmol), HOBT (190 mg, 1.4 mmol) and DIPEA (353 mg, 2.8 mmol) was added at 0°C to a mixture of (4i?,4a'S,9a'i?)-7'-(trifluoromethoxy)- l',2',3',4 , ,4a',9a'-hexahydro-5H-spiro[oxazole-4,9 , -xanthene]-2,2'-diamine (200 mg, 0.
  • Step B A mixture of N ⁇ '-((4J?,4a ,9a'i?)-7 , -(trifluoromethoxy)-l ' ⁇ ' ⁇ ' ⁇ ' ⁇ a' ⁇ a'- hexahydro-5H-spiro[oxazole-4,9'-xanthene]-2,2'-diyl)bis(5-chloropicolinamide) (280 mg, 0.44 mmol) and LiOH H20 (296 mg, 7.0 mmol) in MeOH/H20 (8/8 mL) was stirred at reflux for 1.5 h. Water was added and the mixture was extracted with EtOAc.
  • Step A A suspension of (4S,4a'S,9a' ?)-2-amino-7 , -(trifluoromethoxy)- l 4',4a',9a'-tetrahydro-5H-spiro[oxazole-4,9'-xanthen]-2'(3'H)-one (1.0 g, 2.8 mmol), NH 2 OH HCl (1.0 g, 14.0 mmol) and NaOAc (1.2 g, 14.0 mmol) in MeOH (40 mL) was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and extracted with EtOAc (3 X 50 mL).
  • Step B Raney Ni (1.0 g) was added to a solution of compound (9aS,14S,14a7?)- 5H-2-amino-7'-(trifluoromethoxy)-r,4',4a',9a'-tetrahydro-5H-spiro[oxazole-4,9'-xanthen]- 2'(3'H)-one oxime (1.0 g, 2.7 mmol) in MeOH (40 mL) and NH 3 H 2 0 (20 mL). The reaction mixture was stirred under 3 ⁇ 4 (1 atm) at room temperature for 2 hours.
  • Step C 2,2-Dimethyl-propionyl chloride (200 mg, 1.7 mmol) was added dropwise at 0°C to a solution of (4S,4a'S,9a' ?)-7'-(trifluoromethoxy)-l , ,2',3 , ,4',4a , ,9a , -hexahydro- 5H-spiro[oxazole-4,9'-xanthene]-2,2'-diamine (200 mg, 0.56 mmol) and Et 3 N (340 mg, 3.4 mmol) in DCM (10 mL). The mixture was stirred at room temperature for 2 hours.
  • Step D to a solution of N ⁇ V-((4S,4a'S,9a'i?)-7'-(trifluoromethoxy)- r,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthene]-2,2'-diyl)bis(2,2- dimethylpropanamide) (280 mg, 0.53 mmol) in MeOH (6 mL) and water (6 mL) was added LiOH H 2 0 (336 mg, 8.0 mmol). The reaction mixture was stirred at 100°C for 2 hours. After cooling to room temperature, water was added, and the mixture was extracted with EtOAc.
  • N- ((2 ,4S,4a ,9a' ⁇ )-2-amino-7'-(trifluoromethoxy)-1 ⁇ 2',3',4 * ,4a',9a , -hexahydro-5H-spiro[oxazole- 4,9'-xanthen]-2'-yl)pivalamide (60.1 mg) and N-((2'J?,4S,4a' 1 ?,9a'i?)-2-amino-7'- (trifluoromethoxy)- ,2 , ,3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2'-yl)pivalamide (13.2 mg) as a solid.
  • Step A EDCI (201 mg, 1.05 mmol) and HOBt (135 mg, 1.05 mmol) were added at 0°C to a solution of (4 1 S,4a ,9a' ⁇ )-7'-(trifluoromethoxy)-l',2',3 , ,4',4a',9a'-hexahydro-5H- spiro[oxazole-4,9'-xanthene]-2,2'-diamine (150 mg, 0.42 mmol), 1- (trifluoromethyl)cyclopropanecarboxylic acid (165 mg, 1.05 mmol) and Et 3 N (105 mg, 1.05 mmol) in DCM (6 mL).
  • Step B LiOH (270 mg, 6.3 mmol) was added to a solution of N,7V- ((4S,4a ,9a , ⁇ )-7 , -(trifluoromethoxy)- 1 ',2',3 ⁇ 4 ⁇ 4 ⁇ 9a , -hexahydro-5H-spnO[oxazole-4,9'- xanthene]-2,2'-diyl)bis(l-(trifluoromethyl)cyclopropanecarboxamide) (165 mg, 0.42 mmol) in MeOH (3 mL) and water (3 mL). The reaction mixture was stirred at 100°C for 2 hours.

Abstract

La présente invention concerne des composés tricycliques inédits de formule (I) qui inhibent le clivage de l'APP par la β-sécrétase et qui peuvent être utilisés en tant qu'agents thérapeutiques en vue du traitement des maladies neurodégénératives.
PCT/US2013/034129 2012-03-27 2013-03-27 Composés permettant de traiter les maladies neurodégénératives WO2013148851A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9096615B2 (en) 2013-07-30 2015-08-04 Amgen Inc. Bridged bicyclic amino thiazine dioxide compounds as inhibitors of beta-secretase and methods of use thereof
US9309263B2 (en) 2013-01-29 2016-04-12 Amgen Inc. Fused multi-cyclic sulfone compounds as inhibitors of beta-secretase and methods of use thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011072064A1 (fr) * 2009-12-08 2011-06-16 Array Biopharma Inc. Spiro[chromane-4,4'-imidazol]ones en tant qu'inhibiteurs de bêta-sécrétase
WO2011123674A1 (fr) * 2010-03-31 2011-10-06 Array Biopharma Inc. Composés pour traiter des maladies neurodégénératives
US20110251190A1 (en) * 2010-03-15 2011-10-13 Amgen Inc. Spiro-tetracyclic ring compounds as beta-secretase modulators and methods of use
WO2011130741A1 (fr) * 2010-04-16 2011-10-20 Array Biopharma Inc. Composés pour le traitement de maladies neurodégénératives

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Publication number Priority date Publication date Assignee Title
WO2011072064A1 (fr) * 2009-12-08 2011-06-16 Array Biopharma Inc. Spiro[chromane-4,4'-imidazol]ones en tant qu'inhibiteurs de bêta-sécrétase
US20110251190A1 (en) * 2010-03-15 2011-10-13 Amgen Inc. Spiro-tetracyclic ring compounds as beta-secretase modulators and methods of use
WO2011123674A1 (fr) * 2010-03-31 2011-10-06 Array Biopharma Inc. Composés pour traiter des maladies neurodégénératives
WO2011130741A1 (fr) * 2010-04-16 2011-10-20 Array Biopharma Inc. Composés pour le traitement de maladies neurodégénératives

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9309263B2 (en) 2013-01-29 2016-04-12 Amgen Inc. Fused multi-cyclic sulfone compounds as inhibitors of beta-secretase and methods of use thereof
US9096615B2 (en) 2013-07-30 2015-08-04 Amgen Inc. Bridged bicyclic amino thiazine dioxide compounds as inhibitors of beta-secretase and methods of use thereof

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