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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
• • 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
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  • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
  • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C237/12—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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  • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
  • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C237/14—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated and containing rings
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  • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/81—Amides; Imides
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  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/81—Amides; Imides
  • C07D213/82—Amides; Imides in position 3
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
  • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
  • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
  • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
  • C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
  • C07D285/01—Five-membered rings
  • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
  • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
  • C07D285/10—1,2,5-Thiadiazoles; Hydrogenated 1,2,5-thiadiazoles
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
  • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
  • C07D295/182—Radicals derived from carboxylic acids
  • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
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  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
  • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
  • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
  • C07K5/0207—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)4-C(=0), e.g. 'isosters', replacing two amino acids

Definitions

• Alzheimer's Disease is a progressive dementia in which massive deposits of aggregated protein breakdown products ( ⁇ -amyloid plaques and neurofibrillary tangles) accumulate in the brain, resulting in the loss of memory, cognition, reasoning, judgement, orientation, and eventually death.
• Current therapies for the treatment of Alzheimer's Disease include, but are not limited to, donepezil and tacrine. These therapies are useful for improving the memory of patients during the early stages of Alzheimer's Disease, however they do not modify the progression of aggregated protein breakdown products underlying the pathology of Alzheimer's Disease. It would be desirable to develop therapies that would either stop or slow down this process of aggregation.
• ⁇ -amyloid plaques are predominantly composed of amyloid ⁇ peptide (A ⁇ (or ⁇ A4), which is derived by proteolysis of the amyloid precursor protein (APP). Proteolysis of the amyloid precursor protein is effected by several enzymes called secretases.
• a ⁇ amyloid ⁇ peptide
• APP amyloid precursor protein
• cleavage of APP at the N-terminus of the A ⁇ peptide by ⁇ -secretase and at the C-terminus by one or more ⁇ -secretases constitutes the ⁇ -amyloidogenic pathway, i.e., the pathway by which A ⁇ is formed. It is believed that A ⁇ peptide accumulates as a result of this APP processing by ⁇ - secretase and thus inhibition of this enzyme's activity is desirable for the treatment of Alzheimer's Disease. For example, in vivo processing of APP at the ⁇ -secretase cleavage site is thought to be a rate limiting step in A ⁇ production, and is thus believed to be a therapeutic target for Alzheimer's Disease (Sabbagh et al. A . Dis.
• BACE plays an important role in the development and pathogenesis of Alzheimer's Disease
• inhibitors of BACE as treatments (and possibly as preventative agents) for Alzheimer's Disease and other disorders caused by the accumulation of ⁇ -amyloid plaques.
• novel therapeutics capable of inhibiting the activity of this aspartyl protease.
• the invention provides pharmaceutical compositions comprising an inventive compound, wherein the compound is present in an amount effective to inhibit ⁇ -secretase activity.
• the invention provides pharmaceutical compositions comprising an inventive compound and optionally further comprising an additional therapeutic agent.
• the additional therapeutic agent is an agent for the treatment of Alzheimer's Disease.
• the present invention provides methods for inhibiting ⁇ -secretase activity in a patient or a biological sample, comprising administering to said patient, or contacting said biological sample with an effective inhibitory amount of a compound of the invention.
• the present invention provides methods for treating any disorder involving ⁇ -secretase activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention.
• the invention provides a method for treating or preventing a disease characterized by ⁇ - amyloid deposits in the brain comprising administering to a patient a therapeutically effective amount of a compound of the invention.
• Figure 1A depicts a plasma concentration curve for an exemplary inventive compound.
• Figure IB depicts a brain concentration curve for an exemplary inventive compound.
• protecting group By the term “protecting group”, has used herein, it is meant that a particular functional moiety, e.g., O, S, or N, is temporarily blocked so that a reaction can be carried out selectively at another reactive site in a multifunctional compound.
• a protecting group reacts selectively in good yield to give a protected substrate that is stable to the projected reactions; the protecting group must be selectively removed in good yield by readily available, preferably nontoxic reagents that do not attack the other functional groups; the protecting group may form an easily separable derivative (more preferably without the generation of new stereogenic centers); and the protecting group has a minimum of additional functionality to avoid further sites of reaction.
• oxygen, sulfur, nitrogen and carbon protecting groups may be utilized.
• oxygen protecting groups include, but are not limited to methyl ethers, substituted methyl ethers (e.g., MOM (methoxymethyl ether), MTM (methylthiomethyl ether), BOM (benzyloxymethyl ether), PMBM (p-methoxybenzyloxymethyl ether), to name a few), substituted ethyl ethers, substituted benzyl ethers, silyl ethers (e.g., TMS (trimethylsilyl ether), TES (triethylsilylether), TIPS (triisopropylsilyl ether), TBDMS (t-butyldiniethylsilyl ether), tribenzyl silyl ether, TBDPS (t-butyldiphenyl silyl ether), to name a few), esters (e.g., formate, acetate, benzoate (Bz),
• nitrogen protecting groups are utilized. These nitrogen protecting groups include, but are not limited to, carbamates (including methyl, ethyl and substituted ethyl carbamates (e.g., Troc), to name a few) amides, cyclic imide derivatives, N- Alkyl and N-Aryl amines, imine derivatives, and enamine derivatives, to name a few. Certain other exemplary protecting groups are detailed herein, however, it will be appreciated that the present invention is not intended to be limited to these protecting groups; rather, a variety of additional equivalent protecting groups can be readily identified using the above criteria and utilized in the present invention. Additionally, a variety of protecting groups are described in "Protective Groups in Organic Synthesis" Third Ed.
• the term "substituted" is contemplated to include all permissible substituents of organic compounds.
• the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
• heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms.
• this invention is not intended to be limited in any manner by the pennissible substituents of organic compounds.
• Combinations of substituents and variables envisioned by this invention are preferably those that result in the formation of stable compounds useful in the treatment and prevention, for example of disorders, as described generally above.
• stable preferably refers to compounds which possess stability sufficient to allow manufacture and which maintain the integrity of the compound for a sufficient period of time to be detected and preferably for a sufficient period of time to be useful for the purposes detailed herein.
• aliphatic includes both saturated and unsaturated, straight chain (i.e., unbranched), branched, cyclic, or polycyclic aliphatic hydrocarbons, which are optionally substituted with one or more functional groups.
• aliphatic is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties.
• alkyl includes straight, branched and cyclic alkyl groups.
• alkyl alkenyl
• alkynyl alkynyl
• the terms “alkyl”, “alkenyl”, “alkynyl” and the like encompass both substituted and unsubstituted groups.
• lower alkyl is used to indicate those alkyl groups (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1-6 carbon atoms.
• the alkyl, alkenyl and alkynyl groups employed in the invention contain 1-20 aliphatic carbon atoms.
