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WO2011130741A1 - Composés pour le traitement de maladies neurodégénératives - Google Patents

Composés pour le traitement de maladies neurodégénératives Download PDF

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Publication number
WO2011130741A1
WO2011130741A1 PCT/US2011/032894 US2011032894W WO2011130741A1 WO 2011130741 A1 WO2011130741 A1 WO 2011130741A1 US 2011032894 W US2011032894 W US 2011032894W WO 2011130741 A1 WO2011130741 A1 WO 2011130741A1
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Prior art keywords
alkyl
mmol
halogen
alkoxy
optionally substituted
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PCT/US2011/032894
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English (en)
Inventor
Adam Cook
Kevin W. Hunt
Joseph P. Lyssikatos
Andrew T. Metcalf
James P. Rizzi
Tony P. Tang
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Array Biopharma Inc.
Genentech, Inc.
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Publication of WO2011130741A1 publication Critical patent/WO2011130741A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • 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
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—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 beta peptides also referred to as ⁇ or A-beta
  • nerve cell death leads to nerve cell death, which contributes to the development and progression of AD.
  • Loss of nerve cells due to amyloid plaques in strategic brain areas causes reduction in the neurotransmitters and impairment of memory.
  • the proteins principally responsible for the plaque build up include amyloid precursor protein (APP) and presenilin I and II (PSI and PSII).
  • ⁇ 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) in vitro which is expressed on axons in response to trophic factor (e.g., nerve growth factor) withdrawal resulting in axonal degeneration.
  • trophic factor e.g., nerve growth factor
  • 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.
  • ⁇ -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, I' or I" and a 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, I' or I".
  • 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, ⁇ or l.
  • Formula I, ⁇ or I" in the manufacture of a medicament for the treatment of neurodegenerative diseases, such as Alzheimer's disease.
  • Formula I, I' or I" 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.
  • acyl means a carbonyl containing substituent represented by the formula -C(0)-R in which R is hydrogen, alkyl, a carbocycle, a heterocycle, carbocycle- substituted alkyl or heterocycle-substituted alkyl, wherein the alkyl, alkoxy, carbocycle and heterocycle are as defined herein.
  • Acyl groups include alkanoyl (e.g., acetyl), aroyl (e.g., benzoyl), and heteroaroyl.
  • a particular alkoxycarbonyl group is Q-Q alkoxycarbonyl, wherein the R group is Ci-C 6 alkyl.
  • alkyl means a branched or unbranched, saturated or unsaturated
  • alkenyl i.e., alkenyl, alkynyl
  • alkyl aliphatic hydrocarbon group, having up to 12 carbon atoms unless otherwise specified.
  • alkylamino the alkyl portion may be a saturated hydrocarbon chain, however also includes unsaturated hydrocarbon carbon chains such as “alkenylamino” and “alkynylamino.
  • alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2- dimethylbutyl, n-heptyl, 3-heptyl, 2-methylhexyl, and the like.
  • lower alkyl Q- C 4 alkyl and “alkyl of 1 to 4 carbon atoms” are synonymous and used interchangeably to mean methyl, ethyl, 1 -propyl, isopropyl, cyclopropyl, 1 -butyl, sec-butyl or t-butyl.
  • the alkyl group is CrC 2 , Ci-C ⁇ CrC 4 , C ⁇ -Cs or Q-Q.
  • substituted alkyl groups contain one, two, three or four substituents which may be the same or different.
  • Alkyl substituents are, unless otherwise specified, halogen, amino, hydroxyl, protected hydroxyl, mercapto, carboxy, alkoxy, nitro, cyano, amidino, guanidino, urea, oxo, sulfonyl, sulfinyl, aminosulfonyl, alkylsulfonylamino, arylsulfonylamino, aminocarbonyl, acylamino, alkoxy, acyl, acyloxy, an optionally substituted carbocycle and an optionally substituted heterocycle.
  • Examples of the above substituted alkyl groups include, but are not limited to; cyanomethyl, nitromethyl, hydroxymethyl, trityloxymethyl, propionyloxymethyl, aminomethyl, carboxymethyl, carboxyethyl, carboxypropyl, alkyloxycarbonylmethyl, allyloxycarbonylaminomethyl, carbamoyloxymethyl, methoxymethyl, ethoxymethyl, t-butoxymethyl, acetoxymethyl, chloromethyl, bromomethyl, iodomethyl, trifluoromethyl, 6-hydroxyhexyl, 2,4-dichloro(n-butyl), 2-amino(iso-propyl), 2- carbamoyloxyethyl and the like.
  • the alkyl group may also be substituted with a carbocycle group.
  • Examples include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl groups, as well as the corresponding -ethyl, -propyl, -butyl, -pentyl, -hexyl groups, etc.
  • Substituted alkyls include substituted methyls, e.g., a methyl group substituted by the same substituents as the "substituted C n -C m alkyl" group.
  • substituted methyl group examples include groups such as hydroxymethyl, protected hydroxymethyl (e.g., tetrahydropyranyloxymethyl), acetoxymethyl, carbamoyloxymethyl, trifluoromethyl, chloromethyl, carboxymethyl, bromomethyl and iodomethyl.
  • 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.
  • Ci-Ce alkoxy means -0(Ci-C 6 alkyl).
  • amidine means the group -C(NH)-NHR in which R is hydrogen, alkyl, a carbocycle, a heterocycle, carbocycle-substituted alkyl or heterocycle-substituted alkyl wherein the alkyl, alkoxy, carbocycle and heterocycle are as defined herein.
  • a particular amidine is the group -NH-C(NH)-NH 2 .
  • amino means primary (i.e., -NH 2 ), secondary (i.e., -NRH) and tertiary (i.e., -NRR) amines in which R is hydrogen, alkyl, a carbocycle, a heterocycle, carbocycle-substituted alkyl or heterocycle-substituted alkyl wherein the alkyl, alkoxy, carbocycle and heterocycle are as defined herein.
  • Particular secondary and tertiary amines are alkylamine, dialkylamine, arylamine, diarylamine, aralkylamine and diaralkylamine wherein the alkyl is as herein defined and optionally substituted.
  • Particular secondary and tertiary amines are methylamine, ethylamine, propylamine, isopropylamine, phenylamine, benzylamine dimethylamine, diethylamine, dipropylamine and disopropylamine.
  • amino-protecting group refers to a derivative of the groups commonly employed to block or protect an amino group while reactions are carried out on other functional groups on the compound.
  • protecting groups include carbamates, amides, alkyl and aryl groups, imines, as well as many N-heteroatom derivatives which can be removed to regenerate the desired amine group.
  • Particular amino protecting groups are acetyl, trifluoroacetyl, t-butyloxycarbonyl ("Boc”), benzyloxycarbonyl ("CBz”) and 9-fluorenylmethyleneoxycarbonyl ("Fmoc”). Further examples of these groups, and other protecting groups, are found in T. W. Greene, et al. Greene's Protective Groups in Organic Synthesis. New York: Wiley Interscience, 2006.
  • aryl when used alone or as part of another term means a carbocyclic aromatic group whether or not fused having the number of carbon atoms designated or if no number is designated, up to 14 carbon atoms.
  • Particular aryl groups are phenyl, naphthyl, biphenyl, phenanthrenyl, naphthacenyl, and the like (see e.g., Dean, J. A. Lange's Handbook of Chemistry. 15th ed. New York: McGraw-Hill Professional, 1998).
  • a particular aryl is phenyl.
  • Substituted phenyl or substituted aryl means a phenyl group or aryl group substituted with one, two, three, four or five substituents, for example 1-2, 1-3 or 1-4 substituents chosen, unless otherwise specified, from halogen (F, CI, Br, I), hydroxy, protected hydroxy, cyano, nitro, alkyl (for example C !
  • alkyl for example Ci-C 6 alkoxy
  • benzyloxy carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, aminomethyl, protected aminomethyl, trifluoromethyl, alkylsulfonylamino, alkylsulfonylaminoalkyl, arylsulfonylamino, arylsulonylaminoalkyl, heterocyclylsulfonylamino, heterocyclylsulfonylaminoalkyl, heterocyclyl, aryl, or other groups specified.
  • substituted phenyl includes but is not limited to a mono- or di(halo)phenyl group such as 2-chlorophenyl, 2-bromophenyl, 4-chlorophenyl, 2,6- dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3 -bromophenyl, 4- bromophenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2-fluorophenyl and the like; a mono- or di(hydroxy)phenyl group such as 4-hydroxyphenyl, 3-hydroxyphenyl, 2,4- dihydroxyphenyl, the protected-hydroxy derivatives thereof and the like; a nitrophenyl
  • Particular substituted phenyl groups include the 2-chlorophenyl, 2-aminophenyl, 2-bromophenyl, 3-methoxyphenyl, 3-ethoxy-phenyl, 4- benzyloxyphenyl, 4-methoxyphenyl, 3-ethoxy-4-benzyloxyphenyl, 3,4-diethoxyphenyl, 3- methoxy-4-benzyloxyphenyl, 3-methoxy-4-(l -chloromethyl)benzyloxy-phenyl, 3-methoxy-4- (l-chloromethyl)benzyloxy -6- methyl sulfonyl aminophenyl groups.
  • Fused aryl rings may also be substituted with any, for example 1, 2 or 3, of the substituents specified herein in the same manner as substituted alkyl groups.
  • carbocyclyl refers to a mono-, bi-, or tricyclic aliphatic ring having 3 to 14 carbon atoms, for example 3 to 7 carbon atoms or 3 to 6 carbon atoms, which may be saturated or unsaturated, aromatic or non- aromatic.
  • Particular saturated carbocyclic groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.
  • a particular saturated carbocycle is cyclopropyl.
  • Another particular saturated carbocycle is cyclohexyl.
  • Particular unsaturated carbocycles are aromatic, e.g., aryl groups as previously defined, for example phenyl.
  • substituted carbocyclyl means these groups substituted by the same substituents as the "substituted alkyl” group.
  • carboxy-protecting group refers to one of the ester derivatives of the carboxylic acid group commonly employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups on the compound.
  • carboxylic acid protecting groups include 4-nitrobenzyl, 4- methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6- trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl, 4,4'- dimethoxybenzhydryl, 2,2',4,4'-tetramethoxybenzhydryl, alkyl such as t-butyl or t-amyl, trityl, 4-methoxytrityl, 4,4'-dimethoxytrityl, 4,4',4"-trimethoxytrityl, 2-phenylprop-2-
  • carboxy- protecting group employed is not critical so long as the denvatized carboxylic acid is stable to the condition of subsequent reaction(s) on other positions of the molecule and can be removed at the appropriate point without disrupting the remainder of the molecule.
  • it is important not to subject a carboxy-protected molecule to strong nucleophilic bases, such as lithium hydroxide or NaOH, or reductive conditions employing highly activated metal hydrides such as LiAlH 4 .
  • strong nucleophilic bases such as lithium hydroxide or NaOH
  • reductive conditions employing highly activated metal hydrides such as LiAlH 4 .
  • Such harsh removal conditions are also to be avoided when removing amino-protecting groups and hydroxy-protecting groups, discussed below.
  • Particular carboxylic acid protecting groups are the alkyl (e.g., methyl, ethyl, t-butyl), allyl, benzyl and p-nitrobenzyl groups.
  • protected carboxy refers to a carboxy group substituted with one of the above carboxy-protecting groups. Further examples are found in Greene's Protective Groups in Organic Synthesis, supra.
  • guanidine means the group -NH-C(NH)-NH in which R is hydrogen, alkyl, a carbocycle, a heterocycle, carbocycle-substituted alkyl or heterocycle- substituted alkyl, wherein the alkyl, alkoxy, carbocycle and heterocycle are as defined herein.
  • R is hydrogen, alkyl, a carbocycle, a heterocycle, carbocycle-substituted alkyl or heterocycle- substituted alkyl, wherein the alkyl, alkoxy, carbocycle and heterocycle are as defined herein.
  • a particular guanidine is the group -NH-C(NH)-NH 2 .
  • hydroxy-protecting group refers to a derivative of the hydroxy group commonly employed to block or protect the hydroxy group while reactions are carried out on other functional groups on the compound.
  • protecting groups include tetrahydropyranyloxy, benzoyl, acetoxy, carbamoyloxy, benzyl, and silylethers (e.g., tert-butyldimethylsilyl (“TBS”), tert-butyldiphenylsilyl (“TBDPS”)) groups. Further examples are found in Greene's Protective Groups in Organic Synthesis, supra.
  • protected hydroxy refers to a hydroxy group substituted with one of the above hydroxy-protecting groups.
  • heterocyclic group alone and when used as a moiety in a complex group such as a heterocycloalkyl group, are used interchangeably and refer to any mono-, bi-, or tricyclic, saturated or unsaturated, aromatic (heteroaryl) or non-aromatic ring having the number of atoms designated, generally from 5 to about 14 ring atoms, where the ring atoms are carbon and at least one heteroatom (nitrogen, sulfur or oxygen), for example 1 to 4 heteroatoms.
  • the sulfur heteroatoms may optionally be oxidized (e.g., SO, S0 2 ), and any nitrogen heteroatom may optionally be quaternized.
  • a 5-membered ring has 0 to 2 double bonds and 6- or 7-membered ring has 0 to 3 double bonds.
  • heterocyclic groups are four to seven membered cyclic groups containing one, two or three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • non-aromatic heterocycles are morpholinyl (morpholino), pyrrolidinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, 2,3-dihydrofuranyl, 2H-pyranyl, tetrahydropyranyl, thiiranyl, thietanyl, tetrahydrothietanyl, aziridinyl, azetidinyl, l-methyl-2-pyrrolyl, piperazinyl and piperidinyl.
  • a "heterocycloalkyl” group is a heterocycle group as defined above covalently bonded to an alkyl group as defined above.
  • Particular 5-membered heterocycles containing a sulfur or oxygen atom and one to three nitrogen atoms are thiazolyl, in particular thiazol-2-yl and thiazol-2-yl N-oxide, thiadiazolyl, in particular l,3,4-thiadiazol-5-yl and 1 ,2,4-thiadiazol-5- yl, oxazolyl, for example oxazol-2-yl, and oxadiazolyl, such as l,3,4-oxadiazol-5-yl, and
  • Particular 5-membered ring heterocycles containing 2 to 4 nitrogen atoms include imidazolyl, such as imidazol-2-yl; triazolyl, such as l,3,4-triazol-5-yl; 1,2,3- triazol-5-yl, l,2,4-triazol-5-yl, and tetrazolyl, such as lH-tetrazol-5-yl.
  • Particular benzo- fused 5-membered heterocycles are benzoxazol-2-yl, benzthiazol-2-yl and benzimidazol-2-yl.
  • Particular 6-membered heterocycles contain one to three nitrogen atoms and optionally a sulfur or oxygen atom, for example pyridyl, such as pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl; pyrimidyl, such as pyrimid-2-yl and pyrimid-4-yl; triazinyl, such as l,3,4-triazin-2-yl and
  • pyridazinyl in particular pyridazin-3-yl, and pyrazinyl.
