WO2011130383A1 - Composés contenant des cycles fusionnés qui inhibent l'activité bêta secrétase et leurs méthodes d'utilisation - Google Patents

Composés contenant des cycles fusionnés qui inhibent l'activité bêta secrétase et leurs méthodes d'utilisation Download PDF

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WO2011130383A1
WO2011130383A1 PCT/US2011/032281 US2011032281W WO2011130383A1 WO 2011130383 A1 WO2011130383 A1 WO 2011130383A1 US 2011032281 W US2011032281 W US 2011032281W WO 2011130383 A1 WO2011130383 A1 WO 2011130383A1
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compound
solvate
pharmaceutically acceptable
acceptable salt
optionally substituted
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PCT/US2011/032281
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English (en)
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Geoffrey M. Bilcer
John C. Lilly
Lisa M. Swanson
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Comentis, Inc.
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Publication of WO2011130383A1 publication Critical patent/WO2011130383A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • Alzheimer's disease is a progressive mental deterioration in a human resulting, inter alia, in loss of memory, confusion and disorientation. Alzheimer's disease accounts for the majority of senile dementias and is a leading cause of death in adults (Anderson, R. N., Natl. Vital Stat. Rep. 49: ⁇ -%l (2001), the teachings of which are incorporated herein in their entirety). Histologically, the brain of persons afflicted with Alzheimer's disease is
  • ⁇ -amyloid protein ⁇
  • APP amyloid precursor protein
  • APP is cleaved initially by ⁇ -secretase followed by ⁇ -secretase to generate ⁇ (Lin, X., et al., Proc. Natl. Acad. Sci. USA 97: 1456-1460 (2000); De Strapper, B., et al, Nature 397 :387-390 (1998)).
  • Inhibitors of ⁇ -secretase are described in US 7,214,715; US 7,504,420; US
  • novel beta-secretase inhibitors and methods for their use, including methods of treating Alzheimer's disease.
  • the invent provides a compound of the formula (I):
  • R 1 is A ⁇ L 1 -;
  • R 2 is hydrogen, -N(R 8 )R 9 , -S(0) 2 R n , -C(0)R 12 , or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;
  • R 1 and R 2 together with the nitrogen to which they are bonded form a 5-membered heterocycloalkyl ring substituted with A ⁇ L 1 -, R 6 and R 6A ;
  • a 1 is an optionally substituted heteroaryl
  • R 3 and R 5 are each independently hydrogen, -N(R 8 )R 9 , -S(0) 2 R n , -C(0)R 12 , or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;
  • L 1 and L 4 are each independently a bond, -N(R 17 )-, -S(0) q - , or an optionally substituted alkylene;
  • R 4 , R 6 , R 6A , R 7A and R 7B are each independently hydrogen, halogen, -OH, - N0 2 ,
  • N(R 8 )R 9 heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;
  • R is independently hydrogen, -C(0)R , -S(0) 2 R , or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;
  • R 9 is independently hydrogen, or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl,
  • heterocycloalkyl-alkyl aryl, aralkyl, heteroaryl, and heteroaralkyl;
  • R 10 is independently -C(0)R 13 , or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl,
  • heterocycloalkyl-alkyl aryl, aralkyl, heteroaryl, and heteroaralkyl;
  • R 11 is independently hydrogen, or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl,
  • R 11 can also be
  • R 12 and R 13 are each independently hydrogen, -N(R 18 )R 19 , -OR 19 , or an
  • optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl- alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;
  • R 14 is independently hydrogen, -N(R 18 )R 19 , or an optionally substituted
  • R 15 , R 16 , R 17 , R 18 , and R 19 are each independently hydrogen, or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;
  • A is a moiety of the formula
  • R , R and R" are independently hydrogen, halogen, -N(R )R , or an
  • optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl- alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;
  • R 24 and R 25 are independently hydrogen, -C(0)R 26 , or -S(0) 2 R 27 , or an
  • optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl- alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;
  • R is independently hydrogen, -N(R )R , or -OR , an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;
  • R is independently an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;
  • R , R and R JU are independently hydrogen, or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; and n and q are each independently 0, 1, or 2;
  • the ⁇ -secretase inhibitor compound includes any one, any combination, or all of the compounds of Example 2 and/or Table 1 ; or a pharmaceutically acceptable salt or solvate thereof.
  • the compound has a memapsin 2 Kj of less than about 250 nM.
  • the compound has an apparent memapsin 2 K; of less than about 250 nM as measured by inhibition of memapsin 2 catalytic activity toward the fluorogenic substrate FS-2 (MCA-SEVNLDAEFK-DNP; SEQ ID NO.: 2).
  • the compound is capable of inhibiting cellular ⁇ production with an IC50 of less than about 750 nM, or less than about 250 nM.
  • the compound has a memapsin 1 K; and/or cathepsin D K; of greater than about 300 nM. In some embodiments, the compound has an apparent memapsin 1 K; and/or apparent cathepsin D K; of greater than about 300 nM, as measured by the substrate peptide MCA- GKPILFFRLK(DNP) -dR (SEQ ID NO.: 1). In some embodiments, the compound has a CYP 3 A Kj of greater than about ⁇ , or greater than 5 ⁇ , or greater than 10 ⁇ , as determined by the metabolism of midazolam.
  • the compound is capable of selectively reducing memapsin 2 catalytic activity relative to memapsin 1 catalytic activity. In some embodiments, the compound is capable of selectively reducing memapsin 2 catalytic activity relative to cathepsin D catalytic activity. In some embodiments, the compound is capable of selectively reducing memapsin 2 catalytic activity relative to CYP3A catalytic activity. In some of these embodiments, the relative reduction is greater than about 5-fold. In other embodiments, the reduction is greater than about 10-fold.
  • the ⁇ -secretase inhibitor compound (a) has a memapsin 2 Kj of less than about 750 nM (or less than about any one of 250 nM, 100 nM, 50 nM, or 10 nM); (b) is capable of inhibiting cellular ⁇ production with an IC50 of less than about 1 ⁇ (or less than about any one of 500 nM, 250 nM, 100 nM, 40 nM, or 10 nM); (c) is capable of selectively reducing memapsin 2 catalytic activity relative to memapsin 1 or cathepsin D catalytic activity by greater than about 5-fold (or greater than about 10-fold, or about 100-fold), and/or (d) is capable of selectively reducing memapsin 2 catalytic activity relative to CYP3A catalytic activity by greater than about 5-fold (or greater than about 10-fold, or about 100-fold).
  • the compound has a hepatic intrinsic clearance in liver microsomes
  • the compound has an AUC more than 50 hrng/ml, or more than 500 hrng/ml, as measured in rats after an oral dose of 10 mg/kg of the drug is administered.
  • any one of the ⁇ -secretase inhibitor compounds is present in substantially pure form.
  • formulations comprising any one of the compounds described herein and a carrier (e.g., a pharmaceutically acceptable carrier).
  • a carrier e.g., a pharmaceutically acceptable carrier
  • the formulation is suitable for administration to an individual.
  • formulations comprising an effective amount of any one of the compounds described herein and a carrier (e.g., a pharmaceutically acceptable carrier).
  • compositions comprising a ⁇ - secretase inhibitor compound or a ⁇ -secretase inhibitor compound in combination with a pharmaceutically acceptable carrier.
  • methods of treating Alzheimer's disease in an individual in need thereof comprising administering to the individual an effective amount of any one of the compounds described herein (e.g., any compound of formula I, II, III, or any variations thereof, Example 2 and/or Table 1), or a pharmaceutically acceptable salt or solvate thereof.
  • the individual has one or more symptoms of
  • the individual has been diagnosed with
  • methods of treating of a condition mediated by memapsin 2 catalytic activity comprising administering to the individual an effective amount of a compound of any one of the compounds described herein, or a pharmaceutically acceptable salt or solvate thereof.
  • the individual has one or more symptoms of the condition mediated by memapsin 2 catalytic activity.
  • the individual has been diagnosed with condition mediated by memapsin 2 catalytic activity.
  • methods of reducing memapsin 2 catalytic activity comprising contacting memapsin 2 with an effective amount of any one of the compounds described herein.
  • the memapsin 2 beta-secretase is contacted in a cell.
  • the cell is contacted in vivo.
  • the cell is contacted in vitro.
  • methods of selectively reducing memapsin 2 catalytic activity relative to memapsin 1 catalytic activity comprising contacting memapsin 2 with an effective amount of a compound of any one of the compounds described herein in the presence of memapsin 1.
  • methods of selectively reducing memapsin 2 catalytic activity relative to cathepsin D catalytic activity comprising contacting memapsin 2 with an effective amount of any one of the compounds described herein in the presence of cathepsin D.
  • methods of selectively reducing memapsin 2 catalytic activity relative to memapsin 1 catalytic activity and cathepsin D catalytic activity comprising contacting memapsin 2 with an effective amount of any one of the compounds described herein in the presence of memapsin 1 and cathepsin D.
  • methods of selectively reducing memapsin 2 catalytic activity relative to CYP3A4 catalytic activity comprising contacting memapsin 2 with an effective amount of any one of the compounds described herein in the presence of CYP3A4.
  • methods of selectively reducing memapsin 2 catalytic activity relative to memapsin 1 catalytic activity, cathepsin D catalytic activity, and CYP3A4 catalytic activity comprising contacting memapsin 2 with an effective amount of any one of the compounds described herein in the presence of memapsin 1, cathepsin D, and CYP3A4.
  • methods of treating Glaucoma in an individual in need thereof comprising administering to the individual an effective amount of any one of the compounds described herein.
  • the individual has one or more symptoms ofGlaucoma.
  • the individual has been diagnosed with Glaucoma.
  • any one of the compounds described herein or a pharmaceutically acceptable salt or solvate thereof for use as a medicament is provided.
  • Another aspect is provided the use of any one of the compounds described herein or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment or prevention of a condition mediated by memapsin 2 catalytic activity.
  • the condition is Alzheimer's disease.
  • kits for the treatment or prevention in an individual with Alzheimer's disease comprising any one of the compounds described herein or a pharmaceutically acceptable salt or solvate thereof; and packaging.
  • the kit comprises a formulation of any one of the compounds described herein or a pharmaceutically acceptable salt or solvate thereof; and packaging.
  • kits for the treatment or prevention in an individual of a condition mediated by memapsin 2 catalytic activity comprising any one of the compounds described herein or a pharmaceutically acceptable salt or solvate thereof; and packaging.
  • the kit comprises a formulation of any one of the compounds described herein or a pharmaceutically acceptable salt or solvate thereof; and packaging.
  • the ⁇ -secretase inhibitor compounds can be employed in methods to mediate memapsin 2 activity, e.g., decrease memapsin 2 activity, decrease hydrolysis of a ⁇ -secretase site of a memapsin 2 substrate, and/or decrease the accumulation of ⁇ -amyloid protein relative to the amount of memapsin 2 activity, hydrolysis of a ⁇ -secretase site, and accumulation of ⁇ -amyloid protein, respectively, in the absence of the ⁇ -secretase inhibitor.
  • memapsin 2 activity e.g., decrease memapsin 2 activity, decrease hydrolysis of a ⁇ -secretase site of a memapsin 2 substrate, and/or decrease the accumulation of ⁇ -amyloid protein relative to the amount of memapsin 2 activity, hydrolysis of a ⁇ -secretase site, and accumulation of ⁇ -amyloid protein, respectively, in the absence of the ⁇ -secretase inhibitor.
  • the ⁇ -secretase inhibitor compounds can be employed in the treatment of diseases or conditions associated with ⁇ -secretase activity, hydrolysis of a ⁇ - secretase site of a ⁇ -amyloid precursor protein, and/or ⁇ -amyloid protein accumulation.
  • a mammal is treated for the disease or condition.
  • the disease is Alzheimer's disease.
  • the invention provides, inter alia, compositions of beta-secretase inhibitors and methods for their use, e.g. methods of treating Alzheimer's disease.
  • substituent groups are specified by their conventional chemical formula, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH 2 O- is equivalent to -OCH 2 -.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e. unbranched) or branched hydrocarbon chain, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated ⁇ i.e. Q-Qo means one to ten carbons).
  • saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec -butyl,
  • an unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2- propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl,
  • An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-0-).
  • alkylene by itself or as part of another substituent means a divalent radical derived from an alkyl, as exemplified, but not limited, by -CH 2 CH 2 CH 2 CH 2 -.
  • an alkyl (or alkylene) group will have from 1 to 24 carbon atoms.
  • an alkyl group will have from 1 to 6 carbon atoms.
  • the alkylene groups are metheylene and methylmethylene.
  • cycloalkyl by itself or in combination with other terms, represents, unless otherwise stated, cyclic versions of “alkyl.” Additionally, cycloalkyl may contain multiple rings, but excludes aryl and heteroaryl groups. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3- cyclohexenyl, cycloheptyl, norbornyl, and the like.
  • cyclo alkylene by itself or as part of another substituent means a divalent radical derived from a cycloalkyl, as exemplified, but not limited, by -cyclohexyl-.
  • heterocycloalkyl represents a stable saturated or unsaturated cyclic hydrocarbon radical containing of at least one carbon atom and at least one annular heteroatom selected from the group consisting of O, N, P, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom(s) O, N, P, S and Si may be placed at any interior position of the heterocycloalkyl group or at the position at which the heterocycloalkyl group is attached to the remainder of the molecule.
  • heterocycloalkyl may contain multiple rings, but excludes aryl and heteroaryl groups.
  • heterocycloalkyl examples include, but are not limited to, 1 -(1,2,5, 6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2- yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1 -piperazinyl, 2- piperazinyl, and the like.
  • heterocycloalkylene by itself or as part of another substituent means a divalent radical derived from a heterocycloalkyl, as exemplified, but not
  • cycloalkyl-alkyl and “heterocycloalkyl- alkyl” designates an alkyl- substituted cycloalkyl group and alkyl- substituted heterocycloalkyl, respectively, where the alkyl portion is attached to the parent structure.
  • Non-limiting examples include cyclopropyl- ethyl, cyclobutyl-propyl, cyclopentyl-hexyl, cyclohexyl-isopropyl, 1-cyclohexenyl-propyl, 3- cyclohexenyl-t-butyl, cycloheptyl-heptyl, norbornyl-methyl, 1-piperidinyl-ethyl, 4- morpholinyl-propyl, 3-morpholinyl-t-butyl, tetrahydrofuran-2-yl-hexyl, tetrahydrofuran-3-yl- isopropyl, and the like.
  • Cycloalkyl-alkyl and heterocycloalkyl-alkyl also include substituents in which a carbon atom of the alkyl group (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g. , cyclopropoxymethyl,
  • aryl means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent.
  • Aryl may contain additional fused rings (e.g., from 1 to 3 rings), including additionally fused aryl, heteroaryl, cycloalkyl, and/or heterocycloalkyl rings.
  • aryl groups include, but are not limited to, phenyl, 1-naphthyl, 2-naphthyl, 4- biphenyl.
  • heteroaryl refers to aryl groups (or rings) that contain from one to four annular heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule at an annular carbon or annular heteroatom.
  • Heteroaryl may contain additional fused rings (e.g., from 1 to 3 rings), including additionally fused aryl, heteroaryl, cycloalkyl, and/or heterocycloalkyl rings.
  • additional fused rings e.g., from 1 to 3 rings
  • Non-limiting examples of heteroaryl groups are 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl,
  • arylene and heteroarylene means a divalent radical derived from an aryl and heteroaryl, respectively. Each of the two valencies of arylene and heteroarylene may ⁇ ⁇ ).
  • arylene include phenylene, biphenylene, naphthylene, and the like.
  • heteroarylene groups include, but are not limited to, pyridinylene, oxazolylene, thioazolylene, pyrazolylene, pyranylene, and furanylene.
  • aralkyl designates an alkyl- substituted aryl group, where the alkyl portion is attached to the parent structure. Examples are benzyl, phenethyl, phenylvinyl, phenylallyl, pyridylmethyl, and the like.
  • Heteroaralkyl designates a heteroaryl moiety attached to the parent structure via an alkyl residue. Examples include furanylmethyl, pyridinylmethyl, pyrimidinylethyl, and the like.
  • Aralkyl and heteroaralkyl also include substituents in which a carbon atom of the alkyl group (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g. , phenoxymethyl, 2-pyridyloxymethyl, 3-(l- naphthyloxy)propyl, and the like).
  • an oxygen atom e.g. , phenoxymethyl, 2-pyridyloxymethyl, 3-(l- naphthyloxy)propyl, and the like.
  • halo or halogen
  • haloalkyl by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C4)alkyl is mean to include, but not be limited to,
  • substituted refers to the replacement of one or more hydrogen atoms of a moiety with a monovalent or divalent radical.
  • Optionally substituted indicates that the moiety may be substituted or unsubstituted.
  • a moiety lacking the terms “optionally substituted” and “substituted” is intended an unsubstituted moiety (e.g., "phenyl” is intended an unsubstituted phenyl unless indicated as a substituted phenyl or an optionally substituted phenyl).
  • an “optionally substituted” group is an unsubstituted group.
  • an “optionally substituted” group is a substituted group.
  • an "optionally substituted alkyl” in one embodiment is an unsubstituted alkyl and in another embodiment is a substituted alkyl.
  • pharmaceutically effective amount refers to an amount that results in a desired pharmacological and/or physiological effect for a specified condition (e.g., disease, disorder, etc.) or one or more of its symptoms and/or to completely or partially prevent the occurrence of the condition or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for the condition and/or adverse effect attributable to the condition.
  • a specified condition e.g., disease, disorder, etc.
  • a pharmaceutically or therapeutically effective amount comprises an amount sufficient to, among other things, cause antagonism of memapsin 2 beta-secretase.