• the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-10 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-8 aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-4 carbon atoms.
• Illustrative aliphatic groups thus include, but are not limited to, for example, methyl, ethyl, n- propyl, isopropyl, cyclopropyl, -CH 2 -cyclopropyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, -CH 2 -cyclobutyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, cyclopentyl, -CH 2 -cyclopentyl-n, hexyl, sec-hexyl, cyclohexyl, -CH 2 -cyclohexyl moieties and the like, which again, may bear one or more substituents.
• Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1- methyl-2-buten-l-yl, and the like.
• Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl and the like.
• alkoxy or "alkyloxy"
• thioalkyl refers to an alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom or through a sulfur atom. In certain embodiments, the alkyl group contains 1-20 aliphatic carbon atoms.
• the alkyl group contains 1-10 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-8 aliphatic carbon atoms. In still other embodiments, the alkyl group contains 1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl group contains 1-4 aliphatic carbon atoms. Examples of alkoxy, include but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and n-hexoxy.
• thioalkyl examples include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like.
• alkylamino refers to a group having the structure - NHR'wherein R' is alkyl, as defined herein.
• dialkylamino refers to a group having the structure -N(R') 2 , wherein R' is alkyl, as defined herein.
• aminoalkyl refers to a group having the structure NH 2 R'-, wherein R' is alkyl, as defined herein.
• the alkyl group contains 1-20 aliphatic carbon atoms. In certain other embodiments, the alkyl group contains 1-10 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-8 aliphatic carbon atoms. In still other embodiments, the alkyl group contains 1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl group contains 1-4 aliphatic carbon atoms. Examples of alkylamino include, but are not limited to, methylamino, ethylamino, iso- propylamino and the like.
• substituents of the above-described aliphatic (and other) moieties of compounds of the invention include, but are not limited to aliphatic; heteroaliphatic; aryl; heteroaryl; alkylaryl; alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; -OH; -NO 2 ; -CN; -CF 3 ; -CH 2 CF 3 ; -CHC1 2 ; -CH 2 OH; - CH 2 CH 2 OH; -CH 2 NH 2 ; -CH 2 SO 2 CH 3 ; -C(O)R x ; -CO 2 (R x ); -CON(R x ) 2 ; -OC(O)R x ; - OCO 2 R x ; -OCON(R
• aromatic moiety and “heteroaromatic moiety”, as used herein, refer to stable mono- or polycyclic, heterocyclic, polycyclic, and polyheterocyclic unsaturated moieties having preferably 3-14 carbon atoms, each of which may be substituted or unsubstituted.
• aromatic and heteroaromatic moieties may be attached via an alkyl or heteroalkyl moiety and thus also include -(alkyl)aromatic, -(heteroalkyl)aromatic, - (heteroalkyl)heteroaromatic, and -(heteroalkyl)heteroaromatic moieties.
• aromatic or heteroaromatic moieties and “aromatic, heteroaromatic, -(alkyl)aromatic, -(heteroalkyl)aromatic,
• heteroalkyl heteroaromatic
• -(heteroalkyl)heteroaromatic are interchangeable.
• Substituents include, but are not limited to, any of the previously mentioned substituents, i.e., the substituents recited for aliphatic moieties, or for other moieties as disclosed herein, resulting in the formation of a stable compound.
• aryl does not differ significantly from the common meaning of the term in the art, and refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.
• heteroaryl does not differ significantly from the common meaning of the term in the art, and refers to a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is selected from S, O and N; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like.
• aryl and heteroaryl groups can be unsubstituted or substituted, wherein substitution includes replacement of one or more of the hydrogen atoms thereon independently with any one or more of the following moieties including, but not limited to: aliphatic; heteroaliphatic; aryl; heteroaryl; alkylaryl; alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; -OH; -NO 2 ; -CN; -CF 3 ; -CH 2 CF 3 ; -CHC1 2 ; -CH 2 OH; -CH 2 CH 2 OH; - CH 2 NH 2 ; -CH 2 SO 2 CH 3 ; -C(O)R x ; -CO 2 (R x ); -CON
• cycloalkyl refers specifically to cyclic moieties having three to seven, preferably three to ten carbon atoms.
• Suitable cycloalkyls include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, which, as in the case of other aliphatic, heteroaliphatic or heterocyclic moieties, may optionally be substituted with substituents including, but not limited to aliphatic; heteroaliphatic; aryl; heteroaryl; alkylaryl; alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; -OH; -NO 2 ; -CN; -CF 3 ; - CH 2 CF 3 ; -CHC1 2 ; -CH 2 OH; -CH 2 CH 2 OH; -CH 2 NH 2 ; -CH 2 SO 2 CH 3 ;
• any of the cycloaliphatic or cycloheteroaliphatic moieties described above and herein may comprise an aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl moiety fused thereto. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein. [0022]
• heteroaliphatic refers to aliphatic moieties in which one or more carbon atoms in the main chain have been substituted with a heteroatom.
• heteroaliphatic group refers to an aliphatic chain which contains one or more oxygen sulfur, nitrogen, phosphorus or silicon atoms, e.g., in place of carbon atoms.
• Heteroaliphatic moieties may be branched, unbranched, cyclic or acyclic and include saturated and unsaturated heterocycles such as morpholino, pyrrolidinyl, etc.
• heteroaliphatic moieties are substituted by independent replacement of one or more of the hydrogen atoms thereon with one or more moieties including, but not limited to aliphatic; heteroaliphatic; aryl; heteroaryl; alkylaryl; alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; -OH; -NO 2 ; -CN; -CF 3 ; -CH 2 CF 3 ; -CHC1 2 ; -CH 2 OH; -CH 2 CH 2 OH; - CH 2 NH 2 ; -CH 2 SO 2 CH 3 ; -C(O)R x ; -CO 2 (R x ); -CON(R x ) 2 ; -OC(O)R x ; -OCO 2 R x ; -
• cycloaliphatic refers to a cyclic aliphatic moiety, wherein the term aliphatic is as defined above.
• a cycloaliphatic moiety may be substituted or unsubstituted and saturated or unsaturated.
• Substituents include, but are not limited to, any of the previously mentioned substituents, i.e., the substituents recited for aliphatic moieties, or for other moieties as disclosed herein, resulting in the formation of a stable compound.
• cycloaliphatic compounds include but are not limited to monocyclic, or polycyclic aliphatic hydrocarbons and bridged cycloalkyl compounds, which are optionally substituted with one or more functional groups.
• cycloaliphatic is intended herein to include, but is not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, which are optionally substituted with one or more functional groups.