  • the pyridine N- oxides and pyridazine N-oxides and the pyridyl, pyrimid-2-yl, pyrimid-4-yl, pyridazinyl and the l,3,4-triazin-2-yl groups, are a particular group.
  • Substituents for "optionally substituted heterocycles", and further examples of the 5- and 6-membered ring systems discussed above can be found in W. Druckheimer et al., U.S. Patent No. 4,278,793.
  • such optionally substituted heterocycle groups are substituted with hydroxyl, alkyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyl, acyl, halo-substituted alkyl, amino, cyano, nitro, amidino and guanidino.
  • heteroaryl alone and when used as a moiety in a complex group such as a heteroaralkyl group, refers to any mono-, bi-, or tricyclic aromatic ring system having the number of atoms designated where at least one ring is a 5-, 6- or 7-membered ring containing from one to four heteroatoms selected from the group nitrogen, oxygen, and sulfur, and in a particular embodiment at least one heteroatom is nitrogen (see Lange's Handbook of Chemistry, supra).
  • the heteroaryl is a 5-membered aromatic ring containing one, two or three heteroatoms selected from nitrogen, oxygen and sulfur.
  • Particular heteroaryls incorporate a nitrogen or oxygen heteroatom.
  • the heteroaryl is a 5-membered aromatic ring containing one, two or three heteroatoms selected from nitrogen, oxygen and sulfur.
  • the heteroaryl group is a 6-membered aromatic ring containing one, two or three heteroatoms selected from nitrogen, oxygen and sulfur.
  • heteroaryl groups substituted and unsubstituted: thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazinyl, oxazinyl, triazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, tetrazinyl, thiatriazinyl, imidazolinyl, dihydropyr
  • the heteroaryl group may be: l,3-thiazol-2-yl, 4-(carboxymethyl)-5 -methyl- 1, 3 -thiazol-2-yl, 4- (carboxymethyl)-5-methyl-l,3-thiazol-2-yl sodium salt, l,2,4-thiadiazol-5-yl, 3 -methyl- 1,2,4- thiadiazol-5-yl, l ,3,4-triazol-5-yl, 2-methyl-l,3,4-triazol-5-yl, 2-hydroxy-l,3,4-triazol-5-yl, 2-carboxy-4-methyl-l,3,4-triazol-5-yl sodium salt, 2-carboxy-4-methyl-l,3,4-triazol-5-yl, l,3-oxazol-2-yl, l,3,4-oxadiazol-5-yl, 2-methyl-l,3,4-oxadiazol-5-yl, 2-(hydroxymethyl)- l,3,4
  • heteroaryl includes; 4-(carboxymethyl)-5-methyl-l,3-thiazol-2-yl, 4-(carboxymethyl)-5- methyl-l,3-thiazol-2-yl sodium salt, l,3,4-triazol-5-yl, 2-methyl-l,3,4-triazol-5-yl, 1H- tetrazol-5-yl, 1 -methyl- lH-tetrazol-5-yl, l-(l-(dimethylamino)eth-2-yl)-lH-tetrazol-5-yl, 1- (carboxymethyl)-lH-tetrazol-5-yl, l-(carboxymethyl)-lH-tetrazol-5-yl sodium salt, 1- (methylsulfonic acid)-lH-tetrazol-5-yl, l-(methylsulfonic acid)-lH-tetrazol-5-yl sodium salt, 1 ,2,3-
  • inhibitor means a compound which reduces or prevents the enzymatic cleavage of APP by ⁇ -secretase.
  • inhibitor means a compound which prevents or slows the formation of beta-amyloid plaques in mammalian brain.
  • inhibitor means a compound that prevents or slows the progression of a disease or condition associated with ⁇ -secretase enzymatic activity, e.g., cleavage of APP.
  • inhibitor means a compound which prevents Alzheimer's disease.
  • inhibitor means a compound which slows the progression of Alzheimer's disease or its symptoms.
  • 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.
  • composition is compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
  • pharmaceutically acceptable salts include both acid and base addition salts.
  • pharmaceutically acceptable acid addition salt refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like, and organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid,
  • base addition salts include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particularly base addition salts are the ammonium, potassium, sodium, calcium and magnesium salts.
  • Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2- diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, polyamine resins and the like.
  • Particularly organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, trimethamine, dicyclohexylamine, choline, and caffeine.
  • sulfanyl means -S-R group in which R is alkyl, a carbocycle, a heterocycle, carbocycle-substituted alkyl or heterocycle-substituted alkyl, wherein the alkyl, alkoxy, carbocycle and heterocycle are as defined herein.
  • Particular sulfanyl groups are alkylsulfanyl (i.e., -SCValkyl), for example methylsulfanyl; arylsulfanyl, for example phenylsulfanyl; aralkylsulfanyl, for example benzylsulfanyl.
  • sulfinyl means -SO-R group in which R is hydrogen, alkyl, a carbocycle, a heterocycle, carbocycle-substituted alkyl or heterocycle-substituted alkyl, wherein the alkyl, alkoxy, carbocycle and heterocycle are as defined herein.
  • Particular sulfonyl groups are alkylsulfinyl (i.e., -SO-alkyl), for example methylsulfinyl; arylsulfinyl, for example phenylsulfmyl; aralkylsulfinyl, for example benzylsulfmyl.
  • sulfonyl means a -S0 2 -R group in which R is hydrogen, alkyl, a carbocycle, a heterocycle, carbocycle-substituted alkyl or heterocycle-substituted alkyl wherein the alkyl, alkoxy, carbocycle and heterocycle are as defined herein.
  • Particular sulfonyl groups are alkylsulfonyl (i.e., -S0 2 -alkyl), for example methylsulfonyl; arylsulfonyl, for example phenylsulfonyl; aralkylsulfonyl, for example benzylsulfonyl.
  • 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.
  • the "effective amount" of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to inhibit cleavage of APP by ⁇ - secretase, for example by 10% or greater in situ. In a particular embodiment an "effective amount" of the compound inhibits cleavage of APP by ⁇ -secretase by 25% or greater in situ. In a particular embodiment the effective amount inhibits cleavage of APP by ⁇ -secretase by 50% or greater in situ. In a particular embodiment the effective amount inhibits cleavage of APP by ⁇ -secretase by 70% or greater in situ. In a particular embodiment the effective amount inhibits cleavage of APP by ⁇ -secretase by 80% or greater in situ.
  • an "effective amount” is the amount of compound necessary to reduce A-beta levels in plasma or cerebrospinal fluid of a mammal, for example, by 10% or greater.
  • an "effective amount” is the amount of compound necessary to reduce A-beta levels in plasma or cerebrospinal fluid of a mammal by 25% or greater.
  • an "effective amount” is the amount of compound necessary to reduce A-beta levels in plasma or cerebrospinal fluid of a mammal by 50% or greater.
  • an “effective amount” is the amount of compound necessary to reduce A-beta levels in plasma or cerebrospinal fluid of a mammal by 75% or greater.
  • an “effective amount” of the compound may be the amount of compound necessary to slow the progression of AD or symptoms thereof.
  • X 1 is selected from O, S, S(O), S0 2 , NR 11 or CHR 11 ;
  • X is selected from CR or N;
  • X 3 is selected from CR 3 or N;
  • X 4 is selected from CR 4 or N;
  • X 5 is selected from CR 5 or N;
  • X 6 is selected from CR 6 or N, wherein only one of X 2 , X 3 , X 4 , X 5 or X 6 may be N;
  • R 1 is selected from hydrogen, alkyl, aralkyl, heteroaryl or heteroaralkyl;
  • R is selected from hydrogen, halogen and alkyl
  • R 3 is selected from hydroxy, halogen, amino, cyano, nitro, alkyl, alkoxy, acyl, acyloxy, alkoxycarbonyl, sulfonyl, sulfinyl, sulfanyl, aryloxy, a carbocycle or a heterocycle wherein said alkyl, alkoxy, acyl, acyloxy, alkoxycarbonyl, sulfonyl, sulfinyl, sulfanyl, aryloxy, carbocycle and heterocycle are optionally substituted with hydroxy, halogen, amino, cyano, nitro, oxo, optionally substituted alkyl, optionally substituted alkoxy, sulfanyl, acyl, alkoxycarbonyl, haloalkyl and optionally substituted carbocycle;
  • R 4 is selected from hydrogen, hydroxy, halogen, amino, cyano, nitro, alkyl, alkoxy, acyl, acyloxy, alkoxycarbonyl, sulfonyl, sulfinyl, sulfanyl, aryloxy, a carbocycle or a heterocycle wherein said alkyl, alkoxy, acyl, acyloxy, alkoxycarbonyl, sulfonyl, sulfinyl, sulfanyl, aryloxy, carbocycle and heterocycle are optionally substituted with hydroxy, halogen, amino, cyano, nitro, oxo, optionally substituted alkyl, optionally substituted alkoxy, sulfanyl, acyl, alkoxycarbonyl, haloalkyl and optionally substituted carbocycle, or
  • R 3 and R 4 together with the atoms to which they are attached form a 3 to 6 membered carbocycle or heterocycle optionally substituted with hydroxy, halogen, amino, cyano, nitro, alkyl, alkoxy, acyl and haloalkyl;
  • R 5 is selected from hydrogen, halogen, alkyl, alkoxy and a carbocycle
  • R 6 is selected from hydrogen, halogen and alkyl
  • R 7 is selected from hydrogen, hydroxy, halogen, amino, cyano, nitro, alkyl, alkoxy, acyl, acyloxy, alkoxycarbonyl, sulfonyl, sulfinyl, sulfanyl, aryloxy, a carbocycle, a heterocycle or -O(heterocycle) wherein said alkyl, alkoxy, acyl, acyloxy, alkoxycarbonyl, sulfonyl, sulfinyl, sulfanyl, aryloxy, carbocycle and heterocycle are optionally substituted with hydroxy, halogen, amino, cyano, nitro, oxo, optionally substituted alkyl, optionally substituted alkoxy, sulfanyl, acyl, alkoxycarbonyl, haloalkyl and optionally substituted carbocycle; and
  • R u is selected from hydrogen and alkyl.
  • X 1 is selected from O, S, S(O), S0 2 , NR 11 or CHR 11 ;
  • X 2 is selected from CR 2 or N;
  • X is selected from CR or N;
  • X 4 is selected from CR 4 or N;
  • X 5 is selected from CR 5 or N;
  • X 6 is selected from CR 6 or N, wherein only one of X 2 , X 3 , X 4 , X 5 or X 6 may be N;
  • R 1 is selected from hydrogen, alkyl, aralkyl, heteroaryl or heteroaralkyl;
  • R 2 is selected from hydrogen, halogen and alkyl
  • R 3 is selected from hydroxy, halogen, amino, cyano, nitro, alkyl, alkoxy, acyl, acyloxy, alkoxycarbonyl, sulfonyl, sulfinyl, sulfanyl, aryloxy, a carbocycle or a heterocycle wherein said alkyl, alkoxy, acyl, acyloxy, alkoxycarbonyl, sulfonyl, sulfinyl, sulfanyl, aryloxy, carbocycle and heterocycle are optionally substituted with hydroxy, halogen, amino, cyano, nitro, oxo, optionally substituted alkyl, optionally substituted alkoxy, sulfanyl, acyl, alkoxycarbonyl, haloalkyl and optionally substituted carbocycle;
  • R 4 is selected from hydrogen, halogen, amino, cyano, nitro, alkyl, alkoxy, acyl, acyloxy, alkoxycarbonyl, sulfonyl, sulfinyl, sulfanyl, aryloxy, a carbocycle or a heterocycle wherein said alkyl, alkoxy, acyl, acyloxy, alkoxycarbonyl, sulfonyl, sulfinyl, sulfanyl, aryloxy, carbocycle and heterocycle are optionally substituted with hydroxy, halogen, amino, cyano, nitro, oxo, optionally substituted alkyl, optionally substituted alkoxy, sulfanyl, acyl, alkoxycarbonyl, haloalkyl and optionally substituted carbocycle, or
  • R 3 and R 4 together with the atoms to which they are attached form a 3 to 6 membered carbocycle or heterocycle optionally substituted with hydroxy, halogen, amino, cyano, nitro, alkyl, alkoxy, acyl and haloalkyl;
  • R 5 is selected from hydrogen, halogen, alkyl, alkoxy and a carbocycle
  • R 6 is selected from hydrogen, halogen and alkyl
  • R 7 is selected from hydroxy, halogen, amino, cyano, nitro, alkyl, alkoxy, acyl, acyloxy, alkoxycarbonyl, sulfonyl, sulfinyl, sulfanyl, aryloxy, a carbocycle or a heterocycle wherein said alkyl, alkoxy, acyl, acyloxy, alkoxycarbonyl, sulfonyl, sulfinyl, sulfanyl, aryloxy, carbocycle and heterocycle are optionally substituted with hydroxy, halogen, amino, cyano, nitro, oxo, optionally substituted alkyl, optionally substituted alkoxy, sulfanyl, acyl, alkoxycarbonyl, haloalkyl and optionally substituted carbocycle; and
  • R 11 is selected from hydrogen and alkyl.
  • X 1 is selected from O or S
  • X 2 is selected from CR 2 or N;
  • X 3 is selected from CR 3 or N;
  • X 4 is selected from CR 4 or N;
  • X 5 is selected from CR 5 or N;
  • X 6 is selected from CR 6 or N, wherein only one of X 2 , X 3 , X 4 , X 5 or X 6 may be N;
  • R 1 is selected from hydrogen, alkyl, aralkyl, heteroaryl or heteroaralkyl;
  • R 2 is selected from hydrogen, halogen and alkyl
  • R 3 is selected from hydroxy, halogen, amino, cyano, nitro, alkyl, alkoxy, acyl, acyloxy, alkoxycarbonyl, sulfonyl, sulfinyl, sulfanyl, aryloxy, a carbocycle or a heterocycle wherein said alkyl, alkoxy, acyl, acyloxy, alkoxycarbonyl, sulfonyl, sulfinyl, sulfanyl, aryloxy, carbocycle and heterocycle are optionally substituted with hydroxy, halogen, amino, cyano, nitro, oxo, optionally substituted alkyl, optionally substituted alkoxy, sulfanyl, acyl, alkoxycarbonyl, haloalkyl and optionally substituted carbocycle;
  • R 4 is selected from hydrogen, hydroxy, halogen, cyano, alkyl, alkoxy, a carbocycle or a heterocycle, wherein said alkyl, alkoxy, carbocycle and heterocycle are optionally substituted with hydroxy, halogen, optionally substituted alkyl, or optionally substituted alkoxy, or R 3 and R 4 together with the atoms to which they are attached form a 3 to 6 membered carbocycle or heterocycle optionally substituted with hydroxy, halogen, amino, cyano, nitro, alkyl, alkoxy, acyl and haloalkyl;
  • R 5 is selected from hydrogen, halogen, alkyl, alkoxy and a carbocycle
  • R 6 is selected from hydrogen, halogen and alkyl
  • R 7 is selected from hydrogen, hydroxy, halogen, amino, cyano, nitro, alkyl, alkoxy, acyl, acyloxy, alkoxycarbonyl, sulfonyl, sulfinyl, sulfanyl, aryloxy, a carbocycle, a heterocycle or -O(heterocycle) wherein said alkyl, alkoxy, acyl, acyloxy, alkoxycarbonyl, sulfonyl, sulfinyl, sulfanyl, aryloxy, carbocycle and heterocycle are optionally substituted with hydroxy, halogen, amino, cyano, nitro, oxo, optionally substituted alkyl, optionally substituted alkoxy, sulfanyl, acyl, alkoxycarbonyl, haloalkyl and optionally substituted carbocycle.