  • a pharmaceutically or therapeutically effective amount comprises an amount sufficient to, among other things, decrease intraocular pressure; and/or halt, reverse, and/or diminish the loss of retinal ganglion cells (RGCs).
  • RRCs retinal ganglion cells
  • pharmaceutically effective amount is sufficient to prevent the condition, as in being administered to an individual prophylactically.
  • a “pharmaceutically suitable carrier” or “pharmaceutically acceptable carrier,” as used herein refers to pharmaceutical excipients, for example, pharmaceutically,
  • physiologically, acceptable organic, or inorganic carrier substances suitable for enteral or parenteral application which do not deleteriously react with the extract.
  • an individual "in need thereof may be an individual who has been diagnosed with or previously treated for the condition to be treated. With respect to prevention, the individual in need thereof may also be an individual who is at risk for a condition (e.g., a family history of the condition, life-style factors indicative of risk for the condition, etc.).
  • a condition e.g., a family history of the condition, life-style factors indicative of risk for the condition, etc.
  • the individual has been identified as having one or more of the conditions described herein. Identification of the conditions as described herein by a skilled physician is routine in the art and may also be suspected by the individual or others, for example, due to loss of memory in the case of Alzheimer's, exhibiting the symptoms of schizophrenia, etc., and due to a decrease and/or loss of contrast sensitivity or vision in the case of Glaucoma.
  • the individual has been identified as susceptible to one or more of the conditions as described herein.
  • the susceptibility of an individual may be based on any one or more of a number of risk factors and/or diagnostic approaches appreciated by the skilled artisan, including, but not limited to, genetic profiling, family history, medical history (e.g., appearance of related conditions), lifestyle or habits.
  • the individual is a mammal, including, but not limited to, bovine, horse, feline, rabbit, canine, rodent, or primate.
  • the mammal is a primate.
  • the primate is a human.
  • the individual is human, including adults, children and premature infants.
  • the individual is a non-mammal.
  • the primate is a non-human primate such as chimpanzees and other apes and monkey species.
  • the mammal is a farm animal such as cattle, horses, sheep, goats, and swine; pets such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds, and the like.
  • the term "individual” does not denote a particular age or sex.
  • “Pharmaceutically acceptable salts” are those salts which retain the biological activity and which can be administered as drugs or pharmaceuticals to and individual (e.g., a human).
  • isomer includes all stereoisomers of the compounds referred to in the formulas herein, including enantiomers, diastereomers, as well as all conformers, rotomers, and tautomers.
  • a "transition state isostere,” or “isostere,” as used herein, is a compound comprising the hydroxyethylamine linking group -CH(OH)-CH 2 -NH-. This isostere is also referred to herein as a "hydroxyethylamine isostere.”
  • the hydroxyethylamine linking group may be found between a pair of natural or non-natural amino acids of a peptide.
  • hydroxyethylamine group is an isostere of the transition state of hydrolysis of an amide bond.
  • Amyloid precursor protein refers to a ⁇ -amyloid precursor comprising a ⁇ -secretase site.
  • Memapsin-2 refers to proteins identified by National Center for Biotechnology Information (“NCBI”) accession number NP_036236 (sometimes referred to as “ ⁇ -site APP-cleaving enzyme 1 " or “BACE- 1 " or generically as “ ⁇ -secretase” or “beta- secretase”), including homologs, isoforms and subdomains thereof that retain proteolytic activity. Sequence identities of active memapsin 2 proteins and protein fragments (and nucleic acid coding sequences thereof) have been previously disclosed and discussed in detail in U.S. Application No. 20040121947, and International Application No. PCT/US02/34324 (Publication No. WO 03/039454), which are herein incorporated by reference for all purposes in their entirety.
  • NCBI National Center for Biotechnology Information
  • Memapsin-1 refers to proteins identified by National Center for Biotechnology Information (“NCBI”) accession number NP_036237 (sometimes referred to as “ ⁇ -site APP-cleaving enzyme 2" or "BACE-2”) and/or those previously disclosed and discussed in detail in see U.S. Patent Application Publication No. 20040121947, and
  • Cathepsin D refers to proteins identified by National Center for Biotechnology Information (“NCBI”), for example accession number NP_599161, and/or proteins identified by Enzyme Commission number EC3.4.23.5, including that from any species, homologs, isoforms, and subdomains thereof that retain proteolytic activity.
  • a " ⁇ -secretase site” is an amino acid sequence that is cleaved by an active memapsin 2 or active fragment thereof. Specific ⁇ -secretase sites have also been previously set forth and discussed in detail in U.S. Application No. 20040121947, and International Application No. PCT/US02/34324 (Publication No.
  • ⁇ -secretase inhibitors may be tested for their ability to decrease the hydrolysis of the ⁇ -secretase site of a substrate, such as the ⁇ -amyloid precursor protein, compounds of ⁇ -amyloid precursor protein, or fragments of ⁇ -amyloid precursor protein.
  • a "beta-secretase inhibitor” refers to a compound capable of reducing the proteolytic activity of memapsin-2 relative to the activity in the absence of inhibitor.
  • Cytochrome P450 3A4" or "CYP3A4,” as used herein refers to proteins identified by Genbank Sequence Accession Number: AF280107; HGNC:2637; Enzyme ID: 1.1.1.161, e.g., which can be found in the product /wV3 ⁇ 4roCYPTMM-classTM Human Liver Microsomes from Celsis.
  • Reference to "about” a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se. For example, description referring to "about X” includes description of "X”.
  • ⁇ -secretase inhibitor 2 ⁇ -secretase inhibitors
  • R is A -L -; and R 2 is hydrogen, -N(R 8 )R 9 , -S(0) 2 R n , -C(0)R 12 , or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;
  • R 1 and R 2 together with the nitrogen to which they are bonded form a 5-membered heterocycloalkyl ring substituted with A ⁇ L 1 -, R 6 and R 6A ;
  • a 1 is an optionally substituted heteroaryl
  • R 3 and R 5 are each independently hydrogen, -N(R 8 )R 9 , -S(0) 2 R n , -C(0)R 12 , or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;
  • L 1 and L 4 are each independently a bond, -N(R 17 )-, -S(0) q - , or an optionally substituted alkylene;
  • R 4 , R 6 , R 6A , R 7A and R 7B are each independently hydrogen, halogen, -OH, - N0 2 , -N(R 8 )R 9 , -OR 10 , -S(0) n R n , -C(0)R 12 , or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, -alkyl-OR 10 , - alkyl-N(R 8 )R 9 , heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;
  • R 8 is independently hydrogen, -C(0)R 13 , -S(0) 2 R 14 , or an optionally
  • substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;
  • R 9 is independently hydrogen, or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl,
  • heterocycloalkyl-alkyl aryl, aralkyl, heteroaryl, and heteroaralkyl;
  • R 10 is independently -C(0)R 13 , or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl,
  • heterocycloalkyl-alkyl aryl, aralkyl, heteroaryl, and heteroaralkyl;
  • R 11 is independently hydrogen, or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl,
  • R 11 can also be
  • R 12 and R 13 are each independently hydrogen, -N(R 18 )R 19 , -OR 19 , or an
  • optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl- alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;
  • R 14 is independently hydrogen, -N(R 18 )R 19 , or an optionally substituted
  • R 15 , R 16 , R 17 , R 18 , and R 19 are each independently hydrogen, or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;
  • A is a moiety of the formula
  • R , R and R" are independently hydrogen, halogen, -N(R )R , or an
  • optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl- alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;
  • R 24 and R 25 are independently hydrogen, -C(0)R 26 , or -S(0) 2 R 27 , or an
  • optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl- alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;
  • R is independently hydrogen, -N(R )R , or -OR , an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;
  • R is independently an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;
  • R , R ⁇ , and R JU are independently hydrogen, or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; and n and q are each independently 0, 1, or 2;
  • heterocycloalkyl may be one, two, three, or more groups selected from, but not limited to, hydroxyl, nitro, amino (e.g., -NH 2 or dialkyl amino), imino, cyano, halo (such as F, CI, Br, I), haloalkyl (such as -CCI 3 or -CF 3 ), thio, sulfonyl, thioamido, amidino, imidino, oxo, oxamidino,
  • aralkylcarbonyl carbonylamino, heteroarylcarbonyl, heteroaralkyl-carbonyl, alkylthio, aminoalkyl, cyanoalkyl, carbamoyl (-NHCOOR- or -OCONHR-), urea (-NHCONHR-), aryl and the like, where R is any suitable group, e.g., alkyl or alkylene.
  • the optionally substituted moiety is optionally substituted only with select radicals, as described herein.
  • the above groups are optionally substituted with, for example, alkyl (e.g., methyl or ethyl), haloalkyl (e.g., -CCI 3 , -CH 2 CHC1 2 or -CF 3 ), cycloalkyl (e.g.
  • a substituent group is itself optionally substituted. In some embodiments, a substituent group is not itself substituted.
  • the group substituted onto the substitution group can be, for example, carboxyl, halo, nitro, amino, cyano, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, aminocarbonyl, -SR, thioamido, - SO 3 H, -S0 2 R or cycloalkyl, where R is any suitable group, e.g., a hydrogen or alkyl.
  • the compound is of the formula (I) where L 2 is a bond or an optionally substituted C m alkylene; L is a bond or an optionally substituted C p alkylene; each m and p is independently an integer between 1 and 5; provided that (i) at least one of L and
  • L is an optionally substituted Q-Cs alkylene, and (ii) when each L and L is an optionally substituted Q-C 5 alkylene, 1 ⁇ m + p ⁇ 6; or a pharmaceutically acceptable salt or solvate thereof.
  • m + p is 2, 3, 4, or 5.
  • m + p is 2-3, 3- 4, 4-5, or 3-5.
  • m + p is 3 or 5.
  • m + p is 2 or 4.
  • m + p is 2 or 5.
  • L 2 is an optionally substituted C 2 -C 5 alkylene and L 3 is a bond. In one variation, L 2 is an optionally substituted 3
  • L 2 is an optionally substituted ethylene and L 3 is a bond.
  • L 2 is an optionally substituted propylene and L 3 is a bond.
  • L 2 is an optionally substituted butylene and L 3 is a bond.
  • L 2 is a C 2 -C 4 alkylene and L 3 is a bond.
  • L 2 is ethylene, propylene or butylene and L 3 is a bond.
  • L 2 is propylene and L 3 is a bond.
  • L 2 is butylene and L is a bond.
  • L 2 is a bond and L 3 is an optionally substituted C 2 -C 5 alkylene. In one variation, L 2 is a bond and L 3 is an optionally substituted C 2 -C 4 alkylene. In another variation, L 2 is a bond and L 3 is an optionally substituted ethylene. In another variation, L 2 is a bond and L 3 is an optionally substituted propylene. In another variation, L 2 is a bond and L 3 is an optionally substituted butylene. In one variation, L 2 is a bond and L 3 is
  • L is a is ethylene, propylene or butylene.
  • L 2 is a bond and L 3 is propylene. In another variation, L 2 is bond and L 3 butylene.
  • L 2 is an optionally substituted Q-C 4 alkylene and L 3 is an optionally substituted methylene.
  • L is an optionally substituted C 2 -C 4 alkylene and L 3 is an optionally substituted methylene.
  • L 2 is an optionally substituted ethylene and L is an optionally substituted methylene.
  • L 2 is an optionally substituted propylene and L 3 is an optionally substituted methylene.
  • L 2 is a C C 3 alkylene and L 3 is methylene.
  • L 2 is methylene or ethylene and L 3 is methylene. In a specific variation, each L 2 and L is methylene.
  • L 2 is an optionally substituted Q-C 3 alkylene; and L 3 is an optionally substituted ethylene.
  • L is an optionally substituted methylene or ethylene; and L 3 is an optionally substituted propylene.
  • L 2 is an optionally substituted methylene; and L is an optionally substituted butylene.
  • A is and the compound is of the formula (II):
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 7A , R 7B , R 20 , R 22 , L 1 , L 2 , L 3 , and L 4 are as defined for Formula (I); or a pharmaceutically acceptable salt or solvate thereof.
  • the compound is of the formula (II), where A 2 is a moiety selected from the group consisting of
  • the compound is of the formula (II), where A 2 is a moiety selected from the group consisting of
  • a 2 is and the compound is of the formula
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 7A , R 7B , R 21 , R 22 , L 1 , L 2 , L 3 , and L 4 are as defined for Formula (I); or a pharmaceutically acceptable salt or solvate thereof.
  • the compound is of the formula (III), where A 2 is a moiety selected from the group consisting of
  • the compound is of the formula (III), where A 2 is a moiety selected from the group consisting of
  • R , R , and R are independently hydrogen, or an
  • R , R , and R are optionally substituted Ci-Cw alkyl.
  • R , R , and R are optionally substituted Ci-Cw alkyl.
  • R 20 21 22 20 21 22 least one of R , R , and R" is hydrogen. In some embodiments, R , R , and R are hydrogen. [0077] In some of these embodiments, R 22 is hydrogen. In some embodiments, R 22 is
  • R or R where applicable, is hydrogen or an optionally substituted C -C
  • R is hydrogen; and R and R , where applicable, is
  • R is hydrogen and R or R , where
  • R 20 21 22 24 25 applicable is methyl.
  • at least on of R , R , or R zz is -N(R Z ")R Z .
  • R or R where applicable, is -N(R )R . In some embodiments, R is -N(R 24 )R 25 .
  • R 24 and R 25 are independently hydrogen, or an
  • R 24 optionally substituted moiety selected from alkyl and heteroalkyl.
  • R 24 optionally substituted moiety selected from alkyl and heteroalkyl.
  • R are independently hydrogen, or an optionally substituted alkyl.
  • At least one of R and R is hydrogen. In some embodiments, wherein R
  • R z " and R ZJ are hydrogen.
  • at least one of R z " and R ZJ is an optionally
  • R and R are independently an optionally
  • R z " and R ZJ is methyl.
  • R and R are independently hydrogen, an optionally substituted
  • R 24 and R 25 is -C(0)R 26
  • one of R ⁇ and R is -C(0)R D . In some embodiments, one of R 24 and R 25 is -S(0) 2 R 27 .
  • R 26 is independently hydrogen, an optionally hydrogen
  • R is independently hydrogen, or an optionally substituted alkyl.
  • R 26 is hydrogen.
  • R 26 is an optionally substituted alkyl.
  • R 26 is
  • R is independently -N(R )R , or -OR .
  • R 26 is -N(R 28 )R 29 .
  • R 26 is -OR 30 .
  • R 27 is an optionally substituted alkyl or aryl.
  • R is an optionally substituted alkyl. In some embodiments, R is methyl.
  • R , R , and R are independently hydrogen, or an optionally substituted alkyl.
  • a 1 is an optionally substituted 5 to 7 membered heteroaryl (e.g. , wherein the heteroaryl is attached to hi at the 1, 2, 3, 4, or 5 position and/or wherein the heteroaryl is substituted at the 1, 2, 3, 4, and/or 5 position(s)).
  • a 1 is an optionally substituted 5-membered heteroaryl (e.g. , wherein the heteroaryl is attached to hi at the 1, 2, 3, 4, or 5 position and/or wherein the heteroaryl is substituted at the 1, 2, 3, 4, and/or 5 position(s)).
  • a 1 is an optionally substituted moiety selected from the group consisting of pyrazolyl, furanyl, imidazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrrolyl, pyridyl, pyrimidyl, pyridazinyl, thiazolyl, triazolyl, thienyl, dihydrothieno- pyrazolyl, thianaphthenyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzooxazolyl, benzimidazolyl, isoquinolinyl, isoindolyl, acridinyl, benzoisazolyl, pyrazinyl, pyrrolinyl, indolyl, and
  • a 1 is an optionally substituted moiety selected from the group consisting of pyridyl (e.g., an optionally substituted 3-pyridyl, such as a 3-(5- substituted)pyridyl), thiazolyl (e.g., an optionally substituted 2-thiazolyl or a an optionally substituted 4-thiazolyl, such as a 2-(4-substituted)thiazolyl or a 4-(2-substituted)thiazolyl), oxazolyl (e.g.
  • an optionally substituted 2-oxazolyl or an optionally substituted 4-oxazolyl such as a 2-(4-substituted)oxazolyl or a 4-(2-substituted)oxazolyl
  • imidazolyl such as a 2-(4-substituted)oxazolyl or a 4-(2-substituted)oxazolyl
  • imidazolyl such as a 2-(4-substituted)oxazolyl or a 4-(2-substituted)oxazolyl
  • imidazolyl such as a 2-(4-substituted)oxazolyl or a 4-(2-substituted)oxazolyl
  • imidazolyl such as a 2-(4-substituted)oxazolyl or a 4-(2-substituted)oxazolyl
  • imidazolyl such as a 2-(4-substituted)ox
  • a 1 is an optionally substituted moiety selected from the group consisting of thiazolyl (e.g., an optionally substituted 2-thiazolyl or a an optionally substituted 4-thiazolyl, such as a 2-(4- substituted)thiazolyl or a 4-(2-substituted)thiazolyl), oxadiazolyl, and oxazolyl (e.g., an optionally substituted 2-oxazolyl or an optionally substituted 4-oxazolyl, such as a 2-(4- substituted)oxazolyl or a 4-(2-substituted)oxazolyl).
  • thiazolyl e.g., an optionally substituted 2-thiazolyl or a an optionally substituted 4-thiazolyl, such as a 2-(4- substituted)thiazolyl or a 4-(2-substituted)thiazolyl
  • a 1 is an optionally substituted pyridyl (e.g., an optionally substituted 3-pyridyl, such as a 3-(5- substituted)pyridyl).
  • a 1 is an optionally substituted thiazolyl (e.g. , an optionally substituted 2-thiazolyl or a an optionally substituted 4-thiazolyl, such as a 2-(4- substituted)thiazolyl or a 4-(2-substituted)thiazolyl).