• Illustrative cycloaliphatic groups thus include, but are not limited to, for example, cyclopropyl, -CH 2 - cyclopropyl, cyclobutyl, -CH 2 -cyclobutyl, cyclopentyl, -CH -cyclopentyl, cyclohexyl, -CH 2 -cyclohexyl, cyclohexenylethyl, cyclohexanylethyl, norborbyl moieties and the like, which again, may bear one or more substituents.
• cycloheteroaliphatic refers to a cyclic heteroaliphatic moiety, wherein the term heteroaliphatic is as defined above.
• a cycloheteroaliphatic moiety may be substituted or unsubstituted and saturated or unsaturated.
• Substituents include, but are not limited to, any of the previously mentioned substituents, i.e., the substituents recited for aliphatic moieties, or for other moieties as disclosed herein, resulting in the formation of a stable compound.
• cycloheteroaliphatic encompasses “heterocycloalkyl", “heterocycle” or
• heterocyclic moieties, as defined herein.
• any of the cycloaliphatic or cycloheteroaliphatic moieties described above and herein may comprise an aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl moiety fused thereto. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.
• haloalkyl denotes an alkyl group, as defined above, having one, two, or three halogen atoms attached thereto and is exemplified by such groups as chloromethyl, bromoethyl, trifluoromethyl, and the like.
• heterocycloalkyl refers to compounds which combine the properties of heteroaliphatic and cyclic compounds and include, but are not limited to, saturated and unsaturated mono- or polycyclic cyclic ring systems having 5-16 atoms wherein at least one ring atom is a heteroatom selected from O, S and N (wherein the nitrogen and sulfur heteroatoms may be optionally be oxidized), wherein the ring systems are optionally substituted with one or more functional groups, as defined herein.
• heterocycloalkyl refers to a non-aromatic 5-, 6- or 7- membered ring or a polycyclic group wherein at least one ring atom is a heteroatom selected from O, S and N (wherein the nitrogen and sulfur heteroatoms may be optionally be oxidized), including, but not limited to, a bi- or tri-cyclic group, comprising fused six-membered rings having between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein (i) each 5 -membered ring has 0 to 2 double bonds, each 6-membered ring has 0 to 2 double bonds and each 7-membered ring has 0 to 3 double bonds, (ii) the nitrogen and sulfur heteroatoms may be optionally be oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to an
• heterocycles include, but are not limited to, heterocycles such as furanyl, thiofuranyl, pyranyl, pyrrolyl, thienyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolyl, oxazolidinyl, isooxazolyl, isoxazolidinyl, dioxazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, triazolyl, thiatriazolyl, oxatriazolyl, thiadiazolyl, oxadiazolyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, dithiazolyl, dithiazolidinyl, tetrahydrofuryl
• a "substituted heterocycle, or heterocycloalkyl or heterocyclic” group refers to a heterocycle, or heterocycloalkyl or heterocyclic group, as defined above, substituted by the independent replacement of one, two or three of the hydrogen atoms thereon with but are not limited to aliphatic; cycloaliphatic; heteroaliphatic; heterocyclic; aromatic; heteroaromatic; aryl; heteroaryl; alkylaryl; heteroalkylaryl; alkylheteroaryl; heteroalkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; - OH; -NO 2 ; -CN; -CF 3 ; -CH 2 CF 3 ; -CHC1 2 ; -CH 2 OH; -CH 2
• heterocycloalkyl encompass substituted and unsubstituted, and saturated and unsaturated groups. Additionally, the terms “cycloalkyl”, “cycloalkenyl”, “cycloalkynyl”, “heterocycloalkyl”,
• heterocycloalkenyl refers to such compounds that are (i) separated from at least some components with which they are associated in nature or when they are made and/or (ii) produced, prepared or manufactured by the hand of man.
• pharmaceutically acceptable derivative denotes any pharmaceutically acceptable salt, ester, or salt of such ester, of such compound, or any other adduct or derivative which, upon administration to a patient, is capable of providing (directly or indirectly) a compound as otherwise described herein, or a metabolite or residue thereof.
• Pharmaceutically acceptable derivatives thus include among others pro-drugs.
• a pro-drug is a derivative of a compound, usually with significantly reduced pharmacological activity, which contains an additional moiety that is susceptible to removal in vivo yielding the parent molecule as the pharmacologically active species.
• An example of a pro-drug is an ester which is cleaved in vivo to yield a compound of interest.
• Pro-drugs of a variety of compounds, and materials and methods for derivatizing the parent compounds to create the pro-drugs, are known and may be adapted to the present invention. Certain exemplary pharmaceutical compositions and pharmaceutically acceptable derivatives will be discussed in more detail herein below.
• the term "treating”, as used herein generally means that the compounds of the invention can be used in humans or animals with at least a tentative diagnosis of disease. The compounds of the invention will delay or slow the progression of the disease thereby giving the individual a more useful life span.
• the term "preventing” as used herein means that the compounds of the present invention are useful when administered to a patient who has not been diagnosed as possibly having the disease at the time of administration, but who would normally be expected to develop the disease or be at increased risk for the disease. The compounds of the invention will slow the development of disease symptoms, delay the onset of disease, or prevent the individual from developing the disease at all.
• Preventing also includes administration of the compounds of the invention to those individuals thought to be predisposed to the disease due to age, familial history, genetic or chromosomal abnormalities, and/or due to the presence of one or more biological markers for the disease, such as a known genetic mutation of APP or APP cleavage products in brain tissues or fluids.
• biological sample includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from an animal (e.g., mammal) or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
• biological sample refers to any solid or fluid sample obtained from, excreted by or secreted by any living organism, including single-celled micro-organisms (such as bacteria and yeasts) and multicellular organisms (such as plants and animals, for instance a vertebrate or a mammal, and in particular a healthy or apparently healthy human subject or a human patient affected by a condition or disease to be diagnosed or investigated).
• the biological sample can be in any form, including a solid material such as a tissue, cells, a cell pellet, a cell extract, cell homogenates, or cell fractions; or a biopsy, or a biological fluid.
• the biological fluid may be obtained from any site (e.g. blood, saliva (or a mouth wash containing buccal cells), tears, plasma, serum, urine, bile, cerebrospinal fluid, amniotic fluid, peritoneal fluid, and pleural fluid, or cells therefrom, aqueous or vitreous humor, or any bodily secretion), a transudate, an exudate (e.g. fluid obtained from an abscess or any other site of infection or inflammation), or fluid obtained from a joint (e.g.
• the biological sample can be obtained from any organ or tissue (including a biopsy or autopsy specimen) or may comprise cells (whether primary cells or cultured cells) or medium conditioned by any cell, tissue or organ.
• Biological samples may also include sections of tissues such as frozen sections taken for histological purposes.
• Biological samples also include mixtures of biological molecules including proteins, lipids, carbohydrates and nucleic acids generated by partial or complete fractionation of cell or tissue homogenates.