  • X 1 is selected from O or S
  • X 2 is selected from CR 2 or N;
  • X 3 is selected from CR 3 or N;
  • X 4 is selected from CR 4 or N;
  • X 5 is selected from CR 5 or N;
  • X 6 is selected from CR 6 or N, wherein only one of X 2 , X 3 , X 4 , X 5 or X 6 may be N;
  • R 1 is selected from hydrogen, alkyl, aralkyl, heteroaryl or heteroaralkyl;
  • R 2 is selected from hydrogen, halogen and alkyl
  • R 3 is selected from hydroxy, halogen, amino, cyano, nitro, alkyl, alkoxy, acyl, acyloxy, alkoxycarbonyl, sulfonyl, sulfinyl, sulfanyl, aryloxy, a carbocycle or a heterocycle wherein said alkyl, alkoxy, acyl, acyloxy, alkoxycarbonyl, sulfonyl, sulfinyl, sulfanyl, aryloxy, carbocycle and heterocycle are optionally substituted with hydroxy, halogen, amino, cyano, nitro, oxo, optionally substituted alkyl, optionally substituted alkoxy, sulfanyl, acyl, alkoxycarbonyl, haloalkyl and optionally substituted carbocycle;
  • R 4 is selected from hydrogen, halogen, alkyl, or alkoxy, or
  • R 3 and R 4 together with the atoms to which they are attached form a 3 to 6 membered carbocycle or heterocycle optionally substituted with hydroxy, halogen, amino, cyano, nitro, alkyl, alkoxy, acyl and haloalkyl;
  • R 5 is selected from hydrogen, halogen, alkyl, alkoxy and a carbocycle
  • R 6 is selected from hydrogen, halogen and alkyl
  • R 7 is selected from hydroxy, halogen, amino, cyano, nitro, alkyl, alkoxy, acyl, acyloxy, alkoxycarbonyl, sulfonyl, sulfinyl, sulfanyl, aryloxy, a carbocycle or a heterocycle wherein said alkyl, alkoxy, acyl, acyloxy, alkoxycarbonyl, sulfonyl, sulfinyl, sulfanyl, aryloxy, carbocycle and heterocycle are optionally substituted with hydroxy, halogen, amino, cyano, nitro, oxo, optionally substituted alkyl, optionally substituted alkoxy, sulfanyl, acyl, alkoxycarbonyl, haloalkyl and optionally substituted carbocycle.
  • X 1 is selected from O, S, S(O), S0 2 , NR 11 or CHR 1 1 ;
  • X 2 is CR 2 ;
  • X 3 is selected from CR 3 or N;
  • X 4 is selected from CR 4 or N;
  • X 5 is CR 5 ;
  • X 6 is CR 6 ;
  • R 1 is selected from hydrogen, benzyl or Ci-C 3 alkyl optionally substituted with R a ;
  • R is hydrogen;
  • R 3 is selected from hydrogen, halogen, CN, C C 6 alkyl, C!-C 6 alkoxy, a 3 to 6 membered carbocycle, a 3 to 6 membered heterocycle, phenyl, and a 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy, carbocycle, heterocycle, phenyl and heteroaryl are optionally substituted with halogen, a 3 to 6 membered carbocycle or Ci-C 6 alkoxy optionally substituted with halogen;
  • R 4 is selected from hydrogen, halogen, OH, CN, C ⁇ -C6 alkyl, C]-C 6 alkoxy, phenyl, a 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy, phenyl and heteroaryl are optionally substituted with halogen, or
  • R 3 and R 4 together with the atoms to which they are attached form a 3 to 6 membered carbocycle or 3 to 6 membered heterocycle;
  • R 5 is selected from hydrogen, halogen, CpQ alkyl, Ci-C alkoxy or a 3 to 6 membered carbocycle;
  • R 6 is selected from hydrogen, halogen or C -Ce alkyl
  • R 7 is selected from hydrogen, halogen, Ci-C 6 alkyl, C ⁇ -Ce alkenyl, C ⁇ -C alkynyl, a 3 to 6 membered saturated or partially unsaturated carbocycle, a 3 to 6 membered saturated or partially unsaturated heterocycle, phenyl, 5 to 6 membered heteroaryl, and -0(3 to 6 membered heterocycle), wherein the alkyl, alkenyl, alkynyl, carbocycle, heterocycles, phenyl and heteroaryl are optionally substituted with halogen, CN, Ci-C alkyl or Ci-C 6 alkoxy, wherein the alkyl and alkoxy are optionally substituted with halogen;
  • R 11 is selected from hydrogen and C ⁇ -C alkyl; and each R a is independently selected from OH, OCH 3 , halogen, a 5 to 6 membered heteroaryl, and a 3-6 membered heterocyclyl optionally substituted with Ci-C 3 alkyl optionally substituted with oxo.
  • X 1 is selected from O, S, S(O), S0 2 , NR. 11 or CHR 11 ;
  • X 2 is CR 2 ;
  • X 3 is CR 3 ;
  • X 4 is selected from CR 4 or N;
  • X 5 is CR 5 ;
  • X 6 is CR 6 ;
  • R 1 is selected from hydrogen, benzyl or Q-C3 alkyl optionally substituted with R a ;
  • R 2 is hydrogen;
  • R 3 is selected from hydrogen, halogen, CN, C ⁇ Q alkyl, C ! -C 6 alkoxy, phenyl, and a
  • heteroaryl wherein the alkyl, alkoxy, phenyl and heteroaryl are optionally substituted with halogen;
  • R 4 is selected from hydrogen, halogen, CN, Q-C 6 alkyl, C!-C 6 alkoxy, phenyl, a 5 to
  • R 3 and R 4 together with the atoms to which they are attached form a 3 to 6 membered carbocycle or 3 to 6 membered heterocycle;
  • R 5 is selected from hydrogen, halogen, ⁇ -C alkyl, C!-C 6 alkoxy or a 3 to 6 membered carbocycle;
  • R 6 is selected from hydrogen, halogen or Q-Q alkyl
  • R 7 is selected from hydrogen, halogen, C C6 alkyl, C C6 alkenyl, C -Ce alkynyl, a 3 to 6 membered carbocycle, a 3 to 6 membered heterocycle, phenyl, 5 to 6 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, carbocycle, heterocycle, phenyl and heteroaryl are optionally substituted with halogen, CN, Ci-Ce alkyl or C ⁇ -Ce alkoxy, wherein the alkyl and alkoxy are optionally substituted with halogen;
  • R 11 is selected from hydrogen and CpC 6 alkyl
  • each R a is independently selected from OH, OCH 3 , halogen, a 5 to 6 membered heteroaryl, and a 3-6 membered heterocyclyl optionally substituted with Ci-C 3 alkyl optionally substituted with oxo.
  • X 1 is selected from O or S;
  • X 2 is CR 2 ;
  • X 3 is selected from CR 3 or N;
  • X 4 is selected from CR 4 or N;
  • X 5 is CR 5 ;
  • X 6 is CR 6 ;
  • R 1 is selected from hydrogen, benzyl or C!-C 3 alkyl optionally substituted with R a ;
  • R 2 is hydrogen;
  • R 3 is selected from hydrogen, halogen, CN, C!-C 6 alkyl, C]-C 6 alkoxy, a 3 to 6 membered carbocycle, a 3 to 6 membered heterocycle, phenyl, and a 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy, carbocycle, heterocycle, phenyl and heteroaryl are optionally substituted with halogen, a 3 to 6 membered carbocycle or C alkoxy optionally substituted with halogen;
  • R 4 is selected from hydrogen, halogen, OH, CN, C!-C 6 alkyl, C!-C 6 alkoxy, phenyl, and a 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy, phenyl and heteroaryl are optionally substituted with halogen, or
  • R 3 and R 4 together with the atoms to which they are attached form a 3 to 6 membered carbocycle or 3 to 6 membered heterocycle;
  • R 5 is selected from hydrogen, halogen or C ⁇ -Ce alkyl
  • R 6 is selected from hydrogen, halogen or Q-C6 alkyl
  • R 7 is selected from hydrogen, halogen, C]-C 6 alkyl, C ⁇ -Ce alkenyl, CpC 6 alkynyl, a 3 to 6 membered carbocycle, a 3 to 6 membered saturated or partially unsaturated heterocycle, phenyl, 5 to 6 membered heteroaryl, and -0(3 to 6 membered heterocycle), wherein the alkyl, alkenyl, alkynyl, carbocycle, heterocycles, phenyl and heteroaryl are optionally substituted with halogen, CN, Q-C6 alkyl or d-C 6 alkoxy, wherein the alkyl and alkoxy are optionally substituted with halogen;
  • each R a is independently selected from OH, OCH 3 , halogen, a 5 to 6 membered heteroaryl, and a 3-6 membered heterocyclyl optionally substituted with Ci-C 3 alkyl optionally substituted with oxo.
  • X 1 is selected from O or S
  • X 2 is CR 2 ;
  • X 3 is CR 3 ;
  • X 4 is selected from CR 4 or N;
  • X 5 is CR 5 ;
  • X 6 is CR 6 ;
  • R 1 is selected from hydrogen, benzyl or C1-C3 alkyl optionally substituted with R a ;
  • R is hydrogen;
  • R is selected from hydrogen, halogen, CN, Ci-C 6 alkyl, C C 6 alkoxy, phenyl, and a 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy, phenyl and heteroaryl are optionally substituted with halogen;
  • R 4 is selected from hydrogen, halogen, C C 6 alkyl, and Ci-C 6 alkoxy, wherein the alkyl and alkoxy are optionally substituted with halogen, or
  • R 3 and R 4 together with the atoms to which they are attached form a 3 to 6 membered carbocycle or 3 to 6 membered heterocycle;
  • R 5 is selected from hydrogen, halogen or C!-C 6 alkyl
  • R 6 is selected from hydrogen, halogen or Ci-C alkyl
  • R 7 is selected from hydrogen, halogen, Ci-C 6 alkyl, Ci-C 6 alkenyl, Ci-C 6 alkynyl, a 3 to 6 membered carbocycle, a 3 to 6 membered heterocycle, phenyl, 5 to 6 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, carbocycle, heterocycle, phenyl and heteroaryl are optionally substituted with halogen, CN, C ⁇ -Ce alkyl or C ⁇ -Ce alkoxy, wherein the alkyl and alkoxy are optionally substituted with halogen;
  • each R a is independently selected from OH, OCH 3 , halogen, a 5 to 6 membered heteroaryl, and a 3-6 membered heterocyclyl optionally substituted with Ci-C 3 alkyl optionally substituted with oxo.
  • X 1 is selected from O or S
  • X 2 is CR 2 ;
  • X 3 is selected from CR 3 or N;
  • X 4 is selected from CR 4 or N;
  • X 5 is CR 5 ;
  • X 6 is CR 6 ;
  • R 1 is C C 3 alkyl
  • R 2 is hydrogen
  • R 3 is selected from hydrogen, halogen, CN, C -Ce alkyl, C C 6 alkoxy, a 3 to 6 membered carbocycle, phenyl, and a 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy, carbocycle, phenyl and heteroaryl are optionally substituted with halogen, a 3 to 6 membered carbocycle or Ci-C 6 alkoxy optionally substituted with halogen;
  • R 4 is selected from hydrogen, OH, Ci-Ce alkyl, C C 6 alkoxy and a 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy and heteroaryl are optionally substituted with halogen, or
  • R 3 and R 4 together with the atoms to which they are attached form a 3 to 6 membered heterocycle
  • R 5 is selected from hydrogen or C ⁇ -C alkyl
  • R 6 is selected from hydrogen or halogen
  • R 7 is selected from halogen, C C 6 alkyl, a 3 to 6 membered carbocycle, 3 to 6 membered saturated or partially unsaturated heterocycle, phenyl, 5 to 6 membered heteroaryl, and -0(3 to 6 membered heterocycle), wherein the alkyl, phenyl, heteroaryl and heterocycle are optionally substituted with halogen, CN, C!-C 6 alkyl or C!-C 6 alkoxy, wherein the alkyl and alkoxy are optionally substituted with halogen.
  • X 1 is selected from O or S
  • X 2 is CR 2 ;
  • X 3 is CR 3 ;
  • X 4 is selected from CR 4 or N;
  • X 5 is CR 5 ;
  • X 6 is CR 6 ;
  • R 1 is C1-C3 alkyl
  • R 2 is hydrogen
  • R 3 is selected from hydrogen, halogen, CN, Cj-Q alkyl, C C 6 alkoxy, a 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy and heteroaryl are optionally substituted with halogen;
  • R 4 is selected from hydrogen and Q-C 6 alkoxy, wherein the alkoxy is optionally substituted with halogen, or
  • R 3 and R 4 together with the atoms to which they are attached form a 3 to 6 membered heterocycle
  • R 5 is selected from hydrogen or CrC 6 alkyl
  • R 6 is selected from hydrogen or halogen
  • R 7 is selected from halogen, C C 6 alkyl, a 3 to 6 membered carbocycle, phenyl, 5 to 6 membered heteroaryl, wherein the alkyl, phenyl and heteroaryl are optionally substituted with halogen, CN, Cj-C 6 alkyl or Ci-C 6 alkoxy, wherein the alkyl and alkoxy are optionally substituted with halogen.
  • X 1 is selected from O, S, S(O), S0 2 , NR 11 or CHR 11 .
  • R 1 1 is selected from hydrogen and alkyl.
  • R 11 is selected from hydrogen and C!-C 6 alkyl.
  • R 1 1 is selected from hydrogen and methyl.
  • X 1 is selected from O or S. In certain embodiments,
  • X 1 is O. In certain embodiments, X 1 is S.
  • X 2 is selected from CR 2 or N
  • X 3 is selected from CR 3 or N
  • X 4 is selected from CR 4 or N
  • X 5 is selected from CR 5 or N
  • X 6 is selected from CR 6 or N.
  • X 2 is selected from CR 2 or N
  • X 3 is selected from CR 3 or N
  • X 4 is selected from CR 4 or N
  • X 5 is selected from CR 5 or N
  • X 6 is selected from CR 6 or N, wherein only one of X 2 , X 3 , X 4 , X 5 or X 6 may be N.