  • a 1 is an optionally substituted oxazolyl (e.g., an optionally substituted 2-oxazolyl or an optionally substituted 4-oxazolyl, such as a 2-(4-substituted)oxazolyl or a 4-(2-substituted)oxazolyl).
  • a 1 is an optionally substituted oxadiazolyl.
  • a 1 is an optionally substituted imidazolyl.
  • a 1 is an optionally substituted pyrazolyl.
  • a 1 is an optionally substituted isoxazolyl.
  • a 1 is an optionally substituted pyrimidyl.
  • a 1 is an optionally substituted furanyl.
  • a 1 is an optionally substituted 2- thiazolyl.
  • a 1 is an optionally substituted 2-oxazoyl.
  • the substituents on an optionally substituted A 1 of formula (I) may be one, two, three, or more groups selected from, but not limited to, hydroxyl, nitro, amino, imino, cyano, halo, haloalkyl, thiol, thioalkyl, sulfonyl, thioamido, amidino, oxo, oxamidino, methoxamidino, imidino, guanidino, sulfonamido, carboxyl, formyl, alkyl, cycloalkyl, alkoxy, alkoxy-alkyl, alkylcarbonyl, alkylcarbonyloxy, aminocarbonyl, aryl, heteroaryl, arylcarbonyl, aralkylcarbonyl, carbonylamino, heteroarylcarbonyl, heteroaralkyl-carbonyl, alkylthio, aminoalkyl, cyanoalkyl, carb
  • substituents on an optionally substituted A 1 may be one, two, three, or more groups selected from, but not limited to, hydroxyl, halo (such as F, CI, Br, I), CrC 6 alkyl (e.g. , methyl, ethyl, propyl, isopropyl) or CrC 6 alkoxy (methoxy, ethoxy, propoxy, isopropoxy, wherein each C -C alkyl and C -C alkoxy is optionally substituted with 1-3 halogens (e.g. , -CF 3 , -CHF 2 , -CH 2 F, -OCH 2 F, OCHF 2 ).
  • halo such as F, CI, Br, I
  • CrC 6 alkyl e.g. , methyl, ethyl, propyl, isopropyl
  • CrC 6 alkoxy methoxy, ethoxy, propoxy, isopropoxy
  • a 1 is pyridyl, substituted with one or more -OCH 3 .
  • a 1 e.g., thiazoyl
  • alkyl such as methyl (e.g., at the 1, 2, 3, or 4 position of A 1 ).
  • the alkyl e.g., methyl
  • the alkyl is optionally substituted with 1-3 halogens (e.g. , - CF 3 , -CHF 2 , -CH 2 F).
  • L 1 is a bond or an optionally substituted alkylene.
  • L is -N(R )-, -S(0) q -, or an optionally substituted alkylene.
  • L is -N(R )- or -S(0) q -. In other embodiments, L is -N(R )-. In other embodiments, L 1 is -S(0) q -. In other embodiments, L 1 is a bond. In other embodiments, L 1 is an optionally substituted alkylene. In other embodiments, L 1 is an optionally substituted Q- C 6 alkylene. In other embodiments, L 1 is a C C 6 alkylene (e.g., methylene or
  • L 1 is a branched Q-C 6 alkylene (e.g.,
  • L 1 is methylene. In other embodiments, L 1 is methylmethylene. In some of these embodiments, A 1 is an optionally substituted moiety selected from the group consisting of pyridyl (e.g., an optionally substituted 3-pyridyl, such as a 3-(5-substituted)pyridyl), thiazolyl (e.g. , an optionally substituted
  • 2-thiazolyl or a an optionally substituted 4-thiazolyl such as a 2-(4-substituted)thiazolyl or a 4-(2-substituted)thiazolyl
  • oxazolyl e.g. , an optionally substituted 2-oxazolyl or an optionally substituted 4-oxazolyl, such as a 2-(4-substituted)oxazolyl or a 4-(2- substituted)oxazolyl
  • a 1 is an optionally substituted moiety selected from the group consisting of thiazolyl (e.g. , an optionally substituted 2-thiazolyl or a an optionally substituted 4-thiazolyl, such as a 2-(4-substituted)thiazolyl or a 4-(2-substituted)thiazolyl), oxadiazolyl, and oxazolyl (e.g., an optionally substituted 2-oxazolyl or an optionally substituted 4-oxazolyl, such as a 2-(4-substituted)oxazolyl or a 4-(2-substituted)oxazolyl).
  • thiazolyl e.g., an optionally substituted 2-thiazolyl or a an optionally substituted 4-thiazolyl, such as a 2-(4-substituted)thiazolyl or a 4-(2-substituted)thiazolyl
  • A is an optionally substituted pyridyl (e.g. , an optionally substituted 3- pyridyl, such as a 3-(5-substituted)pyridyl).
  • a 1 is an optionally substituted thiazolyl (e.g. , an optionally substituted 2-thiazolyl or a an optionally substituted 4-thiazolyl, such as a 2-(4-substituted)thiazolyl or a 4-(2-substituted)thiazolyl).
  • a 1 is an optionally substituted oxazolyl (e.g.
  • an optionally substituted 2- oxazolyl or an optionally substituted 4-oxazolyl such as a 2-(4-substituted)oxazolyl or a 4- (2-substituted)oxazolyl).
  • a 1 is an optionally substituted oxadiazolyl.
  • a 1 is an optionally substituted imidazolyl.
  • a 1 is an optionally substituted pyrazolyl.
  • a 1 is an optionally substituted isoxazolyl.
  • a 1 is an optionally substituted pyrimidyl.
  • a 1 is an optionally substituted furanyl.
  • a 1 is an optionally substituted 2-thiazolyl.
  • a 1 is an optionally substituted 2- oxazoyl.
  • substituents on an optionally substituted L 1 may be one, two, three, or more groups selected from, but not limited to, hydroxyl, halo (such as F, CI, Br, I), Q-C 6 alkyl (e.g. , methyl, ethyl, propyl, isopropyl) or Q-C 6 alkoxy (methoxy, ethoxy, propoxy, isopropoxy, wherein each Q-C 6 alkyl and Q-C 6 alkoxy is optionally substituted with 1-3 halogens (e.g. , -CF 3 , -CHF 2 , -CH 2 F, -OCH 2 F, OCHF 2 ).
  • halo such as F, CI, Br, I
  • Q-C 6 alkyl e.g. , methyl, ethyl, propyl, isopropyl
  • Q-C 6 alkoxy methoxy, ethoxy, propoxy, isopropoxy
  • the compound has the formula (la):
  • R J , R , and R ,D are as defined for Formula (I) and any variations thereof.
  • R 2 is hydrogen, or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl.
  • R is hydrogen, or an optionally substituted moiety selected from alkyl, cycloalkyl, and cycloalkyl-alkyl.
  • R is hydrogen or an optionally substituted alkyl. In some embodiments, R is hydrogen or an optionally substituted Ci-C 6 alkyl. In some embodiments, R is hydrogen.
  • R is an optionally substituted Ci-C 6 alkyl. In some embodiments, R is an optionally substituted Q-C 3 alkyl. In some embodiments, R is an optionally substituted
  • R is cyclopropyl. In some embodiments, R is methyl.
  • substituents on an optionally substituted R 2 may be one, two, three, or more groups selected from, but not limited to, hydroxyl, halo (such as F, CI, Br, I), C -C alkyl (e.g. , methyl, ethyl, propyl, isopropyl) or Q-C 6 alkoxy (methoxy, ethoxy, propoxy, isopropoxy, wherein each Q-C 6 alkyl and Q-C 6 alkoxy is optionally substituted with 1-3 halogens (e.g. , -CF 3 , -CHF 2 , -CH 2 F, -OCH 2 F, -OCHF 2 ).
  • substituents on an optionally substituted R are selected from methyl and cyclopropyl.
  • the compound has the formula (lb):
  • a 1 , A 2 , L 1 , L 4 , R 3 , R 4 , R 5 , R 6 , R 7A , and R 7B are as defined above in the discussion of Formula (I).
  • the compound has the formula (Ic):
  • a 1 , A 2 , L 1 , L 4 , R 3 , R 4 , R 5 , R 6 , R 6A , R 7A , and R 7B are as defined above in the discussion of Formula (I).
  • the A ⁇ L 1 - moiety is substituted on the pyrrolidine heterocyclo alkyl ring according to the formula:
  • R 6A is hydrogen and the A ⁇ L 1 - moiety is substituted on the pyrrolidine heterocycloalkyl ring according to the formula:
  • R 6A is hydrogen
  • L 1 is a bond
  • a 1 is substituted on the pyrrolidine heterocycloalkyl ring according to the formula:
  • R 6A is hydrogen and the A ⁇ L 1 - moiety is substituted on the pyrrolidine heterocycloalkyl ring according to the formula:
  • R 6A is hydrogen, L 1 is a bond, and A 1 is substituted on the pyrrolidine heterocycloalkyl ring according to the formula:
  • R 6A is hydrogen and R 6 is substituted on the pyrrolidine heterocycloalkyl ring according to the formula:
  • R 6A is hydrogen and R 6 is substituted on the pyrrolidine heterocycloalkyl ring according to the formula:
  • L 1 is a bond
  • a 1 , R 6 and R 6A are substituted pyrrolidine heterocycloalkyl ring according to the formula:
  • the A ⁇ L 1 - moiety, R 6 and R 6A are substituted
  • R 6 and R 6A may be substituted on the same carbon atom, e.g.
  • R 6 and R 6A are independently hydrogen
  • R 6 is hydrogen, or an optionally substituted moiety selected from aryl, aralkyl, heteroaryl, and heteroaralkyl.
  • R 6 is hydrogen, halogen (e.g. , F or CI), an optionally substituted alkyl (e.g.
  • haloalkyl e.g. , haloalkyl
  • an optionally substituted -OR 10 e.g. , an optionally substituted -O-alkyl, such as methoxy, ethoxy, propoxy, isopropoxy, or halogenated variants thereof.
  • an optionally substituted -OR 10 e.g. , an optionally substituted -O-alkyl, such as methoxy, ethoxy, propoxy, isopropoxy, or halogenated variants thereof.
  • R 6 is hydrogen, F, an optionally substituted (Q-C- alkyl (e.g. , methyl, ethyl, propyl, butyl, -CF 3 , -CHF 2 , -CH 2 F), an optionally substituted -0-(C 1 -C 4 )alkyl (e.g., -0-(Cr C 4 )alkyl, such as methoxy, ethoxy, propoxy, or isopropoxy, substituted with 1, 2, or 3 fluoro groups, such as -OCH 2 F, -OCHF 2 ).
  • R 6 is hydrogen or halogen.
  • R 6 is halogen, e.g. fluoro.
  • R 6 is hydrogen.
  • R 6A is hydrogen.
  • R 6A is an optionally substituted alkyl. In some variations of these embodiments,
  • R 6A is a halogen (e.g. fluoro). In some particular variations, R 6 and R 6A are independently halogen. In some particular variations, each R 6 and R 6A is fluro.
  • R 3 is hydrogen, or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl.
  • R is hydrogen, or an optionally substituted moiety selected from alkyl, cycloalkyl, and cycloalkyl-alkyl.
  • R is hydrogen or an optionally substituted alkyl. In some embodiments, R is hydrogen or an optionally substituted Ci-C 6 alkyl. In some embodiments, R hydrogen. In
  • R is an optionally substituted Q-C 6 alkyl. In some embodiments, R is methyl.
  • substituents on an optionally substituted R 3 may be one, two, three, or more groups selected from, but not limited to, hydroxyl, halo (such as F, CI, Br, I), Q-C 6 alkyl (e.g. , methyl, ethyl, propyl, isopropyl) or Q-C 6 alkoxy (methoxy, ethoxy, propoxy, isopropoxy, wherein each Q-C 6 alkyl and Q-C 6 alkoxy is optionally substituted with 1-3 halogens (e.g. , -CF 3 , -CHF 2 , -CH 2 F, -OCH 2 F, OCHF 2 ).
  • halo such as F, CI, Br, I
  • Q-C 6 alkyl e.g. , methyl, ethyl, propyl, isopropyl
  • Q-C 6 alkoxy methoxy, ethoxy, propoxy, isopropoxy
  • R 4 is hydrogen. In some embodiments, R 4 is an optionally substituted moiety selected from alkyl and heteroalkyl. In some embodiments, R 4 is an optionally substituted moiety selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. In some embodiments, R 4 is an optionally substituted moiety selected from cycloalkyl and heterocycloalkyl. In some embodiments, R 4 is an optionally substituted moiety selected from aryl and heteroaryl. In some embodiments, R 4 is an optionally substituted aryl (e.g. , phenyl, 3,5-difluorophenyl or 3-fluorophenyl).
  • aryl e.g. , phenyl, 3,5-difluorophenyl or 3-fluorophenyl.
  • R 4 is an optionally substituted heteroaryl. In some embodiments, R 4 is phenyl, optionally substituted with one or more halogens. In some embodiments, R 4 is phenyl, 3,5- difluorophenyl, or 3-fluorophenyl. In some embodiments, R 4 is phenyl or 3-fluorophenyl. In some embodiments, R 4 is phenyl. In some embodiments, R 4 is 3,5-difluorophenyl. In some embodiments, R 4 is 3-fluorophenyl.
  • substituents on an optionally substituted R 4 may be one, two, three, or more groups selected from, but not limited to, hydroxyl, halo (such as F, CI, Br, I), CrC 6 alkyl (e.g. , methyl, ethyl, propyl, isopropyl) or CrC 6 alkoxy (methoxy, ethoxy, propoxy, isopropoxy, wherein each CrC 6 alkyl and CrC 6 alkoxy is optionally substituted with 1-3 halogens (e.g. , -CF 3 , -CHF 2 , -CH 2 F, -OCH 2 F, -OCHF 2 ).
  • halo such as F, CI, Br, I
  • CrC 6 alkyl e.g. , methyl, ethyl, propyl, isopropyl
  • CrC 6 alkoxy methoxy, ethoxy, propoxy, isopropoxy
  • L 4 is a bond, or an optionally substituted alkylene. In some embodiments, L 4 is a bond. In some embodiments, L 4 is an optionally substituted alkylene. In some embodiments, L 4 is an optionally substituted CrC 6 alkylene. In some embodiments, L 4 is a Ci-Ce alkylene. In some embodiments, L 4 is methylene (e.g., when L 4 - R 4 is (e.g., -CH 2 -phenyl or -CH 2 -difluorophenyl).
  • substituents on an optionally substituted L 4 may be one, two, three, or more groups selected from, but not limited to, hydroxyl, halo (such as F, CI, Br, I), C -C alkyl (e.g. , methyl, ethyl, propyl, isopropyl) or C -C alkoxy (methoxy, ethoxy, propoxy, isopropoxy, wherein each C -C alkyl and C -C alkoxy is optionally substituted with 1-3 halogens (e.g. , -CF 3 , -CHF 2 , -CH 2 F, -OCH 2 F, -OCHF 2 ).
  • halo such as F, CI, Br, I
  • C -C alkyl e.g. , methyl, ethyl, propyl, isopropyl
  • C -C alkoxy methoxy, ethoxy, propoxy, isopropoxy
  • R is hydrogen, -C(0)R , or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl.
  • R 5 is hydrogen, -C(0)tBu, or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl.
  • R 5 is hydrogen, or an optionally substituted alkyl.
  • R 5 is hydrogen, or an optionally substituted Q-C 6 alkyl.
  • R 5 is hydrogen. In some embodiments, R 5 is an optionally substituted Q-C 6 alkyl. In some embodiments, R 5 is a Q-C 6 alkyl. In some embodiments, R 5 is an optionally substituted CrC 3 alkyl. In some embodiments, R 5 is a CrC 3 alkyl. In some embodiments, R 5 is methyl.
  • substituents on an optionally substituted R 5 may be one, two, three, or more groups selected from, but not limited to, hydroxyl, halo (such as F, CI, Br, I), Q-C 6 alkyl (e.g. , methyl, ethyl, propyl, isopropyl) or Q-C 6 alkoxy (methoxy, ethoxy, propoxy, isopropoxy, wherein each Q-C 6 alkyl and Q-C 6 alkoxy is optionally substituted with 1-3 halogens (e.g. , -CF 3 , -CHF 2 , -CH 2 F, -OCH 2 F, -OCHF 2 ).
  • halo such as F, CI, Br, I
  • Q-C 6 alkyl e.g. , methyl, ethyl, propyl, isopropyl
  • Q-C 6 alkoxy methoxy, ethoxy, propoxy, isopropoxy
  • R 7A and R 7B are substituted on the pyrrolidine heterocycloalkyl ring according to the formula:
  • R 7A and R 7B are substituted on the pyrrolidine heteroc cloalkyl ring according to the formula:
  • R 7A and R 7B are substituted on the pyrrolidine heterocycloalkyl ring according to the formula:
  • R 7A and R 7B are substituted on the same carbon atom of the pyrrolidine heterocycloalkyl ring. In some embodiments, R 7 A and R 7B are substituted on the pyrrolidine heteroc cloalk l ring according to the formula:
  • R 7A and R 7B are substituted on the pyrrolidine
  • At least one of R /A and R ia is hydrogen.
  • R is hydrogen. In some embodiments, R is hydrogen. In some
  • R is hydrogen and R is other than hydrogen. In some embodiments, R is hydrogen and R 7A is other than hydrogen.
  • R 7A and R 7B are independently hydrogen, halogen, -OH, - N(R 8 )R 9 , -OR 10 , or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl.