• biological samples may be from any animal, plant, bacteria, virus, yeast, etc.
• the term animal refers to humans as well as non-human animals, at any stage of development, including, for example, mammals, birds, reptiles, amphibians, fish, worms and single cells. Cell cultures and live tissue samples are considered to be pluralities of animals.
• the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, or a pig).
• An animal may be a transgenic animal or a human clone.
• the biological sample may be subjected to preliminary processing, including preliminary separation techniques.
• the present invention demonstrates that amino analogs (i.e., where the hydroxyl group has been replaced with an amino group) are unexpectedly equally promising (if not superior) aspartyl protease inhibitors as their hydroxy-containing counte ⁇ arts.
• the present invention shows that certain amino-containing inventive compounds possess several superior biological properties over their hydroxy-containing counte ⁇ arts (e.g., increased potency in cells, increased selectivity for the BACE enzyme, and/or superior ADME properties).
• the present invention provides novel amino-containing compounds capable of inhibiting the activity of BACE. More generally, the compounds of the invention are inhibitors of proteases, and more specifically inhibitors of aspartyl proteases. In certain embodiments of special interest, the inventive compounds are useful for the treatment or prevention of disorders characterized by ⁇ amyloid deposits or plaques. In certain exemplary embodiments, the compounds are useful for the treatment of Alzheimer's Disease.
• the present invention provides pharmaceutically acceptable derivatives of the inventive compounds, and methods of treating a subject using these compounds, pharmaceutical compositions thereof, or either of these in combination with one or more additional therapeutic agents.
• R', R 3 and R 3 are each hydrogen;
• R 2 is alkyl, cycloalkylalkyl or aralkyl;
• R f is hydrogen, substituted or unsubstituted C 1-6 alkyl or (CH CH 2 O) p CH 3 or (CH CH 2 O) p H wherein p is an integer from 0 to 5, and R g is hydrogen, or substituted or unsubstituted aryl, heterocycle, 5- to 7-membered carbocyclic or 7- to 10-membered bicyclic carbocyclic ring;
• R' and R 3' are each hydrogen;
• R c is hydrogen, substituted or unsubstituted aryl, 5- or 6-membered heterocycle, C 1-6 alkyl or C 1-6 alkenyl, C 3 . 7 cycloalkyl, 5- to 7-membered carbocyclic or 7- to 10-membered bicyclic carbocyclic ring, benzofuryl, indolyl, azabicyclo C - ⁇ cycloalkyl or benzopiperidinyl; R is hydrogen, substituted or unsubstituted .
• R is hydrogen, or substituted or unsubstituted aryl, heterocycle, 5- to 7- membered carbocyclic or 7- to 10-membered bicyclic carbocyclic ring;
• R' and R 3' are each hydrogen;
• R is hydrogen or OH; and R c is Y, (CHR w ) n -Y or -CR Z (CHR W ) admir-Y, wherein Y is hydrogen, OH, -NR R q , aryl, heteroaryl or CO-Z, n is an integer from 1 to 4, Z is OH, -NR w R q , OR or an amino acid with a blocked or unblocked carboxy terminus, R q is H, C 1-6 alkyl or arylC 1-6 alykl, and R z and R w are each independently hydrogen, C 1-6 alkyl, C 3- cycloalkyl, aryl, heteroaryl, T-C 1-6 alkyl or T-C 2-6 alkenyl. [0043] In certain embodiments, the present
• Another class of compounds of special interest includes those compounds of formula (I ) wherein, X 2 is absent and the compound has the Formula
• Another class of compounds of special interest includes those compounds of formula (I A ) wherein X 3 is absent and the compound has the Formula
• Another class of compounds of special interest includes those compounds of formula (I ) wherein X 2 and X 3 are each absent and the compound has the Formula (I D ):
• Another class of compounds of special interest includes those compounds of formula (I A ) wherein R 3 is hydrogen, X 2 is CHMe and the compound has the Formula (I E ):
• Another class of compounds of special interest includes those compounds of formula (I A ) wherein R 3 is hydrogen, X 3 is absent, X 2 is -CH(Me)Y-
• Another class of compounds of special interest includes those compounds of formula (I) wherein R' and R ' are each hydrogen, X is CHMe and
• Another class of compounds of special interest includes those compounds of formula (I) wherein R' and R are each hydrogen, X is -NR -, and the compound has the Formula (V): (V) [0053] Another class of compounds of special interest includes those compounds of formula (V) above having the stereochemistry as shown in Formula (V A ):
• Another class of compounds of special interest includes those compounds of formula (I) wherein X is CHR l and the compound has the structure as shown in Formula (VIII):
• Another class of compounds of special interest includes those compounds of formula (X) wherein R A is methyl and the compound has the Formula (X A ):
• R is hydrogen; R is substituted or unsubstituted lower alkyl, lower alkylamino, lower heteroaryl, -(CH 2 )cycloalkyl,-
• R is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -
• R is substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl or alkenyl
• R 1 is substituted or unsubstituted aryl, heteroaryl, -(alkyl)aryl, -
• R 1 is one of: (R ')n C f A
• R 1D is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl; -(alkyl)heteroaryl or acyl;
• R 1E and R 1F are each independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -C(-O)R lc or -SO 2 R lc , where R 1C is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or - (alkyl)heteroaryl; or R 1E and R 1F taken together fonn a 5-8 membered heterocyclic ring; or R 1E and one occurrence of R 1A , taken together, form a substituted or unsub
• R 1 is:
• R 1A is hydrogen, halogen, -CN, -NO 2 , lower alkyl, lower heteroalkyl, -(alkyl)aryl, -(alkyl)heteroaryl, -OR 1B or -N(R 1B )SO 2 R lc ; wherein each occcurrence of R 1B and R 1C is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl; whereby each of the foregoing alkyl and heteroalkyl moieties may be linear or branched, substituted or unsubstituted, cyclic or acylic, and each of the foregoing aryl, heteroaryl, - (alkyl)aryl and -(alkyl)heteroaryl moieties may be substituted or unsusbtituted; [0071] ix) R 1 is: wherein R 1A
• R 1 is:
• R 1A is hydrogen, halogen, -CN, -NO 2 , lower alkyl, lower heteroalkyl, -(alkyl)aryl, -(alkyl)heteroaryl, -OR 1B or -N(R 1B )SO 2 R lc ; wherein each 1 1 C* occcurrence of R and R is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl; whereby each of the foregoing alkyl and heteroalkyl moieties may be linear or branched, substituted or unsubstituted, cyclic or acylic, and each of the foregoing aryl, heteroaryl, - (alkyl)aryl and -(alkyl)heteroaryl moieties may be substituted or unsusbtituted; [0074] xii) R ⁇ s: wherein R