  • X 2 is CR 2 , X 3 is CR 3 , X 4 is selected from CR 4 or N, X 5 is CR 5 , and X 6 is CR 6 .
  • X 2 is CR 2 , X 3 is CR 3 or N, X 4 is selected from CR 4 or N, X 5 is CR 5 , and X 6 is CR 6 .
  • X 2 is CR 2 , X 3 is CR 3 or N, X 4 is selected from CR 4 or N, X 5 is CR 5 , and X 6 is CR 6 , wherein only one of X 3 and X 4 may be N.
  • X is selected from CR or N
  • X is selected from CR or N
  • X 4 is selected from CR 4 or N
  • X 5 is selected from CR 5 or N
  • X 6 is selected from CR 6 or
  • X is CR ,
  • X 3 is CR 3
  • X 4 is selected from CR 4 or N
  • X 5 is CR 5
  • X 6 is CR 6 .
  • R 1 is selected from hydrogen, benzyl or Ci-C 3 alkyl optionally substituted with R a .
  • each R a is independently selected from OH, OCH 3 , halogen, a 5 to 6 membered heteroaryl, and a 3-6 membered heterocyclyl optionally substituted with Ci-Cj alkyl optionally substituted with oxo.
  • R l is selected from hydrogen, benzyl, methyl, ethyl, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 , -CH 2 CH 2 CH 2 OCH 3 ,-CH 2 CF 3 , pyridin-2-ylmethyl, pyridin-4-ylmethyl and (l-acetylpiperdin-4-yl)methyl.
  • R 1 is selected from benzyl, methyl, ethyl, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 , -CH 2 CH 2 CH 2 OCH 3 , -CH 2 CF 3 , pyridin-2-ylmethyl, pyridin-4-ylmethyl and (1-acetylpiperdin- 4-yl)methyl.
  • R 1 is methyl.
  • R is hydrogen
  • R is selected from hydrogen, halogen, CN, Ci-C 6 alkyl, C!-C 6 alkoxy, a 3 to 6 membered carbocycle, a 3 to 6 membered heterocycle, phenyl, and a 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy, carbocycle, heterocycle, phenyl and heteroaryl are optionally substituted with halogen, a 3 to 6 membered carbocycle or Ci- C 6 alkoxy optionally substituted with halogen.
  • R 3 is selected from hydrogen, halogen, CN, C!-C 6 alkyl, Ci-Ce alkoxy, a 3 to 6 membered carbocycle, phenyl, and a 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy, carbocycle, phenyl and heteroaryl are optionally substituted with halogen, a 3 to 6 membered carbocycle or Ci-C 6 alkoxy optionally substituted with halogen.
  • R 3 is selected from hydrogen, halogen, CN, C!-C 6 alkyl, Q-Q alkoxy, a 3 to 6 membered carbocycle, phenyl, and a 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy, phenyl and heteroaryl are optionally substituted with halogen, a 3 to 6 membered carbocycle or d-C 6 alkoxy optionally substituted with halogen.
  • R 3 is selected from halogen, CN, Cj-C 6 alkyl, C!-C 6 alkoxy, a 3 to 6 membered carbocycle, a 3 to 6 membered heterocycle, phenyl, and a 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy, carbocycle, heterocycle, phenyl and heteroaryl are optionally substituted with halogen, a 3 to 6 membered carbocycle or Ci- C 6 alkoxy optionally substituted with halogen.
  • R 3 is selected from halogen, CN, CrC 6 alkyl, Ci-C 6 alkoxy, a 3 to 6 membered carbocycle, phenyl, and a 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy, carbocycle, heterocycle, phenyl and heteroaryl are optionally substituted with halogen, a 3 to 6 membered carbocycle or C]-C 6 alkoxy optionally substituted with halogen.
  • R is selected from halogen, CN, Ci-Ce alkyl, C ⁇ -Ce alkoxy, a 3 to 6 membered carbocycle, phenyl, and a 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy, phenyl and heteroaryl are optionally substituted with halogen, a 3 to 6 membered carbocycle or C C 6 alkoxy optionally substituted with halogen.
  • R 3 is selected a 5 to 6 membered heteroaryl, wherein the heteroaryl contains one, two, three or four heteroatoms selected from N, O and S.
  • R 3 is selected a 5 to 6 membered heteroaryl, wherein the heteroaryl contains one or two nitrogen heteroatoms. In certain embodiments, R is selected a 5 to 6 membered heteroaryl, wherein the heteroaryl is optionally substituted with halogen, and wherein the heteroaryl contains one or two nitrogen heteroatoms. In certain embodiments, R 3 is selected a 5 to 6 membered heteroaryl, wherein the heteroaryl is selected from pyridinyl and pyrimidinyl.
  • R 3 is selected a 5 to 6 membered heteroaryl, wherein the heteroaryl is optionally substituted with halogen, and wherein the heteroaryl is selected from pyridinyl and pyrimidinyl.
  • R is hydrogen, Br, F, CN, propyl, isobutyl, -OCH 3 , -OCF 3 , cyclopropylmethoxy, -OCH 2 CH 3 , -OCH2CHF2, -OCH(CH 3 ) 2 , -OCH 2 CF 3 , -OCH 2 C(CH 3 ) 3 , cyclopropyl, 3- (difiuoromethoxy)phenyl, 5-chloropyridin-3-yl, pyridin-3-yl, 2-fluoropyridin-3-yl, 5- fluoropyridin-3-yl and pyrimidin-5-yl.
  • R 3 is Br, F, CN, propyl, isobutyl, -OCH3, -OCF 3 , cyclopropylmethoxy, -OCH 2 CH 3 , -OCH 2 CHF 2 , -OCH(CH 3 ) 2 , -OCH 2 CF 3 , -OCH 2 C(CH 3 ) 3 , cyclopropyl, 3-(difluoromethoxy)phenyl, 5-chloropyridin-3-yl, pyridin-3-yl, 2-fluoropyridin-3-yl, 5-fluoropyridin-3-yl and pyrimidin-5-yl.
  • R 3 is selected from hydrogen, halogen, CN, Cj-C 6 alkyl, C ⁇ Q alkoxy, phenyl, a 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy, phenyl and heteroaryl are optionally substituted with halogen.
  • R 3 is selected from hydrogen, halogen, CN, Q-Ce alkyl, CrC alkoxy, a 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy and heteroaryl are optionally substituted with halogen.
  • R is hydrogen, Br, F, CN, propyl, -OCH 3 , -OCF 3 , or 5- chloropyridin-3-yl.
  • R 4 is selected from hydrogen, halogen, amino, cyano, nitro, alkyl, alkoxy, acyl, acyloxy, alkoxycarbonyl, sulfonyl, sulfinyl, sulfanyl, aryloxy, a carbocycle or a heterocycle wherein said alkyl, alkoxy, acyl, acyloxy, alkoxycarbonyl, sulfonyl, sulfinyl, sulfanyl, aryloxy, carbocycle and heterocycle are optionally substituted with hydroxy, halogen, amino, cyano, nitro, oxo, optionally substituted alkyl, optionally substituted alkoxy, sulfanyl, acyl, alkoxycarbonyl, haloalkyl and optionally substituted carbocycle.
  • R 4 is selected from hydrogen, halogen, alkyl, or alkoxy.
  • R 4 is selected from hydrogen, halogen, OH, CN, C ⁇ -
  • R 4 is selected from hydrogen, halogen, OH, Cj-C alkyl, Ci-C 6 alkoxy and a 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy and heteroaryl are optionally substituted with halogen.
  • R 4 is selected from hydrogen, OH, C!-C 6 alkyl, Cj-C alkoxy and a 5 to 6 membered heteroaryl, wherein the alkoxy and heteroaryl are optionally substituted with halogen. In certain embodiments, R 4 is selected from hydrogen, OH, CrC6 alkyl, Cj-C 6 alkoxy and a 5 to 6 membered heteroaryl, wherein the alkoxy is optionally substituted with halogen.
  • R 4 is selected from halogen, OH, CN, C C 6 alkyl, C C 6 alkoxy, phenyl, and a 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy, phenyl and heteroaryl are optionally substituted with halogen.
  • R 4 is selected from halogen, OH, Q-Q alkyl, C ⁇ -C alkoxy and a 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy and heteroaryl are optionally substituted with halogen.
  • R 4 is selected from OH, Q-Q alkyl, Q-C6 alkoxy and a 5 to 6 membered heteroaryl, wherein the alkoxy and heteroaryl are optionally substituted with halogen. In certain embodiments, R 4 is selected from OH, Q-Q alkyl, C!-C 6 alkoxy and a 5 to 6 membered heteroaryl, wherein the alkoxy is optionally substituted with halogen. In certain embodiments, R 4 is a 5 to 6 membered heteroaryl, wherein the heteroaryl contains one, two, three or four heteroatoms selected from N, O and S.
  • R 4 is a 5 to 6 membered heteroaryl, wherein the heteroaryl contains one nitrogen heteroatom. In certain embodiments, R 4 is a 5 to 6 membered heteroaryl, wherein the heteroaryl is pyridinyl. In certain embodiments, R 4 is hydrogen, -OH, isobutyl, isopropyl, -OCH 3 , -OCF 3 and pyridin-3-yl. In certain embodiments, R 4 is -OH, isobutyl, isopropyl, -OCH 3 , -OCF 3 and pyridin-3-yl.
  • R 4 is selected from hydrogen, halogen, CN, Cj-C 6 alkyl, Q-C6 alkoxy, phenyl, a 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy, phenyl and heteroaryl are optionally substituted with halogen.
  • R 4 is selected from hydrogen, halogen, d-C 6 alkyl, and CpC alkoxy, wherein the alkyl and alkoxy are optionally substituted with halogen.
  • R 4 is selected from hydrogen and Ci-C 6 alkoxy, wherein the alkoxy is optionally substituted with halogen.
  • R 4 is hydrogen, -OCH 3 , or -OCF 3 .
  • R 4 is selected from hydrogen, hydroxy, halogen, alkyl or alkoxy wherein said alkyl and alkoxy are optionally substituted with halogen. In certain embodiments, R 4 is selected from hydrogen, hydroxy, halogen, alkyl or alkoxy.
  • R 3 and R 4 together with the atoms to which they are attached form a 3 to 6 membered carbocycle or 3 to 6 membered heterocycle. In certain embodiments, R 3 and R 4 together with the atoms to which they are attached form a 3 to 6 membered heterocycle. In certain embodiments, R 3 and R 4 together with the atoms to which they are attached form a 3 to 6 membered heterocycle, wherein the heterocycle contains one, two or three heteroatoms selected from oxygen, nitrogen and sulfur. In certain embodiments, R 3 and R 4 together with the atoms to which they are attached form a 3 to 6 membered heterocycle, wherein the heterocycle contains one oxygen heteroatom. In certain embodiments, R 3 and R 4 together with the atoms to which they are attached form a 3 to 6 membered heterocycle, wherein the heterocycle formed is a tetrahydrofuran.
  • R 5 is selected from hydrogen, halogen, alkyl, alkoxy and a carbocycle. In certain embodiments, R 5 is selected from hydrogen, halogen and alkyl.
  • R 5 is selected from hydrogen, halogen, C]-C 6 alkyl,
  • R 5 is selected from hydrogen, halogen or C C 6 alkyl. In certain embodiments, R 5 is selected from hydrogen or d-C 6 alkyl. In certain embodiments, R 5 is hydrogen or methyl.
  • R 6 is selected from hydrogen, halogen or C]-C 6 alkyl. In certain embodiments, R is selected from hydrogen or halogen. In certain embodiments, R 6 is hydrogen or F.
  • R 7 is selected from hydrogen, halogen, Ci-C 6 alkyl, d-C alkenyl, Ci-C alkynyl, a 3 to 6 membered saturated or partially unsaturated carbocycle, a 3 to 6 membered saturated or partially unsaturated heterocycle, phenyl, 5 to 6 membered heteroaryl, and -0(3 to 6 membered heterocycle), wherein the alkyl, alkenyl, alkynyl, carbocycle, heterocycles, phenyl and heteroaryl are optionally substituted with halogen, CN, C!-C alkyl or Cj-C alkoxy, wherein the alkyl and alkoxy are optionally substituted with halogen.
  • R 7 is selected from hydrogen, halogen, Ci- C 6 alkyl, a 3 to 6 membered carbocycle, a 3 to 6 membered partially unsaturated heterocycle, phenyl, 5 to 6 membered heteroaryl, and -0(3 to 6 membered heterocycle), wherein the alkyl, phenyl and heteroaryl are optionally substituted with halogen, CN, Ci-C 6 alkyl or Cj- C alkoxy, wherein the alkyl and alkoxy are optionally substituted with halogen.
  • R 7 is selected from halogen, C !
  • R 7 is a 5 to 6 membered heteroaryl, wherein the heteroaryl contains one, two, three or four heteroatoms selected from the N, O and S.
  • R is a 5 to 6 membered heteroaryl, wherein the heteroaryl contains one or two nitrogen heteroatoms.
  • R 7 is a 5 to 6 membered heteroaryl, wherein the heteroaryl is selected from pyridinyl and pyrimidinyl.
  • R 7 is a 3 to 6 membered partially unsaturated heterocycle, wherein the heterocycle contains one, two or three heteroatoms selected from N, O and S.
  • R 7 is a 3 to 6 membered partially unsaturated heterocycle, wherein the heterocycle contains one oxygen heteroatom.
  • R 7 is a 3 to 6 membered partially unsaturated heterocycle, wherein the heterocycle is 3,6-dihydro-2H- pyran. In certain embodiments, R 7 is -0(3 to 6 membered heterocycle), wherein the heterocycle contains one, two or three heteroatoms selected from N, O and S. In certain embodiments, R is -0(3 to 6 membered heterocycle), wherein the heterocycle contains one oxygen heteroatom. In certain embodiments, R is -0(3 to 6 membered heterocycle), wherein the heterocycle is oxetanyl.
  • R is selected from hydrogen, halogen, d-C 6 alkyl,
  • R 7 is selected from hydrogen, halogen, C !
  • R 7 is selected from halogen, Ci-C 6 alkyl, a 3 to 6 membered carbocycle, phenyl, 5 to 6 membered heteroaryl, wherein the alkyl, phenyl and heteroaryl are optionally substituted with halogen, CN, d-C6 alkyl or Cj-Q alkoxy, wherein the alkyl and alkoxy are optionally substituted with halogen.
  • R 7 is selected from halogen, Ci-C 6 alkyl, a 3 to 6 membered carbocycle, phenyl, 5 to 6 membered heteroaryl, wherein the alkyl, phenyl and heteroaryl are optionally substituted with halogen, CN, Ci-C 6 alkyl or C !