  • R 7A and R 7B are independently hydrogen, halogen, -OH, - N(R 8 )R 9 , -OR 10 , or an optionally substituted moiety selected from alkyl, -alkyl-OR 10 , and -
  • R and R are independently hydrogen, halogen, or an optionally substituted moiety selected from alkyl, -alkyl-OR 10 (e.g. , -CH 2 0-phenyl), and - alkyl-N(R 8 )R 9 (e.g. , -CH 2 N(R 8 )-phenyl).
  • R 7A and R 7B are
  • -alkyl-OR 10 e.g. , -CH 2 0-phenyl
  • -alkyl-N(R 8 )R 9 e.g. , -CH 2 N(R 8 )-phenyl
  • R m and R' D is an optionally substituted moiety selected from -alkyl-OR (e.g. , - CH 2 0-phenyl, -CH(alkyl)O-phenyl), -alkyl-N(R 8 )R 9 (e.g. , -CH 2 N(R 8 )-phenyl).
  • -alkyl-OR e.g. , - CH 2 0-phenyl, -CH(alkyl)O-phenyl
  • -alkyl-N(R 8 )R 9 e.g. , -CH 2 N(R 8 )-phenyl.
  • At least one of R m and R' D is an optionally substituted -alkyl-OR (e.g. , optionally substituted -CH 2 0-phenyl or -CH(alkyl)O-phenyl). In some embodiments, at least
  • R m and R' D is an optionally substituted -alkyl-N(R )R (e.g. , optionally substituted - CH 2 N(R 8 )-phenyl, such as -CH 2 N(alkyl)-phenyl).
  • R 7A and R 7B are independently hydrogen, halogen, -OH, - OR 10 , or an optionally substituted moiety selected from alkyl, aryl, aralkyl, heteroaryl, and
  • R and R are independently hydrogen, or an optionally substituted moiety selected from alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl.
  • R and R are independently hydrogen, or an optionally substituted
  • R and R are independently hydrogen, -OH, -N0 2 , -N(R )R , -OR 10 , -S(0) n R n , -C(0)R 12 .
  • R 7A and R 7B are independently hydrogen, -OH, -N0 2 , -N(R 8 )R 9 , -OR 10 , -SR 11 .
  • at least one of R 7A and R 7B is -N(R 8 )R 9 , -OR 10 , or -SR 11 .
  • R and R are independently hydrogen, -OH, -OR , or an optionally
  • R ,rt and R ,D is -OR lu (e.g. , an optionally substituted moiety selected from -O-alkyl (e.g. , -0-C C 6 alkyl, for example, an unsaturated alkyl such as -OCH 2 CHCH 2 or a saturated alkyl such as -OCH(CH 3 ) 2 ), -O- cycloalkyl, -O-alkyl-cycloalkyl, -O-heterocycloalkyl, -O-alkyl-heterocycloalkyl, -O-aryl, -O- aralkyl, -O-heteroaryl, and -O-heteroaralkyl).
  • R is an optionally substituted -O-alkyl-aryl (e.g., an optionally substituted -0-CH 2 Ph, or - 0-CHCH 2 Ph, such as a 3-substituted -0-CH 2 Ph, or -0-CHCH 2 Ph) or an optionally substituted -O-alkyl-heteroaryl (e.g., -0-CH 2 -heteroaryl and/or wherein the heteroaryl is selected from pyridyl, thiazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, isoxazolyl, pyrimidyl, and furanyl).
  • -O-alkyl-aryl e.g., an optionally substituted -0-CH 2 Ph, or - 0-CHCH 2 Ph, such as a 3-substituted -0-CH 2 Ph, or -0-CHCH 2 Ph
  • At least one of R 7A and R 7B is halogen (e.g. , F, CI, Br, I).
  • halogen e.g. , F, CI, Br, I.
  • R is halogen (e.g. , F, CI, Br, I). In some embodiments, R is halogen
  • R ,rt and R ,D are fluoro.
  • R is fluoro. In some embodiments, R is fluoro. In some embodiments, each R 7A and R 7B is fluoro.
  • At least one of R 7A and R 7B is an optionally substituted
  • R m and R' D is an optionally substituted moiety selected from aryl (e.g., a 3-substituted phenyl) and heteroaryl.
  • At least one of R m and R' D is an optionally substituted aryl (e.g. , a 3-
  • R m and R' D is an optionally
  • R m and R' D is an optionally substituted moiety selected from C C 6 alkyl, C5-C7 cycloalkyl, 5 to 7 membered
  • heterocycloalkyl 6-membered aryl, and 5 to 7 membered heteroaryl.
  • At least one of R 7A and R 7B is an optionally substituted moiety selected from phenyl (e.g., a 3-substituted phenyl), pyrazolyl (e.g., an optionally substituted
  • 3-pyrazolyl an optionally substituted 4-pyrazolyl, or an optionally substituted 5-pyrazolyl such as a 3-(5-substituted)pyrazolyl, a 4-(l-substituted)pyrazolyl, or a 5-(3- substituted)pyrazolyl), furanyl, imidazolyl, isoxazolyl (e.g., an optionally substituted 3- isoxazolyl or an optionally substituted
  • 5-isoxazolyl such as a 3-(5-substituted)isoxazolyl or a 3-(5-substituted)isoxazolyl), oxadiazolyl, oxazolyl (e.g.
  • an optionally substituted 2-oxazolyl or an optionally substituted 4-oxazolyl such as a 2-(4-substituted)oxazolyl or a 4-(2-substituted)oxazolyl
  • pyrrolyl e.g., a 2-(4-substituted)oxazolyl or a 4-(2-substituted)oxazolyl
  • pyridyl e.g., a an optionally substituted 3-pyridyl, such as a 3-(5-substituted)pyridyl
  • pyrimidyl pyridazinyl
  • thiazolyl e.g.
  • an optionally substituted 2-thiazolyl or an optionally substituted 4-thiazolyl such as a 2-(4-substituted)thiazolyl or a 4-(2-substituted)thiazolyl), triazolyl, thienyl, dihydrothieno-pyrazolyl, thianaphthenyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl,
  • benzooxazolyl benzimidazolyl, isoquinolinyl, isoindolyl, acridinyl, benzoisazolyl, dimethylhydantoin, pyrazinyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, morpholinyl, indolyl, diazepinyl, azepinyl, thiepinyl, piperidinyl, and oxepinyl.
  • At least one of R 7A and R 7B is an optionally substituted alkyl
  • R and R together form an optionally substituted cycloalkyl ring.
  • R ,rt and R are selected from hydrogen, optionally substituted alkyl, or R and R together form an optionally substituted C 3 -C 7 cycloalkyl ring (e.g., fused or spiro C 3 -C 7 cycloalkyl
  • R and R together form an optionally substituted C 4 -C 6 cycloalkyl ring (e.g. , fused or spiro C 4 -C 6 cycloalkyl ring).
  • R 7A and R 7B together form an optionally substituted C 4 -C 6 cycloalkyl ring (e.g. , fused or spiro C 4 -C 6 cycloalkyl ring).
  • R together form an optionally substituted cyclohexyl ring (e.g., fused or spiro cyclohexyl ring).
  • At least one of R 7A and R 7B is an optionally substituted moiety selected from pyridyl (e.g. , a an optionally substituted 3-pyridyl, such as a 3-(5- substituted)pyridyl), phenyl (e.g. , a 3-substituted phenyl), thiazolyl (e.g.
  • an optionally substituted 2-thiazolyl or an optionally substituted 4-thiazolyl such as a 2-(4- substituted)thiazolyl or a 4-(2-substituted)thiazolyl
  • oxazolyl e.g., an optionally substituted 2-oxazolyl or an optionally substituted 4-oxazolyl, such as a 2-(4-substituted)oxazolyl or a 4- (2-substituted)oxazolyl
  • oxadiazolyl imidazolyl, pyrazolyl (e.g.
  • At least one of R m and R' D is an optionally substituted
  • R 7 A 7B moiety selected from pyridyl, and phenyl.
  • at least one of R m and R' D is selected from pyridyl, and phenyl.
  • R 7 A 7B is an optionally substituted pyridyl.
  • at least one of R m and R' D is an
  • R ,rt and R ,D is a phenyl substituted with one or more fluoro groups.
  • the substituents on an optionally substituted R and R may be one, two, three, or more groups selected from, but not limited to, hydroxyl, nitro, amino, imino, cyano, halo, haloalkyl, thiol, thioalkyl, sulfonyl, thioamido, amidino, oxo, oxamidino, methoxamidino, imidino, guanidino, sulfonamido, carboxyl, formyl, alkyl, cycloalkyl, alkoxy, alkoxy-alkyl, alkylcarbonyl, alkylcarbonyloxy, aminocarbonyl, aryl, heteroaryl, arylcarbonyl,
  • aralkylcarbonyl carbonylamino, heteroarylcarbonyl, heteroaralkyl-carbonyl, alkylthio, aminoalkyl, cyanoalkyl, carbamoyl, and urea.
  • substituents on an optionally substituted R 7A and R 7B may be one, two, three, or more groups selected from, but not limited to, hydroxyl, halo (such as F, CI, Br, I), C -C alkyl (e.g. , methyl, ethyl, propyl, isopropyl) or Q-C 6 alkoxy (methoxy, ethoxy, propoxy, isopropoxy, wherein each Q-C 6 alkyl and C C 6 alkoxy is optionally substituted with 1-3 halogens (e.g., -CF 3 , -CHF 2 , -CH 2 F, -OCH 2 F, OCHF 2 ).
  • halo such as F, CI, Br, I
  • C -C alkyl e.g. , methyl, ethyl, propyl, isopropyl
  • Q-C 6 alkoxy methoxy, ethoxy, propoxy, isopropoxy
  • n is 0 or 2. In other embodiments, n is 1 or 2. In other embodiments, n is 0. In other embodiments, n is 1. In other embodiments, n is 2.
  • q is 0 or 2. In other embodiments, q is 1 or 2. In other embodiments, q is 0. In other embodiments, q is 1. In other embodiments, q is 2.
  • the compound is a compound of formula (la), wherein A 1 is an optionally substituted heteroaryl (e.g., a 5-membered heteroaryl); A is the same as described herein for formula (I); L 1 and L 4 are each independently an optionally substituted
  • alkylene e.g. , methylene or methylmethylene
  • R and R are each independently hydrogen, or an optionally substituted alkyl
  • R 4 is an optionally substituted aryl (e.g., phenyl, 3,5- difluorophenyl, or
  • R is a hydrogen, an optionally substituted alkyl, or -C(0)R
  • R and R are each independently hydrogen, halogen, -OH, - N(R 8 )R 9 , -OR 10 , or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, -alkyl-OR 10 , -alkyl-N(R 8 )R 9 , heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; or a pharmaceutically acceptable salt or solvate thereof.
  • the compound is a compound of formula (la), wherein A 1 is an optionally substituted thiazolyl (e.g. , an optionally substituted 2-thiazolyl or an optionally substituted 4-thiazolyl) or an optionally substituted oxazolyl (e.g., an optionally substituted 2-
  • L are each independently alkylene (e.g. , methylene or methylmethylene); R is hydrogen
  • R , R , and R are each hydrogen; R is an optionally substituted aryl (e.g., phenyl, 3,5-difluorophenyl, or 3 -fluorophenyl); and R 7A is hydrogen, halogen, -OH, -N(R 8 )R 9 , -OR 10 , or an optionally substituted moiety selected from alkyl, -alkyl-OR 10 , -alkyl-N(R 8 )R 9 , heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; or a pharmaceutically acceptable salt or solvate thereof.
  • R , R , and R are each hydrogen; R is an optionally substituted aryl (e.g., phenyl, 3,5-difluorophenyl, or 3 -fluorophenyl); and R 7A is hydrogen, halogen, -OH, -
  • the compound is a compound of formula (la), wherein A 1 is
  • 2-thiazolyl e.g., 2-(4-substituted)thiazolyl
  • L is an optionally substituted C 2 -C 4 alkylene, L is a bond or an optionally
  • each R and R is independently hydrogen or an optionally
  • L and L are each methylene; R is methyl; R , R , R , and R are each hydrogen; R 4 is phenyl, 3,5 di-fluorophenyl, or 3-fluorophenyl; or a pharmaceutically acceptable salt or solvate thereof.
  • L is an optionally substituted C 2 -C 4 alkylene and L is a bond.
  • the compound is a compound of formula (la), wherein A 1 is an optionally substituted 2-oxazolyl (e.g. , such as a 2-(4-substituted)oxazolyl); A is
  • L 1 and L 4 are each methylene; R 2 is methyl; R 3 , R 5 , R 7A ,
  • R are each hydrogen; R is phenyl, 3,5 di-fluorophenyl, or 3-fluorophenyl; or a pharmaceutically acceptable salt or solvate thereof.
  • L is an optionally substituted
  • the compound has the formula (Ila):
  • A is an optionally substituted heteroaryl
  • L is alkylene (e.g., methylene or methylmethylene);
  • R is hydrogen, an optionally substituted alkyl or an optionally substituted cycloalkyl;
  • t is 0, 1 or 2;
  • R 4 is an optionally substituted aryl;
  • R 7A and R 7B are independently hydrogen, halogen, or an optionally substituted alkyl; or a pharmaceutically acceptable salt or solvate thereof.
  • a 1 is an optionally substituted thiazolyl or an
  • L is methylene
  • R is a moiety selected from the group consisting of methyl, ethyl, propyl, isopropyl and cyclopropyl
  • t is 1 or 2
  • R 4 is an optionally substituted oxazolyl
  • substituted phenyl and R and R are independently hydrogen, halogen, or an optionally substituted alkyl; or a pharmaceutically acceptable salt or solvate thereof.
  • a 1 is (4-methyl)thiazole-2-yl or (4-methyl)oxazole-2-yl.
  • t is 0. In some of these embodiments, t is 1. In some of these embodiments, t is 2. In some of these embodiments, R 4 is phenyl, 3 -fluorophenyl or 3,5-difluorophenyl.
  • each R and R is hydrogen.
  • the compound has the formula (Ilia):
  • A is an optionally substituted heteroaryl
  • L is alkylene (e.g. , methylene or methylmethylene);
  • R is hydrogen, an optionally substituted alkyl or an optionally substituted cycloalkyl;
  • t is 0, 1 or 2;
  • R 4 is an optionally substituted aryl;
  • R 7A and R 7B are independently hydrogen, halogen, or an optionally substituted alkyl; or a pharmaceutically acceptable salt or solvate thereof.
  • a 1 is an optionally substituted thiazolyl or an
  • L is methylene
  • R is a moiety selected from the group consisting of methyl, ethyl, propyl, isopropyl and cyclopropyl
  • t is 1 or 2
  • R 4 is an optionally substituted oxazolyl
  • substituted phenyl and R and R are independently hydrogen, halogen, or an optionally substituted alkyl; or a pharmaceutically acceptable salt or solvate thereof.
  • a 1 is (4-methyl)thiazole-2-yl or (4-methyl)oxazole-2-yl.
  • t is 0. In some of these embodiments, t is 1. In some of these embodiments, t is 2. In some of these embodiments, R 4 is phenyl, 3 -fluorophenyl or 3,5-difluorophenyl.
  • each R and R is hydrogen.
  • the compound is a compound of formula (lb), wherein A is an optionally substituted heteroaryl (e.g., a 5-membered heteroaryl); A is as described herein for formula (I); L 1 is a bond; L 4 is an optionally substituted alkylene (e.g., optionally substituted methylene; R 3 is hydrogen, or an optionally substituted alkyl; R 4 is an optionally substituted aryl (e.g. , phenyl, 3,5-difluorophenyl, or 3-fluorophenyl); R 5 is a hydrogen, an optionally substituted alkyl, or -C(0)R 12 (e.g.
  • R 6 is a hydrogen, halogen, -OR 10 , an optionally substituted alkyl
  • R 7 A and R 7B are each independently hydrogen, halogen, -OH, -N(R 8 )R 9 , -OR 10 , or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, -alkyl-OR 10 , -alkyl-N(R 8 )R 9 , heterocycloalkyl, heterocycloalkyl- alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; or a pharmaceutically acceptable salt or solvate thereof.
  • the compound is a compound of formula (lb), wherein A 1 is an optionally substituted thiazolyl (e.g. , an optionally substituted 2-thiazolyl or an optionally substituted 4-thiazolyl) or an optionally substituted oxazolyl (e.g., an optionally substituted 2- oxazolyl or an optionally substituted 4-oxazolyl); 2 1
  • a 1 is an optionally substituted thiazolyl (e.g. , an optionally substituted 2-thiazolyl or an optionally substituted 4-thiazolyl) or an optionally substituted oxazolyl (e.g., an optionally substituted 2- oxazolyl or an optionally substituted 4-oxazolyl); 2 1
  • a 1 is an optionally substituted thiazolyl (e.g. , an optionally substituted 2-thiazolyl or an optionally substituted 4-thiazolyl) or an optionally substituted oxazolyl (e.g., an optional
  • A is as described herein for formula (I); L is a bond; L 4 is an optionally substituted alkylene hylene); R 3 , R 5 , and R 7B
  • R 4 is an optionally substituted aryl (e.g., phenyl, 3,5-difluorophenyl, or 3- fluorophenyl);
  • R 6 is a hydrogen, halogen (e.g., F), an optionally substituted -0(C 1 -Cs)alkyl (e.g., methyl, ethyl, propyl, optionally substituted with 1, 2, or 3 fluoro groups), an optionally substituted (Q-Cs ⁇ lkyl (e.g., methoxy, ethyloxy, propoxy, optionally substituted with 1, 2, or 3 fluoro groups); and
  • R 7A is hydrogen, halogen, -OH, -N(R 8 )R 9 , -OR 10 , or an optionally substituted moiety selected from alkyl, -alkyl-OR 10 , -alkyl-N(R 8 )R 9 , heterocycloalkyl, heterocyclo
  • the compound is a compound of formula (lb), wherein A 1 is
  • 2-thiazolyl e.g., 2-(4-substituted)thiazolyl
  • A is , wherein L 2 is an optionally substituted 3
  • L is a bond or an optionally substituted methylene, and each R 20 and R 22 is independently hydrogen or an optionally substituted alkyl;
  • L 1 is a bond;
  • L 4 is methylene;
  • R 3 , R 5 , R 6 , R 7A , and R 7B are each hydrogen;
  • R 4 is phenyl, 3,5 di-fluorophenyl,or 3-fluorophenyl; or a pharmaceutically acceptable salt or solvate thereof.