• R 1A and R 1B are each independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl; [0080] xviii) compounds of subset xvii) wherein R 1 and R 1B are each independently cyclic or acyclic lower alkyl;
• R 1A and R 1B are each independently methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, sec-butyl, isopentyl or cyclopropyl; [0082] xx) R 1 is:
• R 1A is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, - (alkyl)aryl or -(alkyl)heteroaryl
• R 1 is one of:
• R 1 is one of:
• R 1 is one of:
• R 2 is lower alkyl, -CH 2 NR 2A R 2B or -(CH 2 )phenyl, wherein the phenyl group is optionally substituted with one or more occurrences of R , wherein R is hydrogen, alkyl, alkoxy or halogen; and wherein R and R are each independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl; whereby each of the foregoing alkyl and heteroalkyl moieties may be linear or branched, substituted or unsubstituted, cyclic or acylic, and each of the foregoing aryl, heteroaryl, -(alkyl)aryl and -(alkyl)heteroaryl moieties may be substituted or unsusbtituted; [0090] xxviii) R 2 is one of:
• R is one of:
• each occcurrence of R 2A is independently hydrogen or lower alkyl; each occurrence of X is independently a halogen; s is an integer from 0 to 3 and u is an integer from 1 to 6; whereby each of the foregoing alkyl moieties may be linear or branched, substituted or unsubstituted and cyclic or acylic; [0092] xxx) compounds of subset xxix) wherein X is chlorine or fluorine;
• R 2 is one of:
• R is one of:
• R 2 is one of:
• R 2 is one of:
• R is hydrogen or halogen
• X 2 is CHR X2A and R X2A is hydrogen or linear or branched substituted or unsubstituted alkyl or -alkyl(aryl);
• X 2 is CHR X2A and ⁇ A is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, benzyl or phenethyl;
• Iii) X is CHR ,X ⁇ 2A and R ,X ⁇ 2A A is methyl, ethyl, propyl, isopropyl or phenethyl;
• X 2 is - R 2 - and R X2A is hydrogen or linear or branched substituted or unsubstituted alkyl;
• X is -CH(Me)Y- where Y is where each occurrence R X2B is hydrogen, or an aliphatic, heteroaliphatic, aryl, heteroaryl, - (alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or -(heteroalkyl)heteroaryl moiety; whereby each of the foregoing aliphatic and heteroaliphatic moieties may be linear or branched, substituted or unsubstituted, cyclic or acylic, saturated or unsaturated, and each of the foregoing aryl, heteroaryl, -(alkyl)aryl and -(alkyl)heteroaryl moieties may be substituted or unsusbtituted; [0121] lix) X 2 is absent;
• lxiii) X 3 is CHR X3A , X 2 is -NR 2 - and R MA and R X3A are each independently hydrogen or linear or branched substituted or unsubstituted alkyl; [0126] lxiv) X 3 is CHR 3A and X 2 is NH; wherein R X3A is hydrogen or linear or branched substituted or unsubstituted alkyl; [0127] lxv) X 3 is CH 2 and X 2 is NH;
• X 2 is CHR X2A and X 3 is CH 2 NH; wherein R ⁇ A is hydrogen or linear or branched substituted or unsubstituted alkyl;
• R 4 is substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl, phenyl or -(CH 2 )phenyl, wherein the phenyl group is optionally substituted with one or more occurrences of R 4A , wherein R 4A is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -OR 4B , -SR 4B , -
• R 4B and R 4C are independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteoraryl, -(alkyl)aryl or -(alkyl)heteroaryl;
• R 4 is substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl, phenyl or -(CH 2 )phenyl, wherein the phenyl group is optionally substituted with one or more occurrences of R 4A , wherein R 4A is hydrogen, hydroxyl, alkyl, alkoxy or halogen;
• R 4 is one of:
• R is hydrogen; [0135] lxxiii) R 4 is methyl, ethyl, propyl or one of:
• R is methyl, ethyl, propyl, isopropyl or one of:
• R 4 is one of:
• R 4 is methyl, ethyl, propyl, isopropyl or one of:
• R >4 is methyl, ethyl, propyl or one of:
• R 1 is as described in subset xxiii
• R 2 is as described in subset xxxiv
• X 2 is as described in subset li
• R 4 is as described in subset lxxxiii; [0148] lxxxvi)
• R 1 is as described in subset xxiv
• R 2 is as described in subset xxxv
• X 2 is as described in subset Iii
• R 4 is as described in subset lxxxiv; and/or [0149] lxxxvii)
• any one or more occurrences of aliphatic or heteroaliphatic may independently be substituted or unsubstituted, cyclic or acyclic, linear or branched, saturated or unsaturated and any one or more occurrences of aryl, heteroaryl, cycloaliphatic, cycloheteroaliphatic may be substituted or unsubstituted.
• the invention encompasses any and all compounds of fonnula I generated by taking any possible permutation of variables R', R 1 , X 1 , R 2 , R 3 , R 3 , X 2 , X 3 and R 4 , and other variables/substituents (e.g., R X1A , R ⁇ A , Y, R X3A , R 4A , etc.) as further defined for R', R 1 , X 1 , R 2 , R 3 , R 3' , X 2 , X 3 and R 4 , described in i)- through lxxxvii) above.
• variables R', R 1 , X 1 , R 2 , R 3 , R 3 , X 2 , X 3 and R 4 described in i)- through lxxxvii) above.
• R , R , R , R , X , X and R are as defined generally and in classes and subclasses herein.
• R 3 R X3 R4 has one of the following structures:
• R 3 is hydrogen, halogen or an aliphatic, heteroaliphatic, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or - (heteroalkyl)heteroaryl moiety;
• R 4 is an aliphatic, heteroaliphatic, aryl, heteroaryl, -(alkyl)aryl, - (alkyl)heteroaryl, -(heteroalkyl)aryl, or -(heteroalkylheteroaryl moiety, or R 4 , taken together with R HA or a substituent present on Y or X 3 , may form a cycloaliphatic, cycloheteroaliphatic, aryl, or heteroaryl moiety;
• R X2A is hydrogen or an aliphatic, heteroaliphatic, aryl, heteroaryl, - (alkyl
• R 3 , R 4 , R* 2 , R X2A' , R 213 and t are as defined above and in classes and subclasses herein.
• R 3 R 3 R4 has one of the following structures:
• R and R are as defined above and in classes and subclasses herein.
• R , R , R and R are as defined generally and in classes and subclasses herein.
• R 1 is a substituted or unsubstituted aryl, heteroaryl, -(alkyl)aryl, - (alkyl)heteroaryl or heterocyclic moiety.
• R 1 has one of the following structures:
• R 2 has one of the following structures:
• R is halogen. In certain exemplary embodiments, R is F. In certain other embodiments, R is hydrogen.