  • R 7 is Br, isopentyl, 4-butanenitrile, cyclohexyl, phenyl, 3- (difluoromethoxy)phenyl, 3-methoxyphenyl, 3-chloro-5-methoxyphenyl, 3 -ethoxyphenyl, 3- cyanophenyl (3-benzonitrile), 5-chloro-2-fluorophenyl, 3-fluoro-5-methoxyphenyl, 3-chloro- 5 -fluorophenyl, 3-chlorophenyl, 3-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chloro-2- fluorophenyl, 5-chloro-2-fluorophenyl, pyridin-3-yl, 5-methoxypyridin-3-yl, 2-fluoropyridin- 3-yl, 5-cyano
  • R 7 is selected from hydroxy, halogen, amino, cyano, nitro, alkyl, alkoxy, acyl, acyloxy, alkoxycarbonyl, sulfonyl, sulfinyl, sulfanyl, aryloxy, a carbocycle, a heterocycle or -O(heterocycle) wherein said alkyl, alkoxy, acyl, acyloxy, alkoxycarbonyl, sulfonyl, sulfinyl, sulfanyl, aryloxy, carbocycle and heterocycle are optionally substituted with hydroxy, halogen, amino, cyano, nitro, oxo, optionally substituted alkyl, optionally substituted alkoxy, sulfanyl, acyl, alkoxycarbonyl, haloalkyl and optionally substituted carbocycle.
  • Compounds of the invention contain one or more asymmetric or chiral centers, e.g., a chiral carbon atom. Accordingly, the compounds may exist as diastereomers, enantiomers or mixtures thereof.
  • the syntheses of the compounds may employ racemates, diastereomers or enantiomers as starting materials or as intermediates. Diastereomeric compounds may be separated by chromatographic or crystallization methods. Similarly, enantiomeric mixtures may be separated using the same techniques or others known in the art.
  • Each of the asymmetric carbon atoms may be in the R or S configuration and both of these configurations are within the scope of the invention.
  • compounds of the invention have the stereochemical orientation represented by Formula ⁇ :
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , R 1 and R 7 are as defined herein.
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , R 1 and R 7 are as defined herein.
  • the invention also encompasses prodrugs of the compounds described above.
  • Suitable prodrugs where applicable include known amino-protecting and carboxy-protecting groups which are released, for example hydrolyzed, to yield the parent compound under physiologic conditions.
  • a particular class of prodrugs are compounds in which a nitrogen atom in an amino, amidino, aminoalkyleneamino, iminoalkyleneamino or guanidino group is substituted with a hydroxy (OH) group, an alkylcarbonyl (-CO-R) group, an alkoxycarbonyl (-CO-OR), an acyloxyalkyl-alkoxycarbonyl (-CO-O-R-O-CO-R) group where R is a monovalent or divalent group and as defined above or a group having the formula -C(0)-0- CPlP2-haloalkyl, where PI and P2 are the same or different and are hydrogen, lower alkyl, lower alkoxy, cyano, halo lower alkyl or aryl.
  • the nitrogen atom is one of the nitrogen atoms of the amidino group of the compounds of the invention.
  • These prodrug compounds are prepared by reacting the compounds of the invention described above with an activated acyl compound to bond a nitrogen atom in the compound of the invention to the carbonyl of the activated acyl compound.
  • Suitable activated carbonyl compounds contain a good leaving group bonded to the carbonyl carbon and include acyl halides, acyl amines, acyl pyridinium salts, acyl alkoxides, in particular acyl phenoxides such as p-nitrophenoxy acyl, dinitrophenoxy acyl, fluorophenoxy acyl, and difluorophenoxy acyl.
  • the reactions are generally exothermic and are carried out in inert solvents at reduced temperatures such as -78°C to about 50°C.
  • the reactions are usually also carried out in the presence of an inorganic base such as potassium carbonate or sodium bicarbonate, or an organic base such as an amine, including pyridine, triethylamine, etc.
  • an inorganic base such as potassium carbonate or sodium bicarbonate
  • an organic base such as an amine, including pyridine, triethylamine, etc.
  • Compounds of the invention may exist as stereoisomers, e.g., diastereomers and enantiomers, resonance forms, e.g., tautomers, solvates and salts, and all such stereoisomers, resonance forms, solvates and salts are within the scope of the invention herein.
  • Compounds of the invention are prepared using standard organic synthetic techniques from starting materials and reagents 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 Fieser, Louis F., 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, Aufi. ed. Springer- Verlag, Berlin, including supplements (also available via the Beilstein online database)).
  • Scheme 1 shows a general scheme for the synthesis of compound 4, wherein
  • R 1 and R 7 are as defined herein.
  • Compound 1 may be reacted with a ring closing agent, such as polyphosphoric acid (“PPA”), or SOCl 2 or COCl 2 followed by A1C1 3 , to provide compound 2.
  • PPA polyphosphoric acid
  • DMSO dimethylsulfoxide
  • Scheme 2 shows a general scheme for the synthesis of compound 8, wherein
  • R 1 and R 7 are as defined herein.
  • Compound 5 may be reacted with a ring closing agent, such as KCN under an open air atmosphere, to provide compound 6.
  • Scheme 3 shows a general scheme for the synthesis of compound 14, wherein
  • R 1 and R 7 are as defined herein.
  • Compound 9 may be reacted with benzenethiol to provide compound 10.
  • Compound 10 may be reacted with a ring closing agent, such as polyphosphoric acid, to provide compound 11.
  • Compound 11 may be brominated to provide compound 12.
  • Compound 12 may be reacted with KI, followed by 1 -methylguanidine to provide compound 13.
  • R 7 is not bromine, a Suzuki, Negishi or Stille coupling installs the R 7 group and provides compound 14.
  • a process for preparing compound of Formula 4 comprising:
  • a process for preparing compound of Formula 8 comprising:
  • the ring closing agent is KCN under an open air atmosphere.
  • the oxidizing agent is selenium dioxide.
  • the optional Step C is a Suzuki coupling.
  • the ring closing agent is KCN under an open air atmosphere, the oxidizing agent is selenium dioxide, and the optional Step C is a Suzuki coupling.
  • a process for preparing compound of Formula 14 comprising:
  • the ring closing agent is polyphosphoric acid.
  • the bromination in Step B is performed with a brominating agent.
  • the bromination in Step B is performed with a brominating agent, wherein the brominating agent is CuBr 2 .
  • the optional Step C is a Suzuki coupling.
  • the ring closing agent is polyphosphoric acid, the brominating agent is CuBr 2 , and the optional Step C is a Suzuki coupling.
  • 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.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • 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 S. Wilen. 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 derivatizing 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, a-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.
  • 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.
  • 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.
  • 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.
  • a compound of Formula I in the manufacture of a medicament for the treatment of a neurodegenerative disease.
  • the neurodegenerative disease is Alzheimer's disease.
  • a use of a compound of Formula I in the treatment of neurodegenerative diseases is provided.
  • the neurodegenerative disease is Alzheimer's disease.
  • 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.
  • the invention also includes compositions containing the compounds of the invention and a carrier, diluent or excipient, as well as methods of using the compounds of the invention to prepare such compositions.
  • a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable carrier, diluent or excipient.
  • the compounds of the invention used in the methods of the invention are formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are nontoxic to recipients at the dosages and concentrations employed into a galenical administration form.
  • physiologically acceptable carriers i.e., carriers that are nontoxic to recipients at the dosages and concentrations employed into a galenical administration form.
  • the pH of the formulation depends mainly on the particular use and the concentration of compound, but may range anywhere from about 3 to about 8.
  • Formulation in an acetate buffer at pH 5 is a suitable embodiment.
  • formulations comprising compounds of the invention are sterile.
  • the compounds ordinarily will be stored as a solid composition, although lyophilized formulations or aqueous solutions are acceptable.
  • compositions comprising compounds of the invention will be formulated, dosed, and administered in a fashion consistent with good medical practice.
  • Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of administration, the method of administration, the scheduling of administration, and other factors known to medical practitioners.
  • 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.
  • the initial pharmaceutically effective amount of the compound of the invention administered parenterally per dose will be in the range of about 0.01-100 mg/kg/day, for example about 0.1 to 20 mg/kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg/kg/day.
  • Oral unit dosage forms, such as tablets and capsules, may contain from about 25 to about 1000 mg of the compound of the invention.
  • the compound of the invention may be administered by any suitable means, including oral, sublingual, buccal, topical, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, and intranasal, and, if desired for local treatment, intralesional administration.
  • Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
  • An example of a suitable oral dosage form is a tablet containing about 25 mg, 50 mg, 100 mg, 250 mg, or 500 mg of the compound of the invention compounded with about 90-30 mg anhydrous lactose, about 5-40 mg sodium croscarmellose, about 5-30 mg polyvinylpyrrolidone ("PVP") K30, and about 1- 10 mg magnesium stearate.
  • the powdered ingredients are first mixed together and then mixed with a solution of the PVP.
  • the resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment.
  • An aerosol formulation can be prepared by dissolving the compound, for example 5-400 mg, of the invention in a suitable buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g., a salt such sodium chloride, if desired.
  • the solution is typically filtered, e.g., using a 0.2 micron filter, to remove impurities and contaminants.
  • Another formulation may be 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 al., 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 of the
  • 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. 12 pL of the reagent mixture was added to the required wells of the 384 well assay plate. The assay plate was incubated at 4°C for 17 hours and then analyzed for fluorescence at 665 and 620 nm.
  • Step A Ethyl 2-(2-hydroxyphenyl)acetate (5.0 g, 28 mmol), l-fluoro-4- nitrobenzene (3.6 ml, 33 mmol) and K 2 C0 3 (5.8 g, 42 mmol) were diluted with dimethylformamide (“DMF”) (100 mL). The reaction was heated to 70°C and stirred for 12 hours. The reaction was allowed to cool, diluted with ethyl acetate and washed with water then brine. The organics were dried over MgS0 4 , filtered and concentrated.
  • DMF dimethylformamide
  • Step B Ethyl 2-(2-(4-nitrophenoxy)phenyl)acetate (5.6 g, 19 mmol) was diluted with methanol (50 mL), followed by the addition of palladium 10 wt. % (dry basis), activated carbon, wet, Degussa (0.20 g, 1.9 mmol). The reaction was purged three times with a hydrogen balloon and was left to stir for 12 hours. The reaction was filtered through glass microfibre filter ("GF/F”) paper and concentrated to yield ethyl 2-(2-(4- aminophenoxy)phenyl)acetate (5.0 g, 18 mmol, 99% yield).
  • GPF glass microfibre filter
  • Step C A mixture of tBuN0 2 (2.43 mL, 18.4 mmol) and CuBr 2 (3.29 g, 14.7 mmol) in acetonitrile (100 mL) were stirred at 0°C for 30 minutes. Ethyl 2-(2-(4- aminophenoxy)phenyl)acetate (5.0 g, 18.4 mmol; in 2 mL of acetonitrile (“ACN”)) was slowly added. This was stirred for 2 hours and then allowed to warm to ambient temperature. The reaction was quenched with HC1 (IN) and the organics were extracted with dichloromethane (“DCM"). The combined organics were washed with brine and dried with MgS0 4 .
  • ACN acetonitrile
  • Step D Ethyl 2-(2-(4-bromophenoxy)phenyl)acetate (4.34 g, 12.9 mmol) was diluted with ethanol (50 mL) followed by the addition of NaOH (32.4 mL, 64.7 mmol). After stirring for 12 hours, the reaction was diluted with ethyl acetate and 2N HC1. The layers were separated, and the organic was dried over MgS0 4 , filtered and concentrated to yield 2-(2-(4- bromophenoxy)phenyl)acetic acid (3.7 g, 12.0 mmol, 93.0% yield).
  • Step E 2-(2-(4-Bromophenoxy)phenyl)acetic acid (3.7 g, 12 mmol) was added to a stirring 80°C solution of PPA. After stirring for 12 hours, the reaction was allowed to cool and poured into ice water. The material was extracted twice with DCM. The DCM was combined, dried over MgS0 4 , filtered and concentrated. The material was purified on silica gel eluting with 10-50% ethyl acetate/hexanes to yield 8-bromodibenzo[b,f]oxepin- 10(1 lH)-one (3.3 g, 1 1 mmol, 95% yield).
  • Step F 8-Bromodibenzo[b,f]oxepin-10(l lH)-one (3.3 g, 1 1 mmol) was diluted with dioxane (30 mL) and water (600 uL) followed by the addition of selenium dioxide (2.8 g, 25 mmol). The reaction was heated to reflux and stirred for 12 hours. The reaction was cooled and then filtered. 1-Methylguanidine hydrochloride (5.0 g, 46 mmol) and ethanol (30 mL) were added followed by the addition of Na 2 C0 3 (23 mL, 46 mmol). The reaction was heated to 80°C and stirred for 12 hours.
  • Step G 2-Amino-2'-bromo-l-methylspiro[imidazole-4,9'-xanthen]-5(l H)-one (30 mg, 0.084 mmol) and 5-methoxypyridin-3-ylboronic acid (15 mg, 0.10 mmol) were diluted with dioxane (1 mL) followed by the addition of Pd(PPh 3 ) 4 (4.8 mg, 0.0042 mmol) and Na 2 C0 3 (126 iL, 0.25 mmol). The reaction was sealed, heated to 85°C and stirred for 12 hours.
  • Example 2 was separated on a Berger SFC MGII system using a Chiralpak IB (200 x 21.2 mm, 5u) chiral column eluting at 50 mL/minute with 30% methanol (0.1% DEA). Separation was done at 40°C to afford (S)-2-amino-2'-(2-fluoropyridin-3-yl)-l- methylspiro[imidazole-4,9'-xanthen]-5(lH)-one.
  • Step A 3-Fluoroisonicotinaldehyde (9.7 g, 78 mmol), 5- bromosalicylaldehyde (13 g, 65 mmol) and K 2 C0 3 (9.8 g, 71 mmol) were diluted with DMSO (125 mL). The reaction was heated to 70°C and stirred for 12 hours. The reaction was allowed to cool, diluted with ethyl acetate and water. The layers were separated, and the organics were dried over MgS0 4 , filtered and concentrated.
  • Step B 3-(4-Bromo-2-formylphenoxy)isonicotinaldehyde (5.8 g, 19 mmol) was diluted with DMSO (15 mL) followed by the addition of KCN (0.99 g, 15 mmol). The reaction was stirred at ambient temperature for 12 hours. The reaction was diluted with ethyl acetate and saturated sodium bicarbonate. The layers were separated, and the organic was dried over MgS0 4 , filtered and concentrated. The material was purified on silica gel eluting with 20-90% ethyl acetate hexanes to ield the compound 15B (2.2 g, 7.2 mmol, 38% yield).