  • L is an optionally substituted C 2 -C 4 alkylene and L is a bond.
  • the compound is a compound of formula (lb), wherein A 1 is an optionally substituted 2-oxazolyl (e.g., such as a 2-(4-substituted)oxazolyl); A is
  • L is a bond or an optionally substituted methylene
  • L 1 and L 4 are each methylene
  • R 3 , R 5 , R 7A , and R 7B are each hydrogen
  • R 4 is phenyl, 3,5 di-fluorophenyl, or 3-fluorophenyl; or a pharmaceutically acceptable salt or solvate thereof.
  • L is an optionally substituted C 2 -C 4 alkylene and L is a bond.
  • the compound has the formula (lib):
  • a 1 is an optionally substituted heteroaryl
  • R 6 is hydrogen, halogen, or an optionally substituted alkyl
  • t is 0, 1 or 2
  • R 4 is an optionally substituted aryl
  • R 7A and R 7B are independently hydrogen, halogen, or an optionally substituted alkyl; or a pharmaceutically acceptable salt or solvate thereof.
  • a 1 is an optionally substituted thiazolyl or an optionally substituted oxazolyl
  • R 6 is a hydrogen or halogen (e.g.
  • t is 1 or 2; R 4 is an optionally substituted phenyl; and R 7A and R 7B are independently hydrogen, halogen, or an optionally substituted alkyl; or a pharmaceutically acceptable salt or solvate thereof.
  • a 1 is (4-methyl)thiazol-2-yl or (4- methyl)oxazol-2-yl.
  • R 6 is hydrogen.
  • R 6 is halogen (e.g. fluoro).
  • t is 0.
  • t is 1.
  • t is 2.
  • R 4 is phenyl, 3-fluorophenyl or 3,5-difluorophenyl.
  • each R and R is hydrogen.
  • the compound has the formula (lib- 1): wherein, A 1 is an optionally substituted heteroaryl; R 6 is hydrogen, halogen, or an optionally substituted alkyl; t is 0, 1 or 2; and R 4 is an optionally substituted aryl; or a pharmaceutically acceptable salt or solvate thereof.
  • a 1 is an optionally substituted thiazolyl or an optionally substituted oxazolyl; R 6 is a hydrogen or halogen (e.g. fluoro); t is 1 or 2; and R 4 is an optionally substituted phenyl; or a pharmaceutically acceptable salt or solvate thereof.
  • a 1 is (4-methyl)thiazol-2- yl or (4-methyl)oxazol-2-yl.
  • R 6 is hydrogen.
  • R 6 is halogen (e.g. fluoro).
  • t is 0.
  • t is 1.
  • t is 2.
  • R 4 is phenyl, 3-fluorophenyl or 3,5-difluorophenyl.
  • the compound has the formula (IIb-2):
  • A is an optionally substituted thiazolyl or an optionally substituted oxazolyl; t is 0, 1 or 2; and R 4 is an optionally substituted phenyl; or a pharmaceutically acceptable salt or solvate thereof.
  • a 1 is (4-methyl)thiazol-2-yl or (4- methyl)oxazol-2-yl. In some of these embodiments, A 1 is (4-methyl)thiazol-2-yl.
  • t is 0. In some of these embodiments, t is 1. In some of these embodiments, t is 2.
  • R 4 is phenyl, 3-fluorophenyl or 3,5- difluorophenyl.
  • the compound has the formula (lie):
  • a 1 is an optionally substituted heteroaryl
  • R 6 and R 6A are independently hydrogen, halogen, or an optionally substituted alkyl
  • t is 0, 1 or 2
  • R 4 is an optionally substituted aryl
  • R 7 , A rt and R 7B are independently hydrogen, halogen, or an optionally substituted alkyl; or a pharmaceutically acceptable salt or solvate thereof.
  • a 1 is an optionally substituted thiazolyl or an optionally substituted oxazolyl
  • R 6 and R 6A are independently hydrogen or halogen (e.g. fluoro); t is 1 or 2;
  • R 4 is an optionally substituted phenyl;
  • R 7 A and R 7B are independently hydrogen, halogen, or an optionally substituted alkyl; or a pharmaceutically acceptable salt or solvate thereof.
  • a 1 is (4-methyl)thiazol-2-yl or (4-methyl)oxazol-2-yl.
  • R 6 and R 6A are independently halogen.
  • each R 6 and R 6A is fluoro.
  • t is 0.
  • t is 1.
  • t is 2.
  • R 4 is phenyl, 3- fluorophenyl or 3,5-difluorophenyl.
  • each R 7 A and R 7B is hydrogen.
  • the compound has the formula (lid):
  • a 1 is an optionally substituted heteroaryl
  • R 6 is hydrogen, halogen, or an optionally substituted alkyl
  • t is 0, 1 or 2
  • R 4 is an optionally substituted aryl
  • R 7A and R 7B are independently hydrogen, halogen, or an optionally substituted alkyl; or a pharmaceutically acceptable salt or solvate thereof.
  • a 1 is an optionally substituted thiazolyl or an optionally substituted oxazolyl
  • R 6 is a hydrogen or halogen (e.g. fluoro)
  • t is 0, 1 or 2
  • R 4 is an optionally substituted phenyl
  • R 7A and R 7B are
  • a 1 is (4-methyl)thiazol-2- yl or (4-methyl)oxazol-2-yl.
  • R 6 is hydrogen.
  • R 6 is halogen (e.g. fluoro).
  • t is 0.
  • t is 1.
  • t is 2.
  • R 4 is phenyl, 3-fluorophenyl or 3,5-difluorophenyl.
  • each R 7 A and R 7B is hydrogen.
  • the compound has the formula (Illb):
  • a 1 is an optionally substituted heteroaryl
  • R 6 is hydrogen, halogen, or an optionally substituted alkyl
  • t is 0, 1 or 2
  • R 4 is an optionally substituted aryl
  • R 7A and R 7B are independently hydrogen, halogen, or an optionally substituted alkyl; or a pharmaceutically acceptable salt or solvate thereof.
  • a 1 is an optionally substituted thiazolyl or an optionally substituted oxazolyl
  • R 6 is a hydrogen or halogen (e.g.
  • R 4 is an optionally substituted phenyl
  • R 7A and R 7B are independently hydrogen, halogen, or an optionally substituted alkyl; or a pharmaceutically acceptable salt or solvate thereof.
  • a 1 is (4-methyl)thiazol-2-yl or (4- methyl)oxazol-2-yl.
  • R 6 is hydrogen.
  • R 6 is halogen (e.g. fluoro).
  • t is 0.
  • t is 1.
  • t is 2.
  • R 4 is phenyl, 3-fluorophenyl or 3,5-difluorophenyl.
  • each R 7 A and R 7B is hydrogen.
  • the compound has the formula (IIIb-1): wherein, A 1 is an optionally substituted heteroaryl; R 6 is hydrogen, halogen, or an optionally substituted alkyl; t is 0, 1 or 2; and R 4 is an optionally substituted aryl; or a pharmaceutically acceptable salt or solvate thereof.
  • a 1 is an optionally substituted thiazolyl or an optionally substituted oxazolyl; R 6 is a hydrogen or halogen (e.g. fluoro); t is 1 or 2; and R 4 is an optionally substituted phenyl; or a pharmaceutically acceptable salt or solvate thereof.
  • a 1 is (4-methyl)thiazol-2- yl or (4-methyl)oxazol-2-yl.
  • R 6 is hydrogen.
  • R 6 is halogen (e.g. fluoro).
  • t is 0.
  • t is 1.
  • t is 2.
  • R 4 is phenyl, 3-fluorophenyl or 3,5-difluorophenyl.
  • the compound has the formula (IIIb-2):
  • A is an optionally substituted thiazolyl or an optionally substituted oxazolyl; t is 0, 1 or 2; and R 4 is an optionally substituted phenyl; or a pharmaceutically acceptable salt or solvate thereof.
  • a 1 is (4-methyl)thiazol-2-yl or (4- methyl)oxazole-2-yl. In some of these embodiments, A 1 is (4-methyl)thiazol-2-yl.
  • t is 0. In some of these embodiments, t is 1. In some of these embodiments, t is 2.
  • R 4 is phenyl, 3-fluorophenyl or 3,5- difluorophenyl.
  • the compound has the formula (IIIc): wherein, A 1 is an optionally substituted heteroaryl; R 6 and R 6A are independently hydrogen, halogen, or an optionally substituted alkyl; t is 0, 1 or 2; R 4 is an optionally substituted aryl;
  • R ,rt and R are independently hydrogen, halogen, or an optionally substituted alkyl; or a pharmaceutically acceptable salt or solvate thereof.
  • a 1 is an optionally substituted thiazolyl or an optionally substituted oxazolyl
  • R 6 and R 6A are independently hydrogen or halogen (e.g. fluoro); t is 1 or 2;
  • R 4 is an optionally substituted
  • phenyl and R and R are independently hydrogen, halogen, or an optionally substituted alkyl; or a pharmaceutically acceptable salt or solvate thereof.
  • a 1 is (4-methyl)thiazol-2-yl or (4-methyl)oxazol-2-yl.
  • R 6 and R 6A are independently halogen. In some of these embodiments, each R 6 and R 6A is fluoro. In some of these embodiments, t is 0. In some of these embodiments, t is 1. In some of these embodiments, t is 2. In some of these embodiments, R 4 is phenyl, 3-
  • each R and R is hydrogen.
  • the compounds described herein is in substantially pure form.
  • substantially pure intends a preparation of the compound that contains no more than 25 % impurity, wherein the impurity intends compounds other than the indicated inhibitor compound, but does not include other forms of the inhibitor compound (e.g., different salt form or a different stereoisomer, conformer, rotamer, or tautomer of the compound depicted).
  • a preparation of substantially pure compound wherein the preparation contains no more than 25 % impurity, or no more than 20 % impurity, or no more than 10 % impurity, or no more than 5 % impurity, or no more than 3 % impurity, or no more than 1 % impurity, or no more than 0.5 % impurity.
  • the compound is present with no more than 15% or no more than 10% or no more than 5% or no more than 3% or no more than 1% of the total amount of compound in a different stereochemical form (e.g. , when the an S,S compound no more than 15% or no more than 10% or no more than 5% or no more than 3% or no more than 1% of the total R,R; S,R; and R,S form is present).
  • the compounds described herein include all solvate and/or hydrate forms.
  • the compounds described herein can exist in unsolvated forms as well as solvated forms (i.e., solvates).
  • the compounds may also include hydrated forms (i.e. , hydrates).
  • the compounds described herein include all salt forms of the compounds.
  • the compounds also include all non-salt forms of any salt of a compound described herein, as well as other salts of any salt of a compound described herein.
  • the salts of the compounds are pharmaceutically acceptable salts.
  • the desired salt of a basic functional group of a compound may be prepared by methods known to those of skill in the art by treating the compound with an acid.
  • the desired salt of an acidic functional group of a compound can be prepared by methods known to those of skill in the art by treating the compound with a base.
  • Examples of inorganic salts of acid compounds include, but are not limited to, alkali metal and alkaline earth salts, such as sodium salts, potassium salts, magnesium salts, bismuth salts, and calcium salts; ammonium salts; and aluminum salts.
  • Examples of organic salts of acid compounds include, but are not limited to, procaine, dibenzylamine, N-ethylpiperidine, N,N'-dibenzylethylenediamine, trimethylamine, and triethylamine salts.
  • Examples of inorganic salts of base compounds include, but are not limited to, hydrochloride and hydrobromide salts.
  • organic salts of base compounds include, but are not limited to, tartrate, citrate, maleate, fumarate, and succinate.
  • the compounds in the salt form of hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g., (-i-)-tartrates, (-)-tartrates or mixtures thereof including racemic mixtures), succinates, benzoates and salts with amino acids such as glutamic acid.
  • the compounds described herein exist as a citrate salt (e.g., mono citrate, hydrogen citrate, or dihydrogen citrate) and/or a mesylate salt (e.g. , dimesylate). These salts may be prepared by methods known to those skilled in the art. [0157]
  • the neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the desired compound (e.g., any compound of formula I, II, III, or variations thereof, Example 2 and/or Table 1).
  • prodrugs can be converted to the compounds described herein by chemical or biochemical methods in an ex vivo environment.
  • prodrugs can be slowly converted to the compounds described herein when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
  • Metabolites of the compounds are also embraced. Metabolites may include primary metabolites and/or secondary metabolites. However, metabolites of substances which occur naturally in subjects are excluded from the claimed compounds.
  • stereochemistry is explicitly indicated in a chemical structure or chemical name
  • the chemical structure or chemical name is intended to embrace all possible stereoisomers, conformers, rotomers, and tautomers of the compound depicted.
  • a compound containing a chiral carbon atom is intended to embrace both the (R) enantiomer and the (S) enantiomer.
  • a compound containing multiple chiral carbon atoms is intended to embrace all enantiomers and diastereomers (including (R,R), (S,S), (R,S), and (R,S) isomers).
  • a compound is explicitly indicated in a particular stereochemical arrangement (e.g. , 2S,3R for the
  • the compound may, in other embodiments, be described in another specific stereochemical arrangement (e.g., 2R,3S for the hydroxyethylamine isostere) and/or a mixture of stereochemical arrangements.
  • another specific stereochemical arrangement e.g., 2R,3S for the hydroxyethylamine isostere
  • a composition may contain the compound as mixtures of such stereoisomers, where the mixture may be enantiomers (e.g. , S,S and R,R) or diastereomers (e.g. , S,S and R,S or S,R) in equal or unequal amounts.
  • a composition may contain the compound as a mixture of 2 or 3 or 4 such stereoisomers in any ratio of stereoisomers.
  • a 2 is or , wherein L 2 , L 3 , R 20 , R : and R 22 are as described herein for formula (I).
  • A is , wherein L 2 , L 3 , R 20 ,
  • R and R are as described herein for formula (I).
  • A is , wherein L ,
  • L 3 , R 20 , R 21 and R 2"2 are as described herein for formula (I) or (la).
  • a 1 , A 2 , L 1 , L 4 , R 2 , R 3 , R 4 , R 5 , R 7A , and R 7B are as described herein for formula (I) or
  • L 3 , R 20 , R 21 and R 2"2 are as described herein for formula (I) or (la).
  • a 2 is , wherein L 2 , L 3 ,
  • R 20 , R 21 and R 2"2 are as described herein for formula (I) or (lb).
  • R 20 , R 21 and R 2"2 are as described herein for formula (I) or (lb).
  • A is , wherein L 2 , L 3 ,
  • R 20 , R 21 and R 2"2 are as described herein for formula (I) or (lb).
  • a 1 , A 2 , L 1 , L 4 , R 3 , R 4 , R 5 , R 6 , R 6A , R 7A , and R 7B are as described herein for formula
  • A is , wherein
  • a 1 , R 6 , R 4 and t are as described herein for formula (II) or (IIb-1).
  • a 1 , R 6 , R 6A , R 4 and t are as described herein for formula (II) or (lie).
  • a 1 , R 6 , R 4 and t are as described herein for formula (III) or (IIb-1).
  • a 1 , R 6 , R 4 and t are as described herein for formula (III) or (IIb-1).
  • the compounds herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine- 125 ( 125 I) or carbon- 14 ( 14 C). All isotopic variations of the compounds herein, whether radioactive or not, are contemplated.
  • the compounds herein are synthesized by an appropriate combination of generally well-known synthetic methods. Techniques useful in synthesizing the compounds herein are both readily apparent and accessible to those of skill in the relevant art in light of the teachings described herein. The discussion below is offered to illustrate certain of the diverse methods available for use in assembling the compounds herein. However, the discussion is not intended to define the scope of reactions or reaction sequences that are useful in preparing the compounds herein.
  • a method for synthesizing the inhibitor compounds described herein is by adapting the synthesis for N-((lR,2S)-l-hydroxy-3-phenyl-l-((R)-pyrrolidin-2-yl)propan-2-yl)-5-((R)- 2-(4-methylthiazol-2-yl)pyrrolidine-l-carbonyl)chroman-7-carboxamide (14) below.
  • Scheme 1 shows an exemplary synthesis of a hydroxyamine pyrrolidine fragment (3).
  • (S)-2-(dibenzylamino)-3-phenylpropan-l-ol (1) can be oxidized and the resulting aldehyde coupled with N-Boc-pyrrolidine in the presence of (-)-sparteine to form the coupling product (R)-tert-butyl 2-((lS,2S)-2-(dibenzylamino)-l-hydroxy-3- phenylpropyl)pyrrolidine-l-carboxylate (2).
  • the coupling product can then be debenzylated under standard hydro genation conditions. The conditions for these reactions are as described in the Experimental section below.
  • Scheme 2 shows an exemplary synthesis of desired inhibitor 14.
  • Diene 4 can be cyclized under olefin metathesis conditions to form chromene 5 which can then be hydrogenated to form chroman 6.
  • Monoester hydrolysis followed by coupling with pyrrolidine 9 yields a mixture of esters 10 and 11.
  • Chromatographic separation of the two esters followed by hydrolysis of the minor product yields carboxylic acid 12.
  • This acid can then be coupled with the aforementioned pyrrolidine 3 to form the Boc protected product 13.