• R 4 is substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl, phenyl or -(CH 2 )phenyl, wherein the phenyl group is optionally substituted with one or more occurrences of R 4A , wherein R 4A is hydrogen, hydroxyl, alkyl, alkoxy or halogen.
• R 4 has one of the following structures:
• R X2A is a substituted or unsubstituted, linear or branched lower alkyl moiety.
• R is methyl, ethyl, propyl, isopropyl or phenethyl.
• inventive compounds and pharmaceutical compositions thereof may be in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the fonn of a mixture of stereoisomers.
• the compounds of the mvention are enantiopure compounds. In certain other embodiments, mixtures of stereoisomers or diastereomers are provided. [0166] Furthermore, certain compounds, as described herein may have one or more double bonds that can exist as either the Z or E isomer, unless otherwise indicated.
• the invention additionally encompasses the compounds as individual isomers substantially free of other isomers and alternatively, as mixtures of various isomers, e.g., racemic mixtures of stereoisomers.
• this invention also encompasses pharmaceutically acceptable derivatives of these compounds and compositions comprising one or more compounds of the invention and one or more pharmaceutically acceptable excipients or additives.
• Compounds of the invention may be prepared by crystallization of compound of formula (I) under different conditions and may exist as one or a combination of polymorphs of compound of general formula (I) forming part of this invention.
• different polymorphs may be identified and/or prepared using different solvents, or different mixtures of solvents for recrystallization; by performing crystallizations at different temperatures; or by using various modes of cooling, ranging from very fast to very slow cooling during crystallizations.
• Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling.
• the presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffractogram and/or other techniques.
• the present invention encompasses inventive compounds, their derivatives, their tautomeric fonns, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts their pharmaceutically acceptable solvates and phannaceutically acceptable compositions containing them.
• inventive compounds their derivatives, their tautomeric fonns, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts their pharmaceutically acceptable solvates and phannaceutically acceptable compositions containing them.
• the present invention provides novel compounds, specifically compounds having the following general structure: R ' NH 2 ⁇ x R4 R 2 R 3 R 3' (I) and pharmaceutically acceptable derivatives thereof; wherein R 1 , R 2 , R 3 , R 3' , R , X 1 , X 2 , X 3 and R 4 are as defined generally above and in classes and subclasses herein.
• R 1 , R 2 , R 3 , R 3' , R , X 1 , X 2 , X 3 and R 4 are as defined generally above and in classes and subclasses herein.
• certain classes of compounds are of special interest.
• one class of compounds of special interest includes those compounds wherein the compound has the stereochemistry as shown in Formula (I A ):
• step (i) reacting the compound of step (i) under suitable conditions to generate a compound having the structure:
• step (iii) reacting the compound of step (iii) with suitable reagents to generate the free amine having the structure :
• the present invention encompasses methods for the preparation of compounds having the general formula (I ), and classes and subclasses herein.
• the method comprises: i) providing a compound having the structure: wherein R', R , R , R ' and X are as defined above, p .
• step (iii) reacting the compound of step (iii) with suitable reagents to generate the free amine having the structure (I A ):
• R', R 1 , R 2 , R 3 , R 3' , R 4 , X 1 , X 2 and X 3 are as defmed generally above and in classes and subclasses herein.
• the inventive method comprises i) providing a compound having the structure:
• R P1 is a nitrogen protecting group
• step (iii) reacting the compound of step (iii) with suitable reagents to generate the free amine having the structure :
• the present invention encompasses methods for the preparation of compounds having the general formula (I' A ), and classes and subclasses herein.
• the method comprises: i) providing a compound having the structure:
• R pl is a nitrogen protecting group
• step (iii) reacting the compound of step (ii) with suitable reagents to generate a compound having the structure: H U R "X ⁇ 3 x V B R ; and iv) reacting the compound of step (iii) with suitable reagents to generate the free amine having the structure (T A ):
• step i) involves providing a oxo-tetrahydro-furan-2-yl (as described in the Examples herein). Subsequent ring opening, protection, oxidation and stereoselective reduction yields the desired compound of provided in step i). Subsequent reduction to an azide in step ii) and reaction with a suitable reagent (to yield -X'-R 1 ) is also effected. Finally, reaction with a suitable reagent to generate — X 3 -R 4 and deprotection yields the desired compound. It will be appreciated that a variety of methods can be utilized to effect these transformations, including those detailed in the specification herein, and additional general guidance as also described herein.
• prodrug moieties of interest include, among others, prodrug moieties that can be attached to primary or secondary amine-containing functionalities.
• prodrug moieties of interest include those that can be attached to group -NH 2 .
• prodrug moieties include the following:
• R C1-C4 alkyl, cycloalkyl, oxyalkyl, aminoalkyl, etc.
• R 2 all natural, unnatural amino acids
• the present invention encompasses any prodrug form of the compounds described herein. Although certain other exemplary prodrug moieties generated from the inventive compounds amino group are detailed herein, it will be appreciated that the present invention is not intended to be limited to these prodrug moieties; rather, a variety of additional prodrug moieties can be readily identified by a person skilled in the relevant art. [0187] 3) Pharmaceutical Compositions
• certain of the compounds as described herein exhibit activity generally as inhibitors of aspartyl proteases and more specifically as inhibitors of ⁇ -secretase enzyme activity, and have the ability to halt or reduce the production of A ⁇ from APP and reduce or eliminate the formation of ⁇ -amyloid deposits in the brain.
• the compounds are useful for treating humans or animals suffering from a condition characterized by a pathological form of ⁇ - amyloid peptide, such as ⁇ -amyloid plaques, and for helping to prevent or delay the onset of such a condition.
• compounds of the invention are useful for treating Alzheimer's disease, for helping prevent or delay the onset of Alzheimer's disease, for treating patients with MCI (mild cognitive impairment) and preventing or delaying the onset of Alzheimer's disease in those who would progress from MCI to AD, for treating Down's syndrome, for treating humans who have Hereditary Cerebral Hemmorhage with Amyloidosis of the Dutch-Type, for treating cerebral amyloid angiopathy and preventing its potential consequences, i.e.
• MCI mimild cognitive impairment
• compositions are provided, which comprise any one of the compounds described herein (or a prodrug, pharmaceutically acceptable salt or other pharmaceutically acceptable derivative thereof), and optionally comprise a pharmaceutically acceptable carrier.
• compositions optionally further comprise one or more additional therapeutic agents.
• a compound of this invention may be administered to a patient in need thereof in combination with the administration of one or more other therapeutic agents.