  • Step C Compound 15B (2.2 g, 7.2 mmol) was diluted with dioxane (20 mL) and water (200 ⁇ ) followed by the addition of selenium dioxide (1.6 g, 14 mmol). The reaction was heated to reflux and stirred for 12 hours. The reaction was cooled and then filtered. 1-Methylguanidine hydrochloride (3.1 g, 29 mmol) and ethanol (30 mL) were added, followed by the addition of Na 2 C0 3 (14 mL, 29 mmol). The reaction was heated to 80°C and stirred for 12 hours. The reaction was allowed to cool, diluted with ethyl acetate and water.
  • Step D 2'-Amino-7-bromo- -methylspiro[chromeno[2,3-c]pyridine-5,4'- imidazol]-5'(l'H)-one (30 mg, 0.0835 mmol) and 3-methoxyphenylboronic acid (13.3 mg, 0.0877 mmol) were diluted with dioxane (1 mL) followed by the addition of Pd(PPh 3 ) 4 (4.83 mg, 0.00418 mmol) and Na 2 C0 3 (125 ⁇ , 0.251 mmol). The reaction was sealed, heated to 85°C and stirred for 12 hours.
  • Step A A mixture of methyl 2-(2-fluoro-5-nitrophenyl)acetate (1.0 g, 4.69 mmol), 4-methoxyphenol (0.611 g, 4.93 mmol) and Cs 2 C0 3 (2.29 g, 7.04 mmol) in DMF (0.343 g, 4.69 mmol) was heated to 90°C overnight. The mixture was then partitioned between ethyl acetate and water. The organics were extracted with ethyl acetate twice, washed with brine and dried with Na 2 S0 4 .
  • Step B Methyl 2-(2-(4-methoxyphenoxy)-5-nitrophenyl)acetate (1.30 g, 4.10 mmol) and Pd/C (0.436 g, 4.10 mmol) in MeOH (0.166 mL, 4.10 mmol; d 0.791) under H 2 in a balloon was stirred to completion at room temperature. The mixture was then filtered through GF/F paper. The filtrate was concentrated down to give methyl 2-(5-amino-2-(4- methoxyphenoxy)phenyl)acetate (1.1 1 g, 3.86 mmol, 94.3% yield).
  • Step D NaOH (4.47 mL, 8.94 mmol) was added to a mixture of methyl 2-(5- bromo-2-(4-methoxyphenoxy)phenyl)acetate (0.628 g, 1.79 mmol) in ethanol (15 mL, 1.79 mmol) at room temperature. This was stirred overnight to completion. The mixture was partitioned between ethyl acetate and 2N HC1. The organics were extracted with ethyl acetate, washed with brine and dried with Na 2 S0 4 . This was then concentrated down to give 2-(5-bromo-2-(4-methoxyphenoxy)phenyl)acetic acid (0.60 g, 1.78 mmol, 99.5% yield).
  • Step E A mixture of 2-(5-bromo-2-(4-methoxyphenoxy)phenyl)acetic acid (0.600 g, 1.78 mmol) in PPA (0.174 g, 1.78 mmol) was heated to 90°C overnight. The mixture was then partitioned between DCM and water. The organics were extracted with DCM twice, washed with brine and dried with Na 2 S0 4 . This was then concentrated down and purified on a column using ethyl acetate and hexanes to give 2-bromo-8- methoxydibenzo[b,f]oxepin-10(HH)-one (0.480 g, 1.50 mmol, 84.5% yield).
  • Step F A mixture of 2-bromo-8-methoxydibenzo[b,fJoxepin-10(l lH)-one (0.480 g, 1.50 mmol) and Se0 2 (0.367 g, 3.31 mmol) in dioxane (15 mL, 1.50 mmol) and water (0.5 mL, 1.50 mmol) was refluxed overnight. The mixture was then filtered through GF/F paper, and the filtrate was put in a round bottom flask. Ethanol (15 mL, 1.50 mmol) was added, followed by 1-methylguanidine hydrochloride (0.741 g, 6.77 mmol). This was stirred into solution.
  • Step G A mixture of 2-amino-2'-bromo-7'-methoxy-l- methylspiro[imidazole-4,9'-xanthen]-5(lH)-one (0.040 g, 0.103 mmol), 5-chloropyridin-3- ylboronic acid (0.0195 g, 0.124 mmol), Pd(PPh 3 ) 4 (0.0119 g, 0.0103 mmol) and Na 2 C0 3 (0.0273 g, 0.258 mmol) and dioxane (1 mL, 0.103 mmol) was heated to 90°C overnight.
  • Step A A mixture of methyl 2-(5-bromo-2-hydroxyphenyl)acetate (2.0 g, 8.16 mmol), l-bromo-4-iodobenzene (6.93 g, 24.5 mmol), 2-(dimethylamino)acetic acid hydrochloride (0.683 g, 4.90 mmol), Cs 2 C0 3 (6.65 g, 20.4 mmol) and Cu(I)Cl (0.485 g, 4.90 mmol) in dioxane (20.4 mL, 8.16 mmol) was purged with argon for 10 minutes. The mixture was then refluxed for 4 hours. HPLC showed that the reaction was complete.
  • Step B A mixture of methyl 2-(5-bromo-2-(4-bromophenoxy)phenyl)acetate (0.721 g, 1.80 mmol) and sodium hydroxide (5.41 mL, 10.8 mmol) in ethanol (10 mL, 1.80 mmol) was stirred at room temperature for 4 hours. The mixture was then partitioned between ethyl acetate and 2N HC1. The organics were extracted with ethyl acetate twice, washed with brine and dried with Na 2 S0 4 . This was then concentrated down to give 2-(5- bromo-2-(4-bromophenoxy)phenyl)acetic acid (0.689 g, 1.78 mmol, 99.0% yield).
  • Step C Oxalyl chloride in 2M DCM (0.389 mL, 0.777 mmol) was added to 2- (5-bromo-2-(4-bromophenoxy)phenyl)acetic acid (0.250 g, 0.648 mmol) in DCM (10 mL, 0.648 mmol) at 0°C. A few drops of DMF were added, and this was stirred at room temperature for 15 minutes. This was then concentrated down to give an oil. 1 ,2- Dichloroethane (“DCE”) (10 mL) was added to the oil, and this was chilled to 0°C.
  • DCE 2- Dichloroethane
  • A1C1 3 (0.259 g, 1.94 mmol) in DCE (5 mL) was added, and this was stirred at room temperature for 1 hour. The mixture was then partitioned between DCM and water. The organics were extracted with DCM twice, washed with brine and dried with Na 2 S0 4 . This was then concentrated down and purified on a column using ethyl acetate and hexanes to give 2,8- dibromodibenzo[b,f]oxepin-10(l lH)-one (0.200 g, 0.543 mmol, 83.9% yield).
  • Step D A mixture of 2,8-dibromodibenzo[b,f]oxepin-10(l lH)-one (0.20 g, 0.543 mmol) and selenium dioxide (0.151 g, 1.36 mmol) in dioxane (0.0479 g, 0.543 mmol) was heated to 90°C overnight. The mixture was then filtered through GF/F paper. Ethanol (0.0250 g, 0.543 mmol) was added to the filtrate, followed by the addition of 1- methylguanidine hydrochloride (0.268 g, 2.45 mmol).
  • Step E A mixture of 2-amino-2',7'-dibromo-l-methylspiro[imidazole-4,9'- xanthen]-5(lH)-one (0.030 g, 0.069 mmol), 5-chloropyridin-3-ylboronic acid (0.024 g, 0.15 mmol), Pd(PPh 3 ) 4 (0.0079 g, 0.0069 mmol) and Na 2 C0 3 (0.12 mL, 0.24 mmol) in dioxane (2 mL, 0.069 mmol) was heated to 90°C overnight. The mixture was then partitioned between DCM and water.
  • Steps A-D 2-(5-Bromo-2-(3-methoxy-2-methylphenoxy)phenyl)acetic acid was made according to the procedures in Example 1, Steps A through D, substituting 3- methoxy-2-methylphenol for 4-methoxyphenol.
  • Step E Oxalyl chloride in 2M DCM (3.55 mL, 7.10 mmol) was added to a mixture of 2-(5-bromo-2-(3-methoxy-2-methylphenoxy)phenyl)acetic acid (2.08 g, 5.92 mmol) in DCM (12 mL, 5.92 mmol) at 0°C. A few drops of DMF were added, and the mixture was stirred at room temperature for 4 hours. The mixture was then concentrated down to give an oil. The oil was taken up in DCE (0.586 g, 5.92 mmol; bp83) and A1C1 3 (2.37 g, 17.8 mmol) was added at 0°C. The mixture was stirred at room temperature overnight.
  • Step F A mixture of 2-bromo-7-methoxy-6-methyldibenzo[b,f]oxepin- 10(l lH)-one (1.90 g, 5.70 mmol) and selenium dioxide (0.949 g, 8.55 mmol) in dioxane (14 mL, 5.70 mmol) was heated to 90°C overnight. The mixture was then filtered through GF/F paper. Ethanol (0.263 g, 5.70 mmol) was added to the filtrate, followed by the addition of 1- methylguanidine hydrochloride (2.81 g, 25.7 mmol).
  • Step G A mixture of 2-amino-2'-bromo-6'-methoxy-l ,5'- dimethylspiro[imidazole-4,9'-xanthen]-5(lH)-one (0.050 g, 0.124 mmol), 5-chloropyridin-3- ylboronic acid (0.0215 g, 0.137 mmol), Pd(PPh 3 ) 4 (0.0144 g, 0.0124 mmol) and Na 2 C0 3 (0.155 mL, 0.311 mmol) in dioxane (2 mL, 0.124 mmol) was heated to 90°C overnight. The mixture was then partitioned between DCM and water.
  • Step A A solution of 2-(2-hydroxyphenyl)acetic acid (40.00 g, 262.9 mmol) and phenyltrimethylammonium bromide (98.83 g, 262.9 mmol) in ethanol (1315 mL, 262.9 mmol) was stirred at room temperature overnight. The mixture was evaporated then partitioned between ether and IN HCl. The organic layer was washed with sodium bisulfate (aq), water, brine, dried and concentrated to give a residue that was purified by flash chromatography, eluting with a hexanes/ethyl acetate gradient. The resulting residue was triturated with hexanes to crystallize ethyl 2-(5-bromo-2-hydroxyphenyl)acetate (32.5 g, 125 mmol, 48%).
  • Step B A mixture of ethyl 2-(5-bromo-2-hydroxyphenyl)acetate (6.0 g, 23.2 mmol), 5-chloropyridin-3-ylboronic acid (4.37 g, 27.8 mmol), Pd(PPh 3 ) 4 (0.535 g, 0.463 mmol) and Na 2 C0 3 (28.9 mL, 57.9 mmol) in dioxane (60 mL, 23.2 mmol) was heated to 90°C overnight. The mixture was filtered through GF/F paper. The filtrate was then partitioned between ethyl acetate and 2N HCl.
  • Step C A few drops of H 2 S0 4 (2.08 g, 21.2 mmol) were added to a mixture of 2-(5-(5-chloropyridin-3-yl)-2-hydroxyphenyl)acetic acid (5.6 g, 21.2 mmol) in MeOH (0.860 mL, 21.2 mmol; d 0.791). The mixture was refluxed overnight. The mixture was then partitioned between ethyl acetate and water. The organics were extracted twice with ethyl acetate, washed with brine and dried with Na 2 S0 4 .
  • Step D A mixture of methyl 2-(5-(5-chloropyridin-3-yl)-2- hydroxyphenyl)acetate (2.87 g, 10.3 mmol), l-bromo-4-iodobenzene (11.7 g, 41.3 mmol), 2- (dimethylamino)acetic acid hydrochloride (0.866 g, 6.20 mmol), Cu(I)Cl (0.614 g, 6.20 mmol) and Cs 2 C0 3 (8.42 g, 25.8 mmol) in dioxane (35 mL, 10.3 mmol) was purged with argon for 5 minutes. This was then heated to reflux for 2 hours under N 2 .
  • Step E A mixture of methyl 2-(2-(4-bromophenoxy)-5-(5-chloropyridin-3- yl)phenyl)acetate (1.21 g, 2.80 mmol) and NaOH (8.39 mL, 16.8 mmol) was stirred in ethanol (20 mL, 2.80 mmol) for 4 hours. The mixture was then partitioned between ethyl acetate and IN HCl. The organics were extracted with ethyl acetate twice, washed with brine and dried with Na 2 S0 4 . The mixture was then concentrated down to give 2-(2-(4- bromophenoxy)-5-(5-chloropyridin-3-yl)phenyl)acetic acid (1.17 g, 2.79 mmol, 99.9% yield).
  • Step F Oxalyl dichloride (0.287 mL, 0.573 mmol) was added to a mixture of
  • Step G A mixture of 8-bromo-2-(5-chloropyridin-3-yl)dibenzo[b,f]oxepin- 10(l lH)-one (0.061 g, 0.15 mmol) and selenium dioxide (0.037 g, 0.33 mmol) in dioxane (2 mL, 0.15 mmol) was heated to 90°C overnight. The mixture was then filtered through GF/F paper. Ethanol (2 mL, 0.15 mmol) was added to the filtrate, followed by the addition of 1- methylguanidine hydrochloride (0.075 g, 0.69 mmol).
  • Step H A mixture of 2-amino-2'-bromo-7'-(5-chloropyridin-3-yl)-l- methylspiro[imidazole-4,9'-xanthen]-5(lH)-one (0.015 g, 0.032 mmol), propylzinc(II) bromide (0.20 mL, 0.10 mmol) and Bis(tri-t-butylphosphine)palladium (0) (0.0016 g, 0.0032 mmol) in THF (1 mL, 0.032 mmol) was heated to 90°C for 4 hours. The mixture was filtered through some Celite®.
  • Step A A slurry of ethyl 2-(2-hydroxyphenyl)acetate (2.10 g, 11.7 mmol), 4- bromo-3-fluorophenylboronic acid (5.10 g, 23.3 mmol), diacetoxycopper (2.12 g, 1 1.7 mmol), and triethylamine (3.25 mL, 23.3 mmol) in CH2CI2 (1 17 mL) was stirred at room temperature for 24 hours. The reaction mixture was diluted with CH 2 C1 2 and washed with brine. The organic layer was dried and concentrated, and the residue was by flash chromatography eluting with an ethyl acetate/hexanes gradient to afford ethyl 2-(2-(4-bromo-
  • Step B A solution of ethyl 2-(2-(4-bromo-3-fluorophenoxy)phenyl)acetate (1.70 g, 4.81 mmol) and LiOH hydrate (0.61 g, 14.4 mmol) in MeOH (12 mL) and water (4.81 ml) was stirred at room temperature overnight. The mixture was acidified with 2N HC1 then extracted with ethyl acetate (3 X). The organic layers were dried and concentrated to give 2-(2-(4-bromo-3-fluorophenoxy)phenyl)acetic acid (1.56 g, 4.80 mmol, 99%), which was used without purification.