  • candidate inhibitors capable of selectively mediating, e.g., decreasing, memapsin 2 catalytic activity may be identified in vitro and subsequently tested for their ability to reduce the production of ⁇ .
  • the activity of the inhibitor compounds can be assayed utilizing methods known in the art and/or those methods presented herein.
  • Memapsin 2 can be found in native cells, isolated in vitro, or co-expressed or expressed in a cell.
  • Measuring the reduction in the memapsin 2 catalytic activity in the presence of an inhibitor relative to the activity in the absence of the inhibitor may be performed using a variety of methods known in the art.
  • the compounds may be tested for their ability to cause a detectable decrease in hydrolysis of a ⁇ -secretase site of a peptide in the presence of memapsin 2.
  • Kj is the inhibition equilibrium constant which indicates the ability of compounds to inhibit a given enzyme (such as memapsin 2, memapsin 1, and/or cathepsin D).
  • Kj value is independent of the substrate concentration, and converted from Kj apparent.
  • K; apparent is determined in the presence of substrate according to established techniques (see, for example, Bieth, J., Bayer-Symposium V: Proteinase Inhibitors, pp. 463- 469, Springer- Verlag, Berlin (1994)).
  • the standard error for the Kj apparent is the error from the nonlinear regression of the Vi/V 0 data measured at different concentrations of the compounds herein (e.g., between about 10 nM to about 1000 nM) employing well-known techniques (see, for example, Bieth, J., Bayer-Symposium V: Proteinase Inhibitors, pp.
  • V/V o depicts the ratio of initial conversion velocities of a substrate (Ermolieff, et ah, Biochemistry 40:12450-12456 (2000)) by an enzyme in the absence (V 0 ) or presence (Vj) of an inhibitor.
  • a VyV o value of 1.0 indicates that a compound does not inhibit the enzyme at the
  • Vi/V 0 value less than 1.0 indicates that a compound herein inhibits enzyme activity.
  • the compounds described herein are capable of reducing memapsin 2 beta-secretase activity.
  • the compounds have a memapsin 2 beta-secretase Kj and/or Kj apparent (e.g., using any inhibitory assay described herein) of less than about any one of 10 ⁇ , 5 ⁇ , 1 ⁇ , or less than about any one of 750, 500, 400, 300, 200, 100, 50, 25, 10, 5, 2, or 1 nM; or from about 1 to 5, 1 to 10, 1 to 100, 1 to 300, 1 to 500, 1 to 1000, 100 to 500, 200 to 500, 300 to 500, 100 to 750, 200 to 750, 300 to 750, 400 to 750, 500 to 750, 100 to 1000, 250 to 1000, 500 to 1000, or 750 to 1000 nM.
  • the compounds have a memapsin 2 beta-secretase K; and/or K; apparent (e.g., using any inhibitory assay described herein) of less than about 300, 301 to 500, or greater than 501 nM.
  • memapsin 2 beta-secretase K and/or K; apparent (e.g., using any inhibitory assay described herein) of less than about 300, 301 to 500, or greater than 501 nM.
  • the other enzyme is a peptide hydrolase, such as memapsin 1 or cathepsin D; or from another family of interest, such as Cytochrome P450 3A4 (CYP3A4).
  • a peptide hydrolase such as memapsin 1 or cathepsin D
  • CYP3A4 Cytochrome P450 3A4
  • Compounds that decrease cathepsin D catalytic activity or memapsin 1 catalytic activity are tested using biologically active enzyme, either recombinant or naturally occurring.
  • Cathepsin D or memapsin 1 catalytic activity can be found in native cells, isolated in vitro, or co- expressed or expressed in a cell. Inhibition by a compound described herein is measured using standard in vitro or in vivo assays such as those well known in the art or as otherwise described herein.
  • selectivity of a compound may be measured by determining the extent to which memapsin 2 hydrolyzes a substrate peptide compared to the extent to which the same compound inhibits memapsin 1 and/or cathepsin D cleaving of a substrate peptide in the presence of the compound.
  • Exemplary substrate peptides that are useful in determining the activity of memapsin 2 and or memapsin 1 include APP and derivatives thereof, such as FS-2 (MCA-SEVNLDAEFK-DNP; SEQ ID NO.: 2) (Bachem Americas, Torrance, CA).
  • Exemplary substrate peptides that are useful in determining the activity of cathepsin D include, for example, peptides which include the sequence MCA-GKPILFFRLK(DNP)-dR (SEQ ID NO.: 1). These substrate peptides can be synthesized using known peptide synthesis methods, e.g., solid-phase peptide synthesis (e.g., FMOC amino acid coupling etc.). These data can be expressed, for example, as Ki, Ki apparent, Vi/Vo, or percentage inhibition and depict the inhibition of a compound for memapsin 2 catalytic activity relative to memapsin 1 or cathepsin D catalytic activity.
  • the inhibitor compound inhibits the ⁇ - secretase activity of memapsin 2 with ten-fold selectivity over memapsin 1 or cathepsin D.
  • the compounds described herein may be capable of selectively inhibiting memapsin 2 over Cytochrome P450 3A4 (CYP3A4).
  • CYP3A4 plays an important role in the
  • CYP3A4 metabolism of xenobiotics. Inhibition of CYP3A4 can lead to unwanted drug-drug interactions by modulating the metabolism of other therapeutics. Many patients, particularly those patients in advanced age seeking treatment for conditions such as Alzheimer's disease, are prescribed multiple therapeutics for various conditions, wherein drug-drug interactions caused by inhibition of CYPAA4 would be highly undesirable. Accordingly, the ability to selectively inhibit memapsin 2 over CYP3A4 (e.g. , not effect or minimally effect CYP3A4) may aid in decreasing unwanted drug-drug interacations leading to decreased toxicity and increased effectiveness of beta-secretase inhibitors. Some compounds described herein have been shown to exhibit strikingly selective inhibition of memapsin 2 in the presence of Cytochrome P450 3A4.
  • the compounds described herein are capable of selectively reducing memapsin 2 relative to memapsin 1, cathepsin D and/or CYP3A4.
  • the compounds are capable of selectively reducing memapsin 2 relative to memapsin 1, cathepsin D, and/or CYP3A4 with greater than about 2-fold selectivity, or greater than about any one of 3, 5, 7, 10, 25, 50, 75, 100, 300, 200, 500, 750, 1000, 2000, 5000, or 10000-fold selectivity.
  • the compounds have a memapsin 2 beta-secretase K; and/or K; apparent (e.g., using any inhibitory assay described herein) of less than about 10 ⁇ , 5 ⁇ , 1 ⁇ , or less than about any one of 750, 500, 400, 300, 250, 200, 100, 75, 50, 25, 10, 5, 2, or 1 nM, or from about any of 1 to 5, 1 to 10, 1 to 100, 1 to 250, 1 to 500, 1 to 1000, 100 to 500, 200 to 500, 300 to 500, 100 to 750, 200 to 750, 250 to 750, 300 to 750, 400 to 750, 500 to 750, 100 to 1000, 250 to 1000, 500 to 1000, or 750 to 1000 nM; and have a memapsin 1 and/or cathepsin D Kj and/or Kj apparent of more than about 10 ⁇ , 5 ⁇ , 1 ⁇ , or more than about any one of 750, 500, 400, 300, 200, 100, 50, 25, 10, 5, 2,
  • the compounds have a memapsin 2 beta-secretase Kj and/or Kj apparent (e.g., using any inhibitory assay described herein) of less than about 10 ⁇ , 5 ⁇ , 1 ⁇ , or less than about any one of 750, 500, 400, 300, 250, 200, 100, 50, 25, 10, 5, 2, or 1 nM, or from about any of 1 to 5, 1 to 10, 1 to 100, 1 to 250, 1 to 500, 1 to 1000, 100 to 500, 200 to 500, 300 to 500, 100 to 750, 200 to 750, 250 to 750, 400 to 750, 500 to 750, 100 to 1000, 250 to 1000, 500 to 1000, or 750 to 1000 nM; and have a CYP3A4 K ; and/or K ; apparent of more than about 100 ⁇ , 50 ⁇ , 25 ⁇ , 10 ⁇ , 5 ⁇ , 1 ⁇ , or more than about any one of 750, 500, 400, 300, 200, 100, 50, 25, 10, 5, 2, or 1
  • ⁇ -secretase site of a peptide in the presence of memapsin 2 may be tested in cell models or animal models for their ability to cause a detectable decrease in the amount or production of ⁇ -amyloid protein ( ⁇ ).
  • isosteric inhibitors of memapsin 2 have been tested for their ability to decrease ⁇ production in cultured cells (see U.S. Patent Application Publication No. 20040121947, International Application No. PCT/US02/34324 (Publication No. WO 03/039454), and International Application No. PCT/US06/13342 (Publication No. WO 06/110668, the contents of which are hereby incorporated by reference)).
  • inhibitors may be added to a culture of cells (e.g., human embryonic kidney (HEK293) cells, HeLa cells, Chinese hamster ovary cells, or neuroblastoma line SK-N-BE(2)) stably transfected if needed with a nucleic acid constructs that encode human APP and, if needed, a nucleic acid construct encoding human memapsin 2.
  • HEK293 human embryonic kidney
  • HeLa cells HeLa cells
  • Chinese hamster ovary cells or neuroblastoma line SK-N-BE(2)
  • a nucleic acid constructs that encode human APP and, if needed, a nucleic acid construct encoding human memapsin 2.
  • electrophoresis allows detection and quantitation of the amount of ⁇ produced in the presence and absence of inhibitor.
  • animal models may be used to test inhibitors of memapsin 2 for their ability to decrease ⁇ production.
  • an animal e.g. , rat
  • the plasma may then be collected and ⁇ levels determined by capture ELISA (BioSource International, Camarillo, CA).
  • the compounds described herein are capable of reducing cellular ⁇ production.
  • the compounds are capable of reducing cellular ⁇ production with a IC50 (e.g., using an ⁇ inhibitory assay described herein) of less than about 10 ⁇ , 5 ⁇ , 1 ⁇ , or less than about 750, 500, 400, 300, 200, 100, 50, 25, 10, 5, 2, or 1 nM, or from about 1 to 5, 1 to 10, 1 to 100, 1 to 300, 1 to 500, 1 to 1000, 100 to 500, 200 to 500, 300 to 500, 100 to 750, 200 to 750, 300 to 750, 400 to 750, 500 to 750, 100 to 1000, 250 to 1000, 500 to 1000, or 750 to 1000 nM.
  • the compounds are capable of reducing cellular ⁇ production with a IC50 (e.g., using an ⁇ inhibitory assay described herein) of less than about 10 ⁇ , 5 ⁇ , 1 ⁇ , or less than about 750, 500, 400, 300, 200, 100, 50
  • compartments may be ascertained using a fluorescent tag conjugated to the inhibitor and visualization via confocal microscopy (see U.S. Patent Application Publication No. 20040121947, and International Application No. PCT/US02/34324 (Publication No. WO 03/039454), the contents of which are hereby incorporated by reference in their entirities).
  • the sample obtained from the mammal can be a fluid sample, such as a plasma or serum sample; or can be a tissue sample or extract, such as a brain biopsy.
  • the amount of ⁇ - amyloid protein or a decrease in the production of ⁇ -amyloid protein can be measured using standard techniques (e.g., western blotting and ELISA assays).
  • the compounds herein may have one or more favorable pharmacokinetic properties.
  • the ability for a beta-secretase inhibitor compound to resist hepatic clearance in an individual will result in the compound being available as a therapeutic for a longer duration, which may aid in e.g., lower dosage and/or less frequent dosing.
  • beta-secretase inhibitor compounds with decreased hepatic clearance may have the advantages of potentially decreasing toxicity and may improve patient compliance.
  • Some compounds described herein have been shown to exhibit strikingly lower hepatic intrinsic clearance properties.
  • the compounds described herein e.g., any compound of formula I, II, III, or any variations thereof, Example 2 and/or Table 1 have a hepatic intrinsic clearance in liver microsomes of less than any of about 1000 mL/min/kg, 900 mL/min/kg, 800 mL/min/kg, 700 mL/min/kg, 600 mL/min/kg, 500 mL/min/kg, 300 mL/min/kg , 200 mL/min/kg, 150 mL/min/kg, 100 mL/min/kg, 75 mL/min/kg, 50
  • the compounds herein may have favorable oral absorption.
  • Oral absorption is estimated as the area under the curve (AUC) of an active drug in systemic circulation following oral administration relative to the AUC of the same drug following intravenous administration.
  • AUC area under the curve
  • beta-secretase inhibitor compounds with enhanced AUC after oral dosage may have superior oral absorption.
  • Some compounds described herein have been shown to exhibit surprisingly high AUC after oral administration.
  • the compounds described herein e.g., any compound of formula I, II, III, or any variations thereof, Example 2 and/or Table 1 have an AUC more than any of about 10 hrng/ml, 50 hrng/ml, 100 hrng/ml, 200 hrng/ml, 500 hrng/ml, 1000 hrng/ml, 2000 hrng/ml, or 5000 hrng/ml, as measured in rat after an oral dose of 10 mg/kg of the drug is administered (see Examples section for assay details).
  • formulations comprising a memapsin 2 ⁇ -secretase inhibitor compound(e.g., any compound of formula I, II, III, or any variations thereof, Example 2 and/or Table 1) with a carrier, such as a pharmaceutically acceptable carrier.
  • a carrier such as a pharmaceutically acceptable carrier.
  • the formulations may include optical isomers, diastereomers, or pharmaceutically acceptable salts of the inhibitors disclosed herein.
  • the memapsin 2 ⁇ -secretase inhibitor included in the formulation may be covalently attached to a carrier moiety, as described above. Alternatively, the memapsin 2 ⁇ -secretase inhibitor included in the formulation is not covalently linked to a carrier moiety.
  • Suitable pharmaceutically acceptable carriers include water, salt solutions (such as Ringer's solution), alcohols, oils, gelatins and carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, and polyvinyl pyrrolidine.
  • salt solutions such as Ringer's solution
  • alcohols such as Ringer's solution
  • oils such as Ringer's solution
  • gelatins such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, and polyvinyl pyrrolidine.
  • preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like which preferably do not deleteriously react with the intended compound of use.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like which preferably do not deleteriously react with the intended compound of use.
  • Coadministered to the individual.
  • Coadministration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound).
  • the preparations can also be combined, when desired, with other active substances related to the treatment of a specified condition (e.g., to reduce metabolic degradation).
  • ⁇ -secretase inhibitors described herein can be prepared and administered in a wide variety of oral, parenteral and topical dosage forms.
  • the compounds herein can be administered by injection (e.g. , intravenously, intramuscularly, intracutaneously,
  • the compounds described herein can be administered by inhalation, for example, intranasally. Additionally, the compounds herein can be administered transdermally. Compounds herein may also be administered locally (e.g. , ocular administration such as topical eye drops or ointment). It is also envisioned that multiple routes of administration (e.g. , intramuscular, oral, transdermal) can be used to administer the inhibitor compounds described herein. Accordingly, also provided are pharmaceutical formulations comprising a pharmaceutically acceptable carrier or excipient and one or more inhibitor compounds described herein(e.g., any compound of formula I, II, III, or any variations thereof, Example 2 and/or Table 1).
  • pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substance, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid, which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from 5% to 70% of the active compound.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium
  • carboxymethylcellulose a low melting wax, cocoa butter, and the like.
  • preparation is intended to include the formulation of the active compound with
  • encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed
  • the molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions.
  • liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
  • admixtures for the compounds herein are injectable, sterile solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants, including suppositories.
  • carriers for parenteral administration include aqueous solutions of dextrose, saline, pure water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene-block polymers, and the like.
  • Ampules are convenient unit dosages.
  • the compounds herein can also be incorporated into liposomes or administered via transdermal pumps or patches.
  • Ocular administration preparations include, but are not limited to, formulations in saline, optionally with additional carriers, stabalizers, etc. know to those of skill in the art.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the pharmaceutical preparation is preferably in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • unit dosage forms comprising the formulations described herein. These unit dosage forms can be stored in a suitable packaging in single or multiple unit dosages and may also be further sterilized and sealed.
  • the pharmaceutical formulation e.g., a dosage or unit dosage form of a pharmaceutical formulation
  • the pharmaceutical formulation may include (i) an in inhibitor (e.g., any compound of formula I, II, III, or any variations thereof, Example 2 and/or Table 1) and (ii) a pharmaceutically acceptable carrier.
  • the formulation also includes one or more other compounds (or pharmaceutically acceptable salts thereof).
  • the amount of inhibitor compound in the formulation is included in any of the following ranges: about 5 to about 50 mg, about 20 to about 50 mg, about 50 to about 100 mg, about 100 to about 125 mg, about 125 to about 150 mg, about 150 to about 175 mg, about 175 to about 200 mg, about 200 to about 225 mg, about 225 to about 250 mg, about 250 to about 300 mg, about 300 to about 350 mg, about 350 to about 400 mg, about 400 to about 450 mg, or about 450 to about 500 mg.
  • the amount of compound in the formulation is in the range of about 5 mg to about 500 mg, such as about 30 mg to about 300 mg or about 50 mg to about 200 mg, of the compound.
  • Some compounds may have limited solubility in water and therefore may require a surfactant or other appropriate co-solvent in the composition.
  • co-solvents include: Polysorbate 20, 60 and 80; Pluronic F-68, F-84 and P-103; cyclodextrin; polyoxyl 35 castor oil; or other agents known to those skilled in the art.
  • co-solvents are typically employed at a level between about 0.01 % and about 2% by weight.
  • Viscosity greater than that of simple aqueous solutions may be desirable to decrease variability in dispensing the formulations, to decrease physical separation of components of a suspension or emulsion of formulation and/or otherwise to improve the formulation.