• additional therapeutic agents for conjoint administration or inclusion in a pharmaceutical composition with a compound of this invention may be an approved agent for the treatment of Alzheimer's Disease, or it may be any one of a number of agents undergoing approval in the Food and Drug Administration that ultimately obtain approval for the treatment any disorder suffering from a condition characterized by a pathological form of ⁇ -amyloid peptide.
• certain of the compounds of present invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof.
• a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or a pro-drug or other adduct or derivative of a compound of this invention which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.
• the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
• Pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the ait. For example, S.M. Berge, et al. describe pharmaceutically acceptable salts in detail in J Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by reference.
• suitable pharmaceutically acceptable salts thereof may, include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts.
• Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
• inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
• organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
• salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hernisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
• alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
• Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
• ester refers to esters that hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
• Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
• esters include formates, acetates, propionates, butyrates, acrylates and ethylsuccina ⁇ es.
• prodrugs refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the issues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
• prodrug refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
• the pharmaceutical compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
• a pharmaceutically acceptable carrier includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
• any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this invention.
• materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatine; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil, sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogenfree water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium
• Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
• the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
• the oral compositions can also include adj
• Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
• the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3- butanediol.
• the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil can be employed including synthetic mono- or diglycerides.
• fatty acids such as oleic acid are used in the preparation of injectables.
• the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
• sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
• delayed abso ⁇ tion of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
• Injectable depot may form are made by forming microencapsule matrices of the drag in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include (poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
• compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
• suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
• Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
• the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar—agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) abso ⁇ tion accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetylene glycol, g
• Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
• the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
• Examples of embedding compositions that can be used include polymeric substances and waxes.
• Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
• the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
• the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose and starch.
• Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose.
• additional substances other than inert diluents e.g., tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose.
• the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
• Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
• the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
• Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention.
• the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. These dosage may form are made by dissolving or dispensing the compound in the proper medium. Abso ⁇ tion enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
• the compounds and pharmaceutical compositions of the present invention can be formulated and employed in combination therapies, that is, the compounds and pharmaceutical compositions can be formulated with or administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures.
• compounds of the invention can be used in combination, with each other, or with other therapeutic agents or approaches used to treat or prevent the conditions described above and herein.
• agents include, but are not limited to: acetylcholine esterase inhibitors such as tacrine (tetrahydroaminoacridine, marketed as COGNEX®), donepezil hydrochloride (marketed as Aricept® and rivastigmine (marketed as Exelon®); gamma-secretase inhibitors; anti-inflammatory agents such as cyclooxygenase II inhibitors; anti-oxidants such as Vitamin E and ginkolides; immunological approaches, such as, for example, immunization with A ⁇ peptide or administration of anti-A ⁇ peptide antibodies; statins; and direct or indirect neurotropic agents such as Cerebrolysin®, AIT-082 (Emilieu, 2000, Arch.
• acetylcholine esterase inhibitors such as tacrine (tetrahydroaminoacridine, marketed as COGNEX®), donepezil hydrochloride (marketed as Aricept® and rivastigmine (
• the particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another Alzheimer's agent), or they may achieve different effects (e.g., control of any adverse effects).
• the pharmaceutical compositions of the present invention further comprises one or more additional therapeutically active ingredients (e.g., palliative).
• the term "Palliative" refers to treatment that is focused on the relief of symptoms of a disease and/or side effects of a therapeutic regimen, but is not curative.
• palliative treatment encompasses painkillers, antinausea medications and anti-sickness drugs.
• the inventive compounds may be assayed in any of the available assays known in the art for identifying compounds having protease inhibitory activity.
• the assay may be cellular or non- cellular, in vivo or in vitro, high- or low-throughput format, etc.
• compounds of this invention were assayed for their ability to inhibit aspartyl proteases, more specifically BACE.
• compounds of this invention which are of particular interest include those which: are inhibitors of aspartyl proteases;
• compounds of the invention are aspartyl protease inhibitors.
• inventive compounds are selective BACE inhibitors.
• inventive compounds have BACE ⁇ ; app ⁇ 10 ⁇ M.
• inventive compounds have BACE K app ⁇ 7.5 ⁇ M.
• inventive compounds have BACE j r app ⁇ ⁇ ⁇ j ⁇ n certa j n 0 ther embodiments, inventive compounds have BACE j ⁇ app ⁇ • 2 5 ⁇ ] [_ n cer t a j n other embodiments, inventive compounds have BACE jg app ⁇ - j ⁇ jyj ⁇ j n certain other embodiments, inventive compounds have BACE jg app ⁇ - ⁇ o nM. In certain other embodiments, inventive compounds have BACE j ⁇ a pp ⁇ • ⁇ QQ ⁇ n cer t ain 0 th er embodiments, inventive compounds have BACE jg app ⁇ 250 n M.
• inventive compounds have BACE j app ⁇ jQO nM. In certain other embodiments, inventive compounds have B A CE j ⁇ app ⁇ gQ ⁇ j n certa j n 0 ther embodiments, inventive compounds have BACE jg ap ⁇ ⁇ Q ⁇ j n certa i n other embodiments, inventive compounds have BACE jg app ⁇ ⁇ Q ⁇ j n certa j n other embodiments, inventive compounds have BACE j ' p ⁇ 30 nM. In certain other embodiments, inventive compounds have BACE jg app ⁇ 20 nM. In certain other embodiments, inventive compounds have
• CatD ⁇ 7 app for compounds of the invention is >
• CatD ⁇ ; app for compounds of the invention is > 3 fold greater than BACE ⁇ , app .
• c atD jq app for compounds of the invention is > 4 fold greater than BACE ⁇ app .
• CatD ⁇ , app for compounds of the invention is > 5 fold greater than BACE K .a p P _
• CatD ⁇ , app for compounds of the invention is > 7.5 fold greater than BACE ⁇ , app .
• CatD ⁇ , a p for compounds of the invention is > 10 fold greater than BACE ⁇ , app .
• CatD K, app for compounds of the invention is > 25 fold greater than BACE ⁇ , a p . In certain embodiments, CatD K, app for compounds of the invention is > 50 fold greater than BACE K . app . In certain embodiments, CatD K, app for compounds of the invention is > 75 fold greater than BACE K, app . In certain embodiments, CatD K; app for compounds of the invention is > 100 fold greater than BACE Ki app . In certain embodiments, CatD K, ap for compounds of the invention is > 150 fold greater than BACE , app . In certain embodiments, CatD ⁇ , pp for compounds of the invention is > 200 fold greater than BACE jqa pp .