  • Step C Oxalyl chloride (0.90 mL, 9.84 mmol) was added to a solution of 2- (2-(4-bromo-3-fluorophenoxy)phenyl)acetic acid (1.56 g, 4.80 mmol) in CH 2 C1 2 (25 mL), followed by 3 drops of DMF. The solution was stirred at room temperature for 1 hour and then concentrated to give 2-(2-(4-bromo-3-fluorophenoxy)phenyl)acetyl chloride (1.68 g, 4.80 mmol, 99%), which was used without purification.
  • Step D A1C1 3 (1.31 g, 9.84 mmol) was added to a solution of 2-(2-(4-bromo- 3-fluorophenoxy)phenyl)acetyl chloride (1.68 g, 4.80 mmol) in 1,2-dichloroethane (25 mL, 4.92 mmol), and the resulting solution was stirred at room temperature for 1 hour. The reaction was quenched with water and extracted with ether (3 X).
  • Step E A nitrogen-degassed solution 8-bromo-7-fluorodibenzo[b,fjoxepin- 10(l lH)-one (0.775 g, 2.52 mmol) in ethyl acetate (5.05 mL, 2.52 mmol) and CHC1 3 (5.05 mL, 2.52 mmol) was heated to 80°C. The sparging was continued as CuBr 2 (1.13 g, 5.05 mmol) was slowly added. Sparging was discontinued, and the reaction mixture was heated at 80°C for 1 day under nitrogen. The reaction mixture was filtered, and the filter cake was thoroughly washed with CH 2 C1 2 . The filtrate was concentrated.
  • Step F DMSO (9 mL) was added to a flask containing 8,l l-dibromo-7- fluorodibenzo[b,f]oxepin-10(l lH)-one (0.97 g, 2.52 mmol), and then KI (0.419 g, 2.52 mmol) and Na 2 C0 3 (0.267 g, 2.52 mmol) were added. The resulting mixture was stirred at room temperature for 30 minutes. Upon completion as determined by LCMS and TLC, 1- methylguanidine hydrochloride (0.83 g, 7.57 mmol) was added, followed by aqueous Na 2 C0 3 (2.50 mL, 5.05 mmol).
  • Step G A biphasic mixture of 2-amino-2'-bromo-3'-fluoro-l- methylspiro[imidazole-4,9'-xanthen]-5(lH)-one (15.0 mg, 0.04 mmol), 2-fluoropyridin-3- ylboronic acid (7.02 mg, 0.050 mmol), Pd(PPh 3 ) 4 (4.61 mg, 0.004 mmol) and Na 2 C0 3 (2M, 59.8 ⁇ ,) in dioxane (199 ⁇ , 0.040 mmol) in a pressure vial was degassed for 5 minutes with nitrogen and then capped and stirred at 100°C overnight.
  • Step A The same procedure was followed as in Example 58, Step A, substituting 2,3-dihydrobenzofuran-5-ylboronic acid (1.70 g, 10.4 mmol) for 4-bromo-3- fluorophenylboronic acid to afford ethyl 2-(5-bromo-2-(2,3-dihydrobenzofuran-5- yloxy)phenyl)acetate (0.600 g, 1.59 mmol, 31%).
  • Step B The same procedure was followed as in Example 58, Step B, substituting ethyl 2-(5-bromo-2-(2,3-dihydrobenzofuran-5-yloxy)phenyl)acetate (600 mg, 1.59 mmol) for ethyl 2-(2-(4-bromo-3-fluorophenoxy)phenyl)acetate to afford 2-(5-bromo-2- (2,3-dihydrobenzofuran-5-yloxy)phenyl)acetic acid (0.555 g, 1.59 mmol, 99%).
  • Step C The same procedure was followed as in Example 58, Step C, substituting 2-(5-bromo-2-(2,3-dihydrobenzofuran-5-yloxy)phenyl)acetic acid (0.555 g, 1.59 mmol) for 2-(2-(4-bromo-3-fluorophenoxy)phenyl)acetic acid to afford 2-(5-bromo-2-(2,3- dihydrobenzofuran-5-yloxy)phenyl)acetyl chloride (0.584 g, 1.59 mmol, 99%).
  • Step D The same procedure was followed as in Example 58, Step D, substituting 2-(5-bromo-2-(2,3-dihydrobenzofuran-5-yloxy)phenyl)acetyl chloride (0.584 g, 1.59 mmol) for 2-(2-(4-bromo-3-fluorophenoxy)phenyl)acetyl chloride to afford 8-bromo- 2,3-dihydrobenzo[b]benzofuro[6,5-f]oxepin-l l(10H)-one (0.12 g, 0.36 mmol, 23%).
  • Step E The same procedure was followed as in Example 58, Step E, substituting 8-bromo-2,3-dihydrobenzo[f]benzofuro[5,6-b]oxepin-l l(10H)-one (114 mg, 0.344 mmol) for 8-bromo-7-fluorodibenzo[b,f]oxepin-10(l lH)-one to afford 8,10-dibromo- 2,3-dihydrobenzo[f]benzofuro[5,6-b]oxepin-l l(10H)-one (141 mg, 0.344 mmol, 99%).
  • Step F The same procedure was followed as in Example 58, Step F, substituting 8,1 l-dibromo-2,3-dihydrobenzo[f]benzofuro[5,6-b]oxepin-10(l lH)-one (141 mg, 0.344 mmol) for 8,l l-dibromo-7-fluorodibenzo[b,f]oxepin-10(l lH)-one to afford 2'- amino-8-bromo- T-methyl-2,3 -dihydrospiro [furo [2,3 -b]xanthene- 10,4 -imidazol] -5'( l'H)-one (17 mg, 0.043 mmol, 12%).
  • Step G The same procedure was followed as in Example 58, Step G, substituting 2'-amino-8-bromo-r-methyl-2,3-dihydrospiro[furo[2,3-b]xanthene-10,4'- imidazol]-5'(l'H)-one (15 mg, 0.0375 mmol) for 2-amino-2'-bromo-3'-fluoro-l- methylspiro[imidazole-4,9'-xanthen]-5(lH)-one to afford 2'-amino-r-methyl-8-(pyrimidin-5- yl)-2,3-dihydrospiro[furo[2,3-b]xanthene-10,4'-imidazol]-5'( H)-one (8.3 mg, 0.021 mmol, 55%).
  • Step A A mixture of l-bromo-4-nitrobenzene (25.0 g, 124 mmol) and tert- butyl 2-chloroacetate (19.42 mL, 136.1 mmol) in DMF (250 mL) was slowly added to a solution of KOtBu (1M in THF, 309 mL) in DMF (500 mL) at 0°C. The reaction was stirred at 0°C for 3 hours, then quenched with 5% KHS0 4 and extracted with ethyl acetate (3 X).
  • Step B Raney nickel (0.380 g, 4.44 mmol) was added to a solution of tert- butyl 2-(5-bromo-2-nitrophenyl)acetate (28.1 g, 88.7 mmol) in ethanol (444 mL), and the mixture was evacuated and purged with nitrogen and then introduced to 50 psi hydrogen for 24 hours in a Parr reactor.
  • Step C tert-Butyl 2-(2-amino-5-bromophenyl)acetate (5.00 g, 17.5 mmol) was added to sulfuric acid (concentrated, 87 mL) at 0°C, and the mixture was heated to 50°C until dissolved. The solution was cooled to 0°C, and NaN0 2 (2.65 g, 38.4 mmol) dissolved in a minimal amount of water was slowly added to this solution. The resulting mixture was stirred at 0°C for 10 minutes. Nitrogen was bubbled through the reaction mixture for 5 minutes. The reaction was poured into flask containing KI (17.4 g, 105 mmol) in water (25 mL) at 0°C.
  • KI 17.4 g, 105 mmol
  • Step D A pressure vial was charged with K 2 C0 3 (134 mg, 0.968 mmol), 2- (5-bromo-2-iodophenyl)acetic acid (300 mg, 0.880 mmol), benzenethiol (126 mg, 1.14 mmol), Cu(I)I (4.19 mg, 0.0220 mmol) and N-methylpyrrolidone ("NMP") (170 ⁇ ,, 1.76 mmol).
  • NMP N-methylpyrrolidone
  • Step E Water (2.02 g, 112 mmol) was added to a flask containing polyphosphoric acid (20.0 g, 204 mmol), followed by 2-(5-bromo-2- (phenylthio)phenyl)acetic acid (.220 g, 0.681 mmol).
  • a reflux condenser was added to the flask, and the mixture was stirred at 140°C for lday, adding DCM dropwise through the condenser to facilitate stirring when necessary.
  • the mixture was quenched with ice and extracted with DCM (3 X).
  • the combined organic layers were dried and concentrated to afford 2-bromodibenzo[b,fJthiepin-10(l lH)-one (166 mg, 0.544 mmol, 80%).
  • HPLC Rt 3.41 minutes.
  • Step F A solution of 2-bromodibenzo[b,f]thiepin- 10(11 H)-one (149 mg, 0.488 mmol) in ethyl acetate (1.00 mL) and CHC1 3 (1.00 mL) was degassed with nitrogen sparging. The mixture was heated to 80°C. The sparging was continued as CuBr 2 (0.218 g, 0.976 mmol) was slowly added. The reaction mixture turned green with addition and the color was allowed to disappear before adding the next portion of CuBr2. After addition, the reaction mixture was stirred for 2 hours and then filtered through GF/F paper. The solid was washed with CHC1 3 , and the filtrate was concentrated.
  • Step G 2,l l-Dibromodibenzo[b,fJthiepin-10(l lH)-one (185 mg, 0.49 mmol) was added to a solution of KI (81 mg, 0.49 mmol), Na 2 C0 3 (52 mg, 0.49 mmol) in DMSO (1.60 mL), and the resulting solution was stirred at ambient temperature for 15 minutes. Na 2 C0 3 (2.0M in water, 1 mL) and 1-methylguanidine hydrochloride (215 mg, 1.96 mmol) were added to this mixture, and the mixture was heated at 80°C for 1 hour.
  • Step H The same procedure was followed as in Example 58, Step G, substituting 2-fluoropyridin-3-ylboronic acid (4.71 mg, 0.033 mmol) to afford 2-amino-2'-(2- fluoropyridin-3-yl)-l-methylspiro[imidazole-4,9'-thioxanthen]-5(lH)-one (4.0 mg, 0.010 mmol, 38 %).
  • m/z (APCI-pos) M+l 391.4.
  • Step A Potassium carbonate (0.7132 g, 5.160 mmol) was added to a solution of 3-methoxyphenol (0.5595 mL, 5.160 mmol) and methyl 2-(2-fiuoro-5-nitrophenyl)acetate (1.00 g, 4.691 mmol) in DMSO (6 mL) degassed with argon, and the reaction was heated to 80°C overnight. It was diluted with EtOAc and washed with 10% citric acid, bicarbonate, and brine. It was dried over Na 2 S0 4 , filtered, and concentrated. It was purified on silica gel to yield methyl 2-(2-(3-methoxyphenoxy)-5-nitrophenyl)acetate (0.929 g, 2.928 mmol, 62.4% yield).
  • Step B Palladium on carbon (0.312 g, 0.146 mmol) was added to a solution of methyl 2-(2-(3-methoxyphenoxy)-5-nitrophenyl)acetate (0.929 g, 2.93 mmol) in MeOH (15 mL), and the reaction was put under 1 atmosphere of H 2 . It was stirred vigorously overnight. It was flushed with argon, filtered, and concentrated to yield methyl 2-(5-amino- 2-(3-methoxyphenoxy)phenyl)acetate (0.841 g, 2.93 mmol, 100.0% yield). It was taken onto the next reaction without further purification.
  • Step C tert-Butyl nitrite (0.425 niL, 3.22 mmol) was added to a suspension of copper(II) bromide (0.719 g, 3.22 mmol) in MeCN (15 mL) at 0°C, and the reaction was allowed to stir for 30 minutes at this temperature.
  • Methyl 2-(5-amino-2-(3- methoxyphenoxy)phenyl)acetate (.841 g, 2.93 mmol) in MeCN ( ⁇ 5 mL) was added drop wise to the reaction mixture, and the reaction was stirred at 0°C for 1 hour. It was warmed to room temperature, partitioned between EtOAc and water, and the organic layer was collected.
  • Step D Sodium hydroxide (0.756 mL, 3.78 mmol) was added to a solution of methyl 2-(5-bromo-2-(3-methoxyphenoxy)phenyl)acetate (0.664 g, 1.89 mmol) in 2: 1 MeOH/water (10 mL), and the reaction was allowed to stir overnight. It was diluted with water and acidified with 5M HCl until a pH of about 1 was reached. It was extracted twice with DCM, and the extracts were dried over Na 2 S0 4 , filtered, and concentrated to yield 2-(5- bromo-2-(3-methoxyphenoxy)phenyl)acetic acid (0.581 g, 1.72 mmol, 91.1% yield).
  • Step E A suspension of 2-(5-bromo-2-(3-methoxyphenoxy)phenyl)acetic acid (0.591 g, 1.75 mmol) in polyphosphoric acid (5.15 g, 52.6 mmol) was heated to 100°C with stirring overnight. It was poured onto water, and the solids were collected via filtration. They were then purified on silica gel to yield 2-bromo-7-methoxydibenzo[b,fJoxepin- 10(1 lH)-one (0.447 g, 1.40 mmol, 79.9% yield).
  • Step F Selenium dioxide (0.326 g, 2.94 mmol) was added to a solution of 2- bromo-7-methoxydibenzo[b,fJoxepin-10(l lH)-one (0.447 g, 1.40 mmol) in dioxane (7 mL) with about 10 drops of water, and the reaction was heated to reflux overnight. It was cooled to room temperature and filtered, and the filtrate was concentrated to yield 2-bromo-7- methoxydibenzo[b,fjoxepine-10,l l-dione (0.467 g, 1.40 mmol, 100% yield), which was taken onto the next reaction without further purification.
  • Step G Sodium carbonate (0.669 g, 6.31 mmol) and 1 -methylguanidine hydrochloride (0.691 g, 6.31 mmol) were added to a solution of 2-bromo-7- methoxydibenzo[b,fjoxepine-10,l l-dione (0.467 g, 1.40 mmol) in 1 :1 EtOH/dioxane (7 mL), and the reaction was heated to reflux for 2 hours. It was cooled to room temperature, diluted with water, and extracted twice with DCM. The extracts were dried over Na 2 S0 4 , filtered, and concentrated.
  • Step H Aqueous sodium carbonate (0.19 g, 0.36 mmol) was added to a solution of 2-amino-2'-bromo-6'-methoxy- 1 -methylspiro[imidazole-4,9'-xanthen]-5( 1 H)-one formate (0.044 g, 0.10 mmol) and 5-chloropyridin-3-ylboronic acid (0.021 g, 0.13 mmol) in dioxane (1 mL), and the reaction was degassed with argon. Palladium tetrakis (0.0059 g, 0.0051 mmol) was added to the reaction mixture, and the reaction was heated to 100°C overnight.