  • Such viscosity building agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose, chondroitin sulfate and salts thereof, hyaluronic acid and salts thereof, combinations of the foregoing, and other agents known to those skilled in the art.
  • Such agents are typically employed at a level between about 0.01 and about 2% by weight. Determination of acceptable amounts of any of the above adjuvants is readily ascertained by one skilled in the art.
  • the formulations described may additionally include components to provide sustained release and/or comfort.
  • Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides and finely-divided drug carrier substrates. These components are discussed in greater detail in U.S. Pat. Nos. 4,911,920; 5,403,841; 5,212,162; and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes.
  • compositions described include formulations wherein the active ingredient (e.g., any compound of formula I, II, III, or any variations thereof, Example 2 and/or Table 1) is contained in an effective amount, i.e., in an amount effective to achieve its intended purpose.
  • the actual amount effective for a particular application will depend, inter alia, on the condition being treated. For example, when administered in methods to treat Alzheimer's disease, such compositions will contain an amount of active ingredient effective to achieve the desired result ⁇ e.g., decreasing ⁇ -secretase activity or ⁇ -amyloid production). Determination of an effective amount of a compound herein is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure herein.
  • the dosage and frequency (single or multiple doses) administered to a mammal can vary depending upon a variety of factors, including a disease that results in increased activity of memapsin 2 or increased accumulation of ⁇ -amyloid protein, whether the mammal suffers from another disease, and its route of administration; size, age, sex, health, body weight, body mass index, and diet of the recipient; nature and extent of symptoms of the disease being treated (e.g. , Alzheimer's disease), kind of concurrent treatment, complications from the disease being treated or other health-related problems.
  • Other therapeutic regimens or agents can be used in conjunction with the methods and compounds described herein. Adjustment and manipulation of established dosages (e.g. , frequency and duration) are well within the ability of those skilled in the art.
  • the effective amount can be initially determined from cell culture assays.
  • Target concentrations will be those concentrations of active compound(s) that are capable of reducing the activity of memapsin 2 activity, as measured using the methods described herein or known in the art.
  • therapeutically effective amounts for use in humans can also be determined from animal models.
  • a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals.
  • the dosage in humans can be adjusted by monitoring memapsin 2 inhibition and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods as are well-known in the art is well within the capabilities of the ordinarily skilled artisan, particularly in view of the teaching provided herein.
  • Dosages may be varied depending upon the requirements of the individual and the compound being employed.
  • the dose administered to an individual should be sufficient to affect a beneficial therapeutic response in the individual over time.
  • the size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects.
  • the dosage range is 0.001% to 10% w/v. In another embodiment, the dosage range is 0.1% to 5% w/v.
  • Additional examples of dosages which can be used are an effective amount within the dosage range of about 0.1 g/kg to about 300 mg/kg, or within about 1.0 g/kg to about 40 mg/kg body weight, or within about 1.0 g/kg to about 20 mg/kg body weight, or within about 1.0 g/kg to about 10 mg/kg body weight, or within about 10.0 ⁇ g/kg to about 10 mg/kg body weight, or within about 100 ⁇ g/kg to about 10 mg/kg body weight, or within about 1.0 mg/kg to about 10 mg/kg body weight, or within about 10 mg/kg to about 100 mg/kg body weight, or within about 50 mg/kg to about 150 mg/kg body weight, or within about 100 mg/kg to about 200 mg/kg body weight, or within about 150 mg/kg to about 250 mg/kg body weight, or within about 200 mg/kg to about 300 mg/kg body weight, or within about 250 mg/kg to about 300 mg/kg body weight.
  • Other dosages which can be used are about 0.01 mg/kg body weight, about 0.1 mg/kg body weight, about 1 mg/kg body weight, about 10 mg/kg body weight, about 20 mg/kg body weight, about 30 mg/kg body weight, about 40 mg/kg body weight, about 50 mg/kg body weight, about 75 mg/kg body weight, about 100 mg/kg body weight, about 125 mg/kg body weight, about 150 mg/kg body weight, about 175 mg/kg body weight, about 200 mg/kg body weight, about 225 mg/kg body weight, about 250 mg/kg body weight, about 275 mg/kg body weight, or about 300 mg/kg body weight.
  • Compounds herein may be administered in a single daily dose, or the total daily dosage may be administered in divided dosage of two, three or four times daily.
  • an effective prophylactic or therapeutic treatment regimen can be planned which does not cause substantial toxicity and yet is entirely effective to treat the clinical symptoms demonstrated by the particular individual.
  • This planning should involve the careful choice of active compound by considering factors such as compound potency, relative bioavailability, individual body weight, presence and severity of adverse side effects, preferred mode of administration and the toxicity profile of the selected agent.
  • kits for administration of the compounds described herein e.g., any compound of formula I, II, III, or any variations thereof, Example 2 and/or Table 1, formulations, and dosage forms thereof.
  • kits may include a dosage amount of at least one formulation as disclosed herein. Kits may further comprise suitable packaging and/or instructions for use of the formulation. Kits may also comprise a means for the delivery of the formulation thereof.
  • kits may include other pharmaceutical agents for use in conjunction with the one or more compounds described herein(e.g., any compound of formula I, II, III, or any variations thereof, Example 2 and/or Table 1).
  • the pharmaceutical agent(s) may be one or more anti-psychotic drugs. These agents may be provided in a separate form, or mixed with the compounds described herein, provided such mixing does not reduce the effectiveness of either the pharmaceutical agent or compound described herein and is compatible with the route of administration.
  • the kits may include additional agents for adjunctive therapy or other agents known to the skilled artisan as effective in the treatment or prevention of the conditions described herein.
  • kits may optionally include appropriate instructions for preparation and administration of the composition, side effects of the composition, and any other relevant information.
  • the instructions may be in any suitable format, including, but not limited to, printed matter, videotape, computer readable disk, optical disc or directions to internet-based instructions.
  • kits for treating an individual who suffers from or is susceptible to the conditions described herein comprising a first container comprising a dosage amount of a formulation as disclosed herein, and instructions for use.
  • the container may be any of those known in the art and appropriate for storage and delivery of intravenous formulation.
  • the kit further comprises a second container comprising a pharmaceutically acceptable carrier, diluent, adjuvant, etc. for preparation of the composition to be administered to the individual.
  • Kits may also be provided that contain sufficient dosages of the inhibitor (including formulation thereof) as disclosed herein to provide effective treatment for an individual for an extended period, such as 1-3 days, 1-5 days, a week, 2 weeks, 3, weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months or more.
  • Kits may also include multiple doses of the compound and instructions for use and packaged in quantities sufficient for storage and use in pharmacies, for example, hospital pharmacies and compounding pharmacies.
  • kits may include the compounds as described herein (e.g., any compound of formula I, II, III, or any variations thereof, Example 2 and/or Table 1) packaged in either a unit dosage form or in a multi-use form.
  • the kits may also include multiple units of the unit dose form.
  • the compositions may be provided in a multi-dose form (e.g., a blister pack, etc.).
  • the ratio between toxicity and therapeutic effect for a particular compound is its therapeutic index and can be expressed as the ratio between LD 50 (the amount of compound lethal in 50% of the population) and ED 50 (the amount of compound effective in 50% of the population).
  • LD 50 the amount of compound lethal in 50% of the population
  • ED 50 the amount of compound effective in 50% of the population.
  • Therapeutic index data obtained from cell culture assays and/or animal studies can be used in formulating a range of dosages for use in humans.
  • the dosage of such compounds preferably lies within a range of plasma concentrations that include the ED 50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. See, e.g., Fingl et al, In: THE PHARMACOLOGICAL BASIS OF
  • THERAPEUTICS Ch.l, p.l, 1975.
  • the exact formulation, route of administration and dosage can be chosen by the individual physician in view of the individual's condition and the particular method in which the compound is used.
  • the ⁇ -secretase inhibitor compounds herein can be employed in methods to decrease memapsin 2 activity, decrease hydrolysis of a ⁇ -secretase site of a memapsin 2 substrate, and/or decrease the accumulation of ⁇ -amyloid protein relative to the amount of memapsin 2 activity, hydrolysis of a ⁇ -secretase site, and accumulation of ⁇ - amyloid protein, respectively, in the absence of the ⁇ -secretase inhibitor.
  • a method of reducing memapsin 2 activity includes contacting a memapsin 2 with a ⁇ -secretase inhibitor compound herein.
  • the memapsin 2 may be contacted in any appropriate environment (e.g., in vitro, in vivo).
  • the memapsin 2 activity is decreased relative to the amount of activity in the absence of ⁇ -secretase inhibitor.
  • a method is provided of selectively mediating (e.g., reducing) memapsin 2 activity using an inhibitor described herein (e.g., any compound of formula I, II, III, or any variations thereof, Example 2 and/or Table 1).
  • an inhibitor described herein e.g., any compound of formula I, II, III, or any variations thereof, Example 2 and/or Table 1).
  • Selective reduction of the activity of memapsin 2 means that memapsin 2 is not only reduced relative to its activity in the absence of inhibitor, but is reduced to a greater extent as compared to the reduction in activity due to inhibitor action against another enzyme, such as a peptide hydrolase (e.g., cathepsin D, memapsin 1) and/or Cytochrome P450 3A4.
  • a peptide hydrolase e.g., cathepsin D, memapsin 1
  • the reduction in activity of an enzyme may be expressed in terms of the inhibitory constant (K ; ).
  • K inhibitory constant
  • the Kj of the reaction between an inhibitor compound described herein and memapsin 2 is less than the Kj of the reaction between an inhibitor compound herein and another peptide hydrolase and/or Cytochrome P450 3A4.
  • the K; of the reaction between an inhibitor compound (e.g., any compound of formula I, II, III, or any variations thereof, Example 2 and/or Table 1) and memapsin 2 is less than the K; of the reaction between an inhibitor compound and another peptide hydrolase (e.g. , cathepsin D, memapsin 1).
  • the inhibitor selectively reduces the activity of memapsin 2 as compared to memapsin 1.
  • the inhibitor selectively reduces the activity of memapsin 2 as compared to cathepsin D.
  • the K; of the reaction between an inhibitor compound (e.g., any compound of formula I, II, III, or any variations thereof, Example 2 and/or Table 1) and memapsin 2 is less than the Kj of the reaction between an inhibitor compound and Cytochrome P450 3A4.
  • the Kj of the reaction between an inhibitor compound herein and memapsin 2 is at least 2 times less than the K; of the reaction between an inhibitor compound herein and another peptide hydrolase and/or Cytochrome P450 3A4.
  • the Kj of the reaction between an inhibitor compound herein and memapsin 2 is at least 3, 5, 7, 10, 25, 50, 75, 100, 300, 200, 500, 750, 1000, 2000, 5000, or 10000 times less than the K ; of the reaction between an inhibitor compound herein and another peptide hydrolase and/or Cytochrome P450 3A4.
  • the methods include contacting a memapsin 2 with a ⁇ -secretase inhibitor compound (e.g., any compound of formula I, II, III, or any variations thereof, Example 2 and/or Table 1).
  • a ⁇ -secretase inhibitor compound e.g., any compound of formula I, II, III, or any variations thereof, Example 2 and/or Table 1.
  • the method includes contacting the memapsin 2 with a ⁇ -secretase inhibitor in the presence of memapsin 1.
  • the method includes contacting the memapsin 2 with a ⁇ -secretase inhibitor in the presence of cathepsin D.
  • the method includes contacting the memapsin 2 with a ⁇ -secretase inhibitor in the presence of cathepsin D and memapsin 1. In yet another embodiment, the method includes contacting the memapsin 2 with a ⁇ -secretase inhibitor in the presence of Cytochrome P450 3A4. In still another related embodiment, the method includes contacting the memapsin 2 with a ⁇ -secretase inhibitor in the presence of cathepsin D, memapsin 1, and Cytochrome P450 3A4.
  • the activity of memapsin-2 ⁇ -secretase may be determined by measuring the hydrolysis of a ⁇ -secretase site of a ⁇ -secretase substrate.
  • a memapsin 2 with a ⁇ -secretase inhibitor compound (e.g., any compound of formula I, II, III, or any variations thereof, Example 2 and/or Table 1).
  • a ⁇ -secretase inhibitor compound e.g., any compound of formula I, II, III, or any variations thereof, Example 2 and/or Table 1.
  • the hydrolysis of a ⁇ -secretase site is decreased relative the amount of hydrolysis in the absence of the inhibitor.
  • the hydrolysis is selectively reduced as compared to hydrolysis by memapsin 1 and/or cathepsin D.
  • a method of selectively decreasing hydrolysis of a ⁇ -secretase site of a ⁇ -amyloid precursor protein relative to memapsin 1 and/or cathepsin D in a sample is provided. The method includes contacting a memapsin 2 with a ⁇ -secretase inhibitor compound.
  • ⁇ - amyloid protein in a sample by contacting the memapsin 2 with an inhibitor compound (e.g., any compound of formula I, II, III, or any variations thereof, Example 2 and/or Table 1).
  • an inhibitor compound e.g., any compound of formula I, II, III, or any variations thereof, Example 2 and/or Table 1.
  • the amount of ⁇ -amyloid protein in a sample is decreased relative the amount of ⁇ -amyloid protein in the sample in the absence of the inhibitor.
  • the accumulation of ⁇ -amyloid protein is thereby decreased.
  • Memapsin 2 may be contacted in any suitable environment or any suitable sample.
  • memapsin 2 may be contacted in vitro, within a cell, or within a mammal.
  • the in vitro solution includes a biological sample, such as a mammalian sample.
  • a mammalian samples include plasma or serum samples and tissue samples or extracts, such as a brain biopsy.
  • Any appropriate cell or cellular sample may be selected in which to contact the memapsin 2 with the inhibitor.
  • the cell may contain endogenous memapsin 2 or recombinant memapsin 2 as previously described (see U.S. Patent Application Publication No. 20040121947 (the contents of which are hereby incorporated by reference), and International Application No. PCT/US02/34324 (Publication No.
  • exemplary cells include human embryonic kidney (HEK293) cells, HeLa cells, Chinese hamster ovary cells, or neuroblastoma cell line SK-N-BE(2) (ATCC number CRL- 2271), Hela cells, 293 cells.
  • the compounds herein are administered to a mammal to inhibit the hydrolysis of a ⁇ -secretase site of a ⁇ -amyloid precursor protein (e.g., a mouse, rat or human).
  • the ⁇ -secretase inhibitor compounds herein can be employed in the treatment of diseases or conditions associated with and/or mediated by ⁇ -secretase activity, hydrolysis of a ⁇ -secretase site of a ⁇ -amyloid precursor protein, and/or ⁇ -amyloid protein accumulation.
  • a mammal is treated for the disease or condition.
  • the disease is Alzheimer's disease.
  • a ⁇ -secretase inhibitor e.g., any compound of formula I, II, III, or any variations thereof, Example 2 and/or Table 1.
  • the individual has one or more symptoms of Alzheimer's disease.
  • the individual has been diagnosed with Alzheimer's disease.
  • the mammals treated with the inhibitors may be human primates, nonhuman primates or non-human mammals (e.g., rodents, canines).
  • the mammal is administered a compound herein that reduces ⁇ -secretase activity (inhibits memapsin 1 and memapsin 2 activity). In another embodiment, the mammal is administered a compound that selectively reduces memapsin 2 activity. In a related embodiment, the compound has minimal or no effect on reducing memapsin 1 activity. Therefore, also provided is a method of treating Alzheimer's disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a ⁇ -secretase inhibitor compound.
  • the ⁇ -secretase inhibitor compound is part of a pharmaceutical formulation, as described above.
  • the inhibitor compounds herein can be employed in the treatment of diseases or conditions in an individual associated with ⁇ -secretase activity (e.g., memapsin 2 activity), which can halt, reverse or diminish the progression of the disease or condition, in particular Alzheimer's disease.
  • the individual has one or more symptoms of the disease or condition associated with ⁇ -secretase activity.
  • the individual has been diagnosed with disease or condition associated with ⁇ -secretase activity.
  • compounds that selectively reduce memapsin 2 activity are useful to treat diseases or conditions or biological processes associated with memapsin 2 activity rather than diseases or conditions or biological processes associated with both memapsin 2 activity and another peptide hydrolase (such as cathepsin D or memapsin 1).
  • both memapsin 1 and memapsin 2 cleave amyloid precursor protein (APP) at a ⁇ -secretase site to form ⁇ -amyloid protein (also referred to herein as ⁇ or ⁇ -amyloid protein).
  • APP amyloid precursor protein
  • both memapsin 1 and memapsin 2 have ⁇ -secretase activity (Hussain, I., et ah, J. Biol. Chem. 27 ⁇ 5:23322-23328 (2001)).
  • the ⁇ -secretase activity of memapsin 1 is significantly less than the ⁇ -secretase activity of memapsin 2 (Hussain, I., et ah, J. Biol. Chem.
  • Memapsin 2 is localized in the brain, and pancreas, and other tissues (Lin, X., et ah, Proc. Natl. Acad Sci. USA 97: 1456- 1460 (2000)) and memapsin 1 is localized preferentially in placentae (Lin, X., et ah, Proc. Natl. Acad Sci. USA 97: 1456-1460 (2000)).
  • Alzheimer's disease is associated with the accumulation of ⁇ in the brain as a result of cleaving of APP by ⁇ -secretase (also referred to herein as memapsin 2, ASP2 and BACE).
  • methods employing the compounds which selectively inhibit memapsin 2 activity relative to memapsin 1 activity may be important in the treatment of memapsin 2-related diseases, such as Alzheimer's disease.
  • Selective inhibition of memapsin 2 activity makes the compounds herein suitable drug candidates for use in the treatment of Alzheimer's disease.