• CatD K app for compounds of the invention is > 250 fold greater than BACE K, app . In certain embodiments, CatD ⁇ , app for compounds of the invention is > 300 fold greater than BACE Ki app . In certain embodiments, CatD K, app for compounds of the invention is > 500 fold greater than BACE ⁇ , app . In certain embodiments, CatD ⁇ , app for compounds of the invention is > 1000 fold greater than
• inventive compounds have
• inventive compounds have Cell IC 50 values ⁇ 10 ⁇ M. In certain other embodiments, inventive compounds have Cell IC 5 o values ⁇ 7.5 ⁇ M. In certain other embodiments, inventive compounds have Cell IC 5 o values ⁇ 5 ⁇ M. In certain other embodiments, inventive compounds have Cell IC 50 values ⁇ 2.5 ⁇ M. In certain other embodiments, inventive compounds have CeI1 IC 50 values ⁇ 1 ⁇ M. In certain other embodiments, inventive compounds have Cell IC 50 values ⁇ 750 nM. In certain other embodiments, inventive compounds have CelI IC 50 values ⁇ 500 nM. In certain other embodiments, inventive compounds have CelI IC 50 values ⁇ 250 nM. In certain other embodiments, inventive compounds have Cell IC 5 o values ⁇ 100 nM.
• inventive compounds have Cell IC 5 o values ⁇ 80 nM. In certain other embodiments, inventive compounds have Cell IC 5 o values ⁇ 60 nM. In certain other embodiments, inventive compounds have Cell IC 5 o values ⁇ 50 nM. In certain other embodiments, inventive compounds have Cell IC 5 o values ⁇ 30 nM. In certain other embodiments, inventive compounds have Cell IC 50 values ⁇ 20 nM. In certain other embodiments, inventive compounds have Cell IC 50 values ⁇ 10 nM.
• certain of the compounds as described herein exhibit activity generally as inhibitors of aspartyl proteases and more specifically as inhibitors of ⁇ -secretase enzyme activity.
• compounds exhibit the ability to halt or reduce the production of A ⁇ from APP and reduce or eliminate the formation of ⁇ - amyloid deposits in the brain and thus the compounds are useful for treating humans or animals suffering from a condition characterized by a pathological form of ⁇ - amyloid peptide, such as ⁇ -amyloid plaques, and for helping to prevent or delay the onset of such a condition (e.g., Alzheimer's Disease).
• compounds of the invention are useful for treating Alzheimer's disease, for helping prevent or delay the onset of Alzheimer's disease, for treating patients with MCI (mild cognitive impairment) and preventing or delaying the onset of Alzheimer's disease in those who would progress from MCI to AD, for treating Down's syndrome, for treating humans who have Hereditary Cerebral Hemmorhage with Amyloidosis of the Dutch-Type, for treating cerebral amyloid angiopathy and preventing its potential consequences, i.e.
• MCI mimild cognitive impairment
• the method involves the administration of a therapeutically effective amount of the compound or a pharmaceutically acceptable derivative thereof to a subject (including, but not limited to a human or animal) in need of it.
• compounds of the invention are useful as inhibitors of aspartyl proteases.
• compounds of the invention exhibit the ability to inhibit aspartyl protease enzyme activity and thus compounds of the invention generally are useful for the treatment of disorders mediated by aspartyl protease enzyme activity. More specifically, compounds of the invention exhibit activity as inhibitors of ⁇ -secretase enzyme activity and A ⁇ peptide production.
• the present invention provides compounds useful for the treatment of disorders mediated by a pathological form of ⁇ -amyloid peptide, such as ⁇ amyloid plaques, and for helping to prevent or delay the onset of such a condition.
• compounds of the invention are useful for treating Alzheimer's disease, for helping prevent or delay the onset of Alzheimer's disease, for treating patients with MCI (mild cognitive impairment) and preventing or delaying the onset of Alzheimer's disease in those who would progress from MCI to AD, for treating Down's syndrome, for treating humans who have Hereditary Cerebral Hemmorhage with Amyloidosis of the Dutch-Type, for treating cerebral amyloid angiopathy and preventing its potential consequences, i.e.
• MCI mimild cognitive impairment
• the compounds and compositions of the invention are particularly useful for treating or preventing Alzheimer's disease.
• the compounds of the invention can either be used individually or in combination.
• a method for the treatment of disorders useful for the treatment (or prevention) of disorders mediated by a pathological form of ⁇ -amyloid peptide, such as ⁇ amyloid plaques comprising administering a therapeutically effective amount of a compound of Formula (I) or (I A ), or any classes and subclasses of these compounds as described herein, to a subject in need thereof.
• a compound of Formula (I) or (I A ) or any classes and subclasses of these compounds as described herein, to a subject in need thereof.
• the compounds and compositions, according to the method of the present invention may be administered using any amount and any route of administration effective for the treatment of disorders by a pathological form of ⁇ -amyloid peptide, such as ⁇ amyloid plaques.
• the expression "effective amount” as used herein refers to a sufficient amount of agent to inhibit the production of A ⁇ peptide, and to exhibit a therapeutic effect. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular therapeutic agent, its mode of administration, and the like.
• the compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
• dosage unit form refers to a physically discrete unit of therapeutic agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
• the specific therapeutically effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts (see, for example, Goodman and Gilman's, "The Pharmacological Basis of Therapeutics", Tenth Edition, A. Gilman, J.Hardman and L. Limbird, eds., McGraw-Hill Press, 155-173, 2001, which is inco ⁇ orated herein by reference in its entirety).
• Another aspect of the invention relates to a method for inhibiting ⁇ - secretase activity in a biological sample or a patient, which method comprises administering to the patient, or contacting said biological sample with a compound of formula I or a composition comprising said compound.
• the pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated.
• the compounds of the invention may be administered at dosage levels of about 0.001 mg/kg to about 50 mg/kg, from about 0.01 mg/kg to about 25 mg/kg, or from about 0.1 mg/kg to about 10 mg/kg of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect. It will also be appreciated that dosages smaller than 0.001 mg/kg or greater than 50 mg/kg (for example 50-100 mg/kg) can be administered to a subject. In certain embodiments, compounds are administered orally or parenterally.
• the present invention relates to a kit for conveniently and effectively carrying out the methods in accordance with the present invention.
• the pharmaceutical pack or kit comprises one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention.
• kits are especially suited for the delivery of solid oral forms such as tablets or capsules.
• Such a kit preferably includes a number of unit dosages, and may also include a card having the dosages oriented in the order of their intended use.
• a memory aid can be provided, for example in the form of numbers, letters, or other markings or with a calendar insert, designating the days in the treatment schedule in which the dosages can be administered.
• placebo dosages, or calcium dietary supplements can be included to provide a kit in which a dosage is taken every day.
• Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceutical products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
• This example describes the enzyme assay for determining the apparent Kj of the compounds of the present invention.
• BACE-HT The BACE enzyme used for inhibition analyses, BACE-HT, was produced from baculoviras-infected insect cells, and corresponded to the pro form of the soluble N-terminal