  • Step A A mixture of methyl 2-(2-fluoro-5-nitrophenyl)acetate (30.6 g, 144 mmol), 4-methoxyphenol (18.7 g, 151 mmol) and Cs 2 C0 3 (70.2 g, 215 mmol) in DMF (144 mL, 144 mmol) under Argon was heated to 90°C for 4 hours. HPLC showed that the reaction was complete. The mixture was worked up with EtOAc and water. The organics were washed with water (5 X), and dried with brine and Na 2 S0 4 .
  • Step B A mixture of methyl 2-(2-(4-methoxyphenoxy)-5-nitrophenyl)acetate (36.0 g, 113.5 mmol) and Pd/C (12.07 g, 113.5 mmol) in MeOH (4.596 mL, 113.5 mmol; d. 0.791) under hydrogen balloon was stirred at room temperature overnight. TLC showed that the reaction was complete. The mixture was filtered through GF/F paper, and the filtrate was concentrated down and purified on a column using EtOAc and hexanes to give methyl 2-(5- amino-2-(4-methoxyphenoxy)phenyl)acetate (30.14 g, 104.9 mmol, 92.46% yield).
  • Step C A mixture of CuBr 2 (18.74 g, 83.92 mmol) and t-BuN0 2 (13.85 mL, 104.9 mmol) in acetonitrile (209.8 mL, 104.9 mmol) was stirred at 0°C for 30 minutes. Methyl 2-(5-amino-2-(4-methoxyphenoxy)phenyl)acetate (30.14 g, 104.9 mmol) in ACN was added, and this was stirred at room temperature for 30 minutes. TLC showed that the reaction was complete. The mixture was worked up with EtOAc and water. The organics were extracted twice, washed with brine and dried with Na 2 S0 4 .
  • Step D A mixture of methyl 2-(5-bromo-2-(4- methoxyphenoxy)phenyl)acetate (18.87 g, 53.73 mmol) and NaOH (161.2 mL, 322.4 mmol) in ethanol (300 mL, 53.73 mmol) was heated to 60°C for 3 hours. TLC showed that the reaction was complete. The mixture was worked up with EtOAc and 2N HCl. The organics were extracted with EtOAc (2X), washed with brine and dried with Na 2 S0 4 . This was concentrated down to give 2-(5-bromo-2-(4-methoxyphenoxy)phenyl)acetic acid (18.0 g, 53.39 mmol, 99.36% yield).
  • Step E A mixture of 2-(5-bromo-2-(4-methoxyphenoxy)phenyl)acetic acid (18.0 g, 53.4 mmol) in PPA (5.23 g, 53.4 mmol) was stirred at 120°C for 4 hours. TLC showed that the reaction was complete. The mixture was poured onto ice and worked up with water and DCM. The organics were extracted twice with DCM, washed with brine and dried with Na 2 S0 4 .
  • Step F Trichloroborane (48.7 mL, 48.7 mmol) was added slowly to a mixture of 2-bromo-8-methoxydibenzo[b,fJoxepin-10(l lH)-one (4.71 g, 14.8 mmol) and tetrabutylammonium iodide (6.00 g, 16.2 mmol) in DCM (29.5 mL, 14.8 mmol) at -78°C. This was then stirred at 0°C for 4 hours. TLC showed that the reaction was complete. The mixture was poured onto ice, and the organics were extracted with DCM twice, washed with brine and dried with Na 2 S0 4 .
  • Step G A mixture of selenium dioxide (2.08 g, 18.7 mmol) and 2-bromo-8- hydroxydibenzo[b,f]oxepin-10(HH)-one (2.6 g, 8.52 mmol) in dioxane (26 mL, 8.52 mmol) was heated to 90°C overnight. TLC showed that the reaction was complete. The mixture was filtered through GF/F paper, and then 1-methylguanidine hydrochloride (4.20 g, 38.3 mmol) was added followed by ethanol (26 mL, 8.52 mmol) and 2M Na 2 C0 3 (19.2 mL, 38.3 mmol). This was stirred at 90°C overnight.
  • Step H A mixture of 2-amino-2'-bromo-7'-hydroxy-l-methylspiro[imidazole- 4,9'-xanthen]-5(lH)-one (0.162 g, 0.433 mmol), 2-fluoropyridin-3-ylboronic acid (0.0915 g, 0.649 mmol), Na 2 C0 3 (0.476 mL, 0.952 mmol) and Pd(PPh 3 ) 4 (0.0500 g, 0.0433 mmol) in dioxane (0.0381 g, 0.433 mmol) was heated to 90°C overnight.
  • Step I A mixture of 2-amino-2'-(2-fluoropyridin-3-yl)-7'-hydroxy-l- methylspiro[imidazole-4,9'-xanthen]-5(lH)-one (0.013 g, 0.03330 mmol), (bromomethyl)cyclopropane (0.004845 mL, 0.04995 mmol) and Cs 2 C0 3 (0.02170 g, 0.06660 mmol) in DMF (0.1665 mL, 0.03330 mmol) was stirred at 90°C overnight. The mixture was worked up with DCM and water. The organics were washed with water (2X), then brine and dried with Na 2 S0 4 .
  • Step A 2-Amino-2',7'-dibromo-l-methylspiro[imidazole-4,9'-xanthen]- 5(lH)-one (337 mg, 0.771 mmol; Example 26, Step D) and 2-fluoropyridin-3-ylboronic acid (109 mg, 0.771 mmol) were diluted with dioxane (2 mL), followed by the addition of Pd(PPh 3 ) 4 (8.91 mg, 0.00771 mmol) and Na 2 C0 3 (771 ⁇ , 1.54 mmol). The reaction was sealed, heated to 85°C and stirred for 12 hours. The reaction was allowed to cool, diluted with ethyl acetate and water.
  • Step B 2-Amino-2'-bromo-7'-(2-fluoropyridin-3-yl)-l- methylspiro[imidazole-4,9'-xanthen]-5(lH)-one (25 mg, 0.055 mmol) and pyridin-3- ylboronic acid (8.8 mg, 0.072 mmol) were diluted with dioxane (1 mL), followed by the addition of Pd(PPh 3 ) 4 (0.64 mg, 0.00055 mmol) and Na 2 C0 3 (83 ⁇ ,, 0.17 mmol). The reaction was sealed, heated to 85°C and stirred for 12 hours.
  • Step A Ethyl 2-(5-bromo-2-hydroxyphenyl)acetate (4.29 g, 16.6 mmol) and 4-chloronicotinaldehyde (2.34 g, 16.6 mmol) were diluted with DMF (40 mL), followed by the addition of TEA (2.31 mL, 16.6 mmol; d. 0.726). The reaction was heated to 80°C and stirred for 12 hours. The reaction was allowed to cool and diluted with ethyl acetate and water. The layers were separated, and the organics were dried over MgS0 4 , filtered and concentrated.
  • Step B Ethyl 8-bromobenzo[6,7]oxepino[3,2-c]pyridine-10-carboxylate (400 mg, 1.16 mmol) and 2-fluoropyridin-3-ylboronic acid (179 mg, 1.27 mmol) were diluted with dioxane (3 mL), followed by the addition of Pd(PPh 3 ) 4 (13.4 mg, 0.01 16 mmol) and Na 2 C0 3 (1155 ⁇ , 2.31 mmol). The reaction was sealed, heated to 85°C and stirred for 12 hours.
  • Step C Ethyl 8-(2-fluoropyridin-3-yl)benzo[6,7]oxepino[3,2-c]pyridine-10- carboxylate (329 mg, 0.908 mmol) was diluted with THF (2 mL) and ethanol (1 mL), followed by the addition of NaOH (1362 ⁇ , 2.72 mmol). After stirring for 4 hours, the pH was adjusted to 6 (with 2N HC1), and the product was extracted with ethyl acetate.
  • Step D 8-(2-Fluoropyridin-3-yl)benzo[6,7]oxepino[3,2-c]pyridine-10- carboxylic acid (300 mg, 0.897 mmol) was diluted with quinoline (5 mL), followed by the addition of CuS0 4 (286 mg, 1.79 mmol). The reaction was sealed and heated in the microwave (180°C) for 30 minutes. The reaction was concentrated and diluted with ethyl acetate and water. The organics were dried over MgS0 4 , filtered and concentrated.
  • Step E 8-(2-Fluoropyridin-3-yl)benzo[6,7]oxepino[3,2-c]pyridine (25 mg, 0.086 mmol) was diluted with acetone (300 ⁇ ), followed by the addition of NaHC0 3 (69xL, 0.069 mmol) and MgS0 4 (21 mg, 0.17 mmol) in water (60 ⁇ ). KMn0 4 (34 mg, 0.22 mmol) was added, and the reaction mixture was stirred for 1 hour at ambient temperature. The reaction was diluted with ethyl acetate and hexanes (1 :1) and diluted with water.
  • Step F 8-(2-Fluoropyridin-3-yl)benzo[6,7]oxepino[3,2-c]pyridine-10,l l- dione (20 mg, 0.0624 mmol) was diluted with dioxane (1 mL), followed by the addition of methylguanidine hydrochloride (27.4 mg, 0.250 mmol) and Na 2 C0 3 (125 ⁇ xL, 0.250 mmol). The reaction was heated to 90°C and stirred for 12 hours.
  • Step A Ethyl 2-(5-bromo-2-hydroxyphenyl)acetate (15.25 g, 58.86 mmol), 1 ,4-diiodobenzene (46.60 g, 141.3 mmol), ⁇ , ⁇ -dimethylglycine hydrochloride (4.929 g, 35.32 mmol), Cu(I)Cl (3.496 g, 35.32 mmol) and Cs 2 C0 3 (46.03 g, 141.3 mmol) were diluted with dioxane (200 mL), purged with argon and heated to 70°C. The reaction was stirred for 12 hours, allowed to cool and diluted with ethyl acetate and water.
  • Step B Ethyl 2-(5-bromo-2-(4-iodophenoxy)phenyl)acetate (13.33 g, 28.91 mmol) was diluted with ethanol (100 mL), followed by the addition of NaOH (57.82 mL, 115.6 mmol). After stirring for 3 hours, the reaction was diluted with ethyl acetate and 2N HC1. The layers were separated, and the organics were dried over MgS0 4 , filtered and concentrated to yield 2-(5-bromo-2-(4-iodophenoxy)phenyl)acetic acid (12.37 g, 28.57 mmol, 98.81% yield).
  • Step C 2-(5-Bromo-2-(4-iodophenoxy)phenyl)acetic acid (12.37 g, 28.57 mmol) was diluted with PPA (100 mL), placed under nitrogen and heated to 1 10°C. After stirring for 12 hours, the reaction was poured into ice water and extracted with DCM. The organics were dried over MgS0 4 , filtered and concentrated. The residue was triturated with ether to afford 2-bromo-8-iododibenzo[b,f]oxepin-10(l lH)-one (6.6 g, 15.90 mmol, 55.67%» yield).
  • Step D 2-Bromo-8-iododibenzo[b,f]oxepin-10(l lH)-one (6.6 g, 16 mmol) was diluted with dioxane (70 mL) and water (700 ⁇ ), followed by the addition of selenium dioxide (3.5 g, 32 mmol). The reaction was heated to reflux and stirred for 12 hours. The reaction was cooled and then filtered. 1 -Methylguanidine hydrochloride (5.2 g, 48 mmol) and ethanol (50 mL) were added, followed by the addition of Na 2 C0 3 (24 mL, 48 mmol). The reaction was heated to 80°C and stirred for 12 hours.
  • Step E 2-Amino-2'-bromo-7'-iodo-l-methylspiro[imidazole-4,9'-xanthen]- 5(lH)-one (500 mg, 1.03 mmol) and 3,6-dihydro-2H-pyran-4-boronic acid (132 mg, 1.03 mmol) were diluted with dioxane (3 mL), followed by the addition of Pd(PPh 3 ) (35.8 mg, 0.0310 mmol) and Na 2 C0 3 (1291 ⁇ ,, 2.58 mmol). The reaction was sealed, heated to 85°C and stirred for 12 hours. The reaction was diluted with ethyl acetate and water.
  • Step F 2-Amino-2'-bromo-7'-(3,6-dihydro-2H-pyran-4-yl)-l- methylspiro[imidazole-4,9'-xanthen]-5(lH)-one (20 mg, 0.045 mmol) and 5-chloropyridin-3- ylboronic acid (14 mg, 0.091 mmol) were diluted with dioxane (300 ⁇ ), followed by the addition of Pd(PPh 3 ) 4 (2.6 mg, 0.0023 mmol) and Na 2 C0 3 (68 ⁇ ,, 0.14 mmol). The reaction was sealed, heated to 85°C and stirred for 12 hours.

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Abstract

L'invention concerne de nouveaux composés tricycliques de formule I qui inhibent le clivage de l'APP par la β-secrétase et sont utiles comme agents thérapeutiques pour le traitement de maladies neurodégénératives.
PCT/US2011/032894 2010-04-16 2011-04-18 Composés pour le traitement de maladies neurodégénératives WO2011130741A1 (fr)

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WO2012112462A1 (fr) * 2011-02-15 2012-08-23 Amgen Inc. Composés hétérocycliques spiro-amino-imidazo-condensés en tant que modulateurs de la bêta-secrétase et méthodes d'utilisation
WO2013054108A1 (fr) * 2011-10-10 2013-04-18 Astrazeneca Ab Inhibiteurs de mono fluoro-bêta-secretase
WO2013148851A1 (fr) * 2012-03-27 2013-10-03 Array Biopharma Inc. Composés permettant de traiter les maladies neurodégénératives
US8729071B2 (en) 2009-10-08 2014-05-20 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as BACE inhibitors, compositions and their use
US8865911B2 (en) 2010-12-22 2014-10-21 Astrazeneca Ab Compounds and their use as BACE inhibitors
US8975415B2 (en) 2012-05-30 2015-03-10 Comentis, Inc. Chromane compounds
US9000184B2 (en) 2012-06-20 2015-04-07 Astrazeneca Ab Cyclohexane-1,2′-naphthalene-1′,2″-imidazol compounds and their use as BACE inhibitors
US9000185B2 (en) 2012-06-20 2015-04-07 Astrazeneca Ab Cycloalkyl ether compounds and their use as BACE inhibitors
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US9000182B2 (en) 2012-06-20 2015-04-07 Astrazeneca Ab 2H-imidazol-4-amine compounds and their use as BACE inhibitors
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US9346827B2 (en) 2011-02-07 2016-05-24 Amgen Inc. 5-amino-oxazepine and 5-amino-thiazepane compounds as beta secretase antagonists and methods of use
US9725469B2 (en) 2012-11-15 2017-08-08 Amgen, Inc. Amino-oxazine and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use
US10548882B2 (en) 2012-06-21 2020-02-04 Astrazeneca Ab Camsylate salt
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US10548882B2 (en) 2012-06-21 2020-02-04 Astrazeneca Ab Camsylate salt
US9725469B2 (en) 2012-11-15 2017-08-08 Amgen, Inc. Amino-oxazine and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use
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