  • the ⁇ -secretase inhibitor compounds herein can be employed in the treatment of diseases associated with vision loss (e.g., glaucoma).
  • diseases associated with vision loss e.g., glaucoma
  • methods of treating glaucoma e.g. closed-angle glaucoma and open-angle glaucoma
  • the ⁇ -secretase inhibitor compound is part of a pharmaceutical formulation, as described above.
  • the inhibitor compounds herein can be employed in the treatment of diseases or conditions associated with ⁇ -secretase activity, which can halt, reverse or diminish the progression of glaucoma (e.g. closed-angle glaucoma and open-angle glaucoma).
  • the inhibitor compounds herein can be used to halt, reverse or diminish the loss of retinal ganglion cells (RGCs).
  • RRCs retinal ganglion cells
  • compounds herein e.g., any compound of formula I, II, III, or any variations thereof, Example 2 and/or Table 1 are employed to improve or decrease intraocular pressure (IOP).
  • Compounds desribed herein may be used to treat glaucoma by one of several known routes of administration, including, but not limited to, orally (e.g., in tablet or capsule form), parenterally (e.g., injected into the anterior chamber, intravenous,
  • Compounds herein may also be formulated for sustained release during glaucoma treatment.
  • Additional embodiments for treating glaucoma with compounds herein are described by adapting one or more of the methods in Guo, et. al. Proc. Natl. Acad. Sci., 14, 13444-13449 (2007); Yamamoto, et. al., Neuroscience Letters, 370, 61-64 (2004); and/or Urcola et. al., Exp. Eye Research, 83, 429-437 (2006). The content of these applications are hereby incorporated by reference in its entireties.
  • the inhibitor compounds of herein may be administered to the CNS through either invasive or non-invasive methods.
  • Non-invasive methods of administration include those methods that do not require the use of a mechanical or physical means to breach the integrity of the blood-brain barrier.
  • non-invasive methods include the use of
  • BBBD blood-brain barrier disruption
  • Immunoliposomes are liposomes with antibodies or antibody fragments that bind to receptors or transporters expressed on brain capillary endothelial cells attached to the surface of the liposome.
  • An exemplary immunoliposome combines polymer (e.g., PEGylation) technology with that of chimeric peptide technology.
  • the ⁇ -secretase inhibitor may be packaged into a unilamellar lipid vesicle containing a PEG 2000 derivative that contains a reactive groups at one end, for attachment to a complementary reactive group of an antibody or fragment thereof.
  • Complementary reactive groups are well known in the art and, include, fro example, amine and activated carboxylic acids, thiols and maleimides, and the like (Ambikanandan et al., J. Pharm Pharmaceut Sci 6(2):252-273 (2003); Huwyler et al., Proc. Natl. Acad. Sci. USA, 93: 14164-14169 (1996); and Huwyler et al., J Pharmcol Exp Ther. 282: 1541-1546 (1997); and U.S. Pat. No. 6,372,250, all of which are herein
  • Blood-brain barrier disruption is a temporal loss of the integrity of the tight junctions between endothelial cells that comprise the blood brain barrier.
  • the compound is administered via systemic or intercarotid injection in conjuction with transient blood-brain barrier disruption (BBBD).
  • BBBD transient blood-brain barrier disruption
  • agents useful for inducing BBBD include solvents such as dimethyl sulfoxide (DMSO); ethanol (EtOH); metals (e.g., aluminum); X- irradiation; induction of pathological conditions (e.g., hypertension, hypercapnia, hypoxia, or ischemia); anti-neoplastic agents (e.g., VP-16, cisplatin, hydroxyurea, flurouracil and etoposide); or concurrent systemic administration of the convulsant drug metrazol and the anti-convulsant drug pentobarbital (Ambikanandan et al., J.
  • solvents such as dimethyl sulfoxide (DMSO); ethanol (EtOH); metals (e.g., aluminum); X- irradiation; induction of pathological conditions (e.g., hypertension, hypercapnia, hypoxia, or ischemia); anti-neoplastic agents (e.g., VP-16, cis
  • Olfactory pathway administration is the intranasal delivery of the compound to the olfactory nerves in the upper third of the nasal passages. After intranasal delivery, the compound is transported back along the sensory olfactory neurons to yield significant concentrations in the cerebral spinal fluid (CSF) and olfactory bulb (Thorne et al., Brain Res, 692(l-2):278-282 (1995); Thorne et al., Clin Pharmacokinet 40:907-946 (2001); Ilium, Drug Discov 73 ⁇ 4 ⁇ 7: 1184-1189 (2002); U.S. Pat. 6,180,603; U.S. Pat. 6,313,093; and U.S. Patent Application Publication No. 20030215398).
  • CSF cerebral spinal fluid
  • olfactory bulb Thorne et al., Brain Res, 692(l-2):278-282 (1995); Thorne et al., Clin Pharmacokinet 40:907-946 (2001); Ilium, Drug
  • Invasive methods of administration are those methods that involve a physical breach of the blood-brain barrier typically through a mechanical or physical means to introduce the compound into the CSF, or directly into the parenchyma of the brain.
  • invasive methods of administration may include injection or surgical implantation of the compound.
  • a needle is used to physically breach the BBB and deliver the compound directly into the CSF.
  • exemplary injection methods include intraventricular, intrathecal, or intralumbar routes of administration and may also involve infusion of the compound through a reservoir external to the body (Krewson et al., Brain Res 680: 196-206 (1995); Harbaugh et al., Neurosurg. 23(6):693-698 (1988); Huang et al., J Neurooncol 45:9- 17 (1999); Bobo et al., Proc Natl Acad Sci USA 91:2076-2082 (1994); Neuwalt et al., Neurosurg. 38(4): 1129-1145 (1996)).
  • the compound is placed directly into the parenchyma of the brain.
  • exemplary surgical implantation methods may include
  • a crystallized complex containing a memapsin 2 protein and a ⁇ -secretase inhibitor herein is provided.
  • Memapsin 2 proteins useful in forming co-crystals with isostere compounds e.g., memapsin 2 protein fragments, transmembrane proteins, etc.
  • isostere compounds e.g., memapsin 2 protein fragments, transmembrane proteins, etc.
  • the crystallized complex may be formed employing techniques described in U.S. Patent Application Publication No. 20040121947, and International Application No.
  • a nucleic acid construct encoding the protein is generated, is expressed in a host cell, such as a mammalian host cell (e.g., Hela cell, 293 cell) or a bacterial host cell (e.g., E. coli), is purified and is crystallized with a compound or compounds herein.
  • a mammalian host cell e.g., Hela cell, 293 cell
  • a bacterial host cell e.g., E. coli
  • the diffraction resolution limit of the crystallized protein can be determined, for example, by x-ray diffraction or neutron diffraction techniques.
  • the crystallized protein may have an x-ray diffraction resolution limit not greater than about 4.0 ⁇ (angstroms).
  • the crystallized protein may also have an x-ray diffraction resolution limit not greater than about 4.0 ⁇ , about 3.5 ⁇ , about 3.0 ⁇ , about 2.5 ⁇ , about 2.0 ⁇ , about 1.5 ⁇ , about 1.0 ⁇ , or about 0.5 ⁇ (angstroms).
  • the crystallized protein may also have an x-ray diffraction resolution limit not greater than about
  • the diffraction resolution limit of the crystallized protein can be determined employing standard x-ray diffraction techniques.
  • the ⁇ -secretase inhibitor of the crystallized complex is in association with said protein at an S 3 ' binding pocket, an S 4 ' binding pocket and/or an S 4 binding pocket.
  • S 3 ', S 4 ', and S 4 binding pockets are discussed in detail in U.S. Patent Application Publication No. 20040121947, and International Application No.
  • Beta-Secretase inhibitors and precursor compounds are related to WO 2006/110668, filed on 4/10/2006 and entitled "Compounds Which Inhibit Beta-Secretase Activity and Methods of Use Thereof," the content of which is incorporated herein by reference in its entirety, and particularly with respect to the synthetic methods described therein, e.g., paragraphs 150-153 and paragraphs 215-285; and United States Provisional Patent Application No. 60/952,198, filed on 07/26/2007 and entitled
  • Example 1.1 Synthesis of amine building blocks.
  • Methylthiazole methanol (0.57 g, 4.4 mmol) was treated with mesyl chloride (0.42 mL, 5.4 mmol) and triethyl ethylamine at 0 °C in dichloromethane. The resulting mixture was stirred for 20 minutes followed by quenching with aqueous NH 4 C1. Evaporation of the solvent from the organic layer and flash chromatography of the residue afforded the corresponding mesylate as an oil. The mesylate (0.25g, 1.2 mmol) was then dissolved in DMF and sodium azide (0.62g, 9.6 mmol) was added.
  • DPPA Diphenylphosphoryl azide
  • DBU l,8-Diazabicyclo(5.4.0)undec-7-ene
  • Example 1.1.3 (R)-l-(4-methyloxazol-2-yl)ethanamine [0275] To a solution of L-Serine methyl ester hydrochloride (5.0 g, 32.0 mmol), in CH2C12 (150mL) at 0 oC, were added Et3N ( 4.88 mL, 35.2 mmol), Boc-D-Alalnine (6.06 g, 32 mmol), and DCC (7.26 g, 35.2 mmol) sequentially. The reaction was allowed to warm to room temperature and stirred overnight. All the solvent was evaporated and the residue was triturated with ethyl acetate and the precipitate was filtered off.
  • Deoxo-fluorTM (Bis-(2-methoxy) amino sulfur trifluoride, 1.4 mL , 7.6 mmol) was added drop-wise to a solution of methyl 2-((R)-2-(tert-butoxycarbonylamino)propanamido)- 3- hydroxypropanoate (2.0g, 6.9 mmol) in CH2C12 (50 mL) at -20 oC. The solution was stirred for 30 min and BrCC13 (2.45 mL, 24.8 mmol) was added drop-wise. The reaction was stirred at 2-3 oC, for 8h., quenched with sat. aq. NaHC03 solution and extracted with ethyl actetate.
  • N-methyl-l-(4-methylthiazol-2-yl)methanamine [0284] To a solution of BuLi (1.6 M in hexanes, 12.6 mL, 20.2 mmol) in 25mL of diethyl ether at -78 °C, was added a solution of 5-methylthiazole (2.0 g, 20.2 mmol) in ether (6 mL), drop-wise and stirred at -78 °C for 1.5 h. A solution of DMF (2.33 mL, 30.3 mmol in ether (5 mL) was added at once and the reaction mixture was allowed to warm to room temperature and stirred overnight. Ice was added to the reaction mixture followed by the slow addition of 4N HC1.
  • Example 1.2 Synthesis of cyclic amine building blocks.
  • Oragnaic layer was dried, evaporated and column purified to yield 900mg of the proline 20.
  • Lawesson's reagent (Commercial source: Sigma- Aldrich) (5.41 g, 13.37 mmol) was added to the amide (5.6 g, 22.28 mmol) in DME (Commercial source: Sigma-Aldrich) (100 ml) and the reaction mixture was stirred overnight at rt. Then volatiles were removed in vacuum and the reaction mixture was partitioned between ether and water. Ether layer was concentrated and column purified to obtain 4.6 g of thioamide.
  • Example 1.3 Synthesis of isophthalate building blocks.
  • the unsaturated 7-membered fused ether was synthesized from the allyl ether following the general procedure as described above for the 6-membered fused ether.
  • Method A n BuLi (1.6 M in hexanes, 7.6 ml, 12.2 mmol, 1.5 eq) was added slowly to a stirred solution of (S)-4-isopropyloxazolidin-2-one (Aldrich, 1.5 g, 11.6 mmol, 1 eq) in 20 ml anhydrous THF at -78 °C. After 10 min 3-phenylpropanoyl chloride (Aldrich, 1.9 ml, 2.15 g, 12.8 mmol, 1.1 eq) was added dropwise. The reaction was warmed to 0 °C. After 1 h the reaction was quenched with saturated aqueous NH 4 C1.
  • DPPA (0.66 ml, 0.84 g, 3.07 mmol, 1.05 eq) was added to a stirred solution of (2S,3S)-2-benzyl-3-((4R)-4-(benzyloxy)-l-(tert-butoxycarbonyl)pyrrolidin-2-yl)-3- hydroxypropanoic acid (1.3299 g, 2.9 mmol, 1 eq) in 20 ml anhydrous toluene under Ar. After heating to 80 °C Et N (0.45 ml, 0.32 g, 3.21 mmol, 1.1 eq) was added. After 2 h the solvent was removed via rotary evaporation.
  • Method B l-phenyl-2-nitroethane was prepared by mixing nitromethane (21.03 g, 0.344 mol) and benzaldehyde (33.24 g, 0.313 mol) in methanol (100 mL) at 0 °C. An aqueous solution of sodium hydroxide (15.66 g/40 mL of water) was added to the stirring solution over a period of 30 minutes. The stirring was continued for another hour in the temperature range of 0°C. The mixture was diluted with water (100 mL) and poured over crushed ice containing 32 mL of cone. HC1. The yellow solid precipitated out and was extracted with ether three times.
  • (2S,4R)-tert-butyl 4-(benzyloxy)-2- formylpyrrolidine-l-carboxylate (2.1 g, 6.867 mmol) in THF (10 mL) was added slowly and stirred 90 min, diluted with ethyl acetate, washed with water (3 x 50 mL), saturated aqueous sodium chloride, dry (magnesium sulfate) and purified (silica gel chromatography, eluting with hexanes and ethyl acetate) to give (2R,4R)-tert-butyl 4-(benzyloxy)-2-((lR,2S)-l- hydroxy-2-nitro-3-phenylpropyl)pyrrolidine-l-carboxylate as a syrup (1.1 g, 35%).
  • Boc difluorophenylalanine 1.5 g, 5.0 mmol
  • ⁇ , ⁇ -dimethylhydroxylamine hydrochloride 536 mg, 5.5 mmol
  • (S)-tert-butyl 3-(3,5-difluorophenyl)-l-(methoxy(methyl)amino)-l-oxopropan-2-ylcarbamate (1.44 g, 84%) as a colorless oil.
  • Example 1.7 Isophthalate/Amine Coupling followed by hydroxylamine coupling
  • Example 1.10.3 N-((lR,2S)-3-(3,5-difluorophenyl)-l-hydroxy-l-((R)-pyrrolidin-2-yl)propan- -yl)-3-((R)-2-(4-methylthiazol-2-yl)pyrrolidine-l-carbonyl)-5-(pyrazin-2-yl)benzamide
  • Example 1.10.4 N-((lR,2S)-3-(3,5-difluorophenyl)-l-hydroxy-l-((R)-pyrrolidin-2-yl)propan- -yl)-3-((R)-2-(4-methyloxazol-2-yl)pyrrolidine-l-carbonyl)-5-(oxazol-2-yl)benzamide
  • N 7 ((lR,2S)-l-hydroxy-3-phenyl-l-((R)-pyrrolidin-2-yl)propan-2-yl)-N 5 -((5- methyl- 1 ,2,4-oxadiazol-3-yl)methyl)chroman-5,7-dicarboxamide.
  • N 7 ((lR,2S)-l-hydroxy-3-phenyl-l-((R)-pyrrolidin-2-yl)propan-2-yl)-N 5 -((R)-l-(4- methyloxazol-2-yl)ethyl)chroman-5,7-dicarboxamide.

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Abstract

L'invention concerne de nouveaux inhibiteurs de bêta secrétase et des méthodes pour leur utilisation, y compris des méthodes de traitement de la maladie d'Alzheimer.
PCT/US2011/032281 2010-04-14 2011-04-13 Composés contenant des cycles fusionnés qui inhibent l'activité bêta secrétase et leurs méthodes d'utilisation WO2011130383A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105669686A (zh) * 2014-11-19 2016-06-15 上海合全药业股份有限公司 一种6-(叔丁氧羰基)八氢呋喃[2,3-c]吡啶-4-羧酸的合成方法
CN107935840A (zh) * 2017-12-05 2018-04-20 常州工程职业技术学院 一种4‑羟基间苯二甲酸衍生物以及合成方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004043916A1 (fr) * 2002-11-12 2004-05-27 Merck & Co., Inc. Inhibiteurs de beta-secretase phenylcarboxamide utilises dans le traitement de la maladie d'alzheimer
WO2006099352A1 (fr) * 2005-03-10 2006-09-21 Bristol-Myers Squibb Company Nouveaux isophtalates utilises comme inhibiteurs de la beta-secretase
WO2010042892A1 (fr) * 2008-10-10 2010-04-15 Comentis, Inc. Composés de pyrrolidine qui empêche l'activité bêta-secrétase et procédés pour leur utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004043916A1 (fr) * 2002-11-12 2004-05-27 Merck & Co., Inc. Inhibiteurs de beta-secretase phenylcarboxamide utilises dans le traitement de la maladie d'alzheimer
WO2006099352A1 (fr) * 2005-03-10 2006-09-21 Bristol-Myers Squibb Company Nouveaux isophtalates utilises comme inhibiteurs de la beta-secretase
WO2010042892A1 (fr) * 2008-10-10 2010-04-15 Comentis, Inc. Composés de pyrrolidine qui empêche l'activité bêta-secrétase et procédés pour leur utilisation

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105669686A (zh) * 2014-11-19 2016-06-15 上海合全药业股份有限公司 一种6-(叔丁氧羰基)八氢呋喃[2,3-c]吡啶-4-羧酸的合成方法
CN105669686B (zh) * 2014-11-19 2018-08-03 上海合全药业股份有限公司 一种6-(叔丁氧羰基)八氢呋喃[2,3-c]吡啶-4-羧酸的合成方法
CN107935840A (zh) * 2017-12-05 2018-04-20 常州工程职业技术学院 一种4‑羟基间苯二甲酸衍生物以及合成方法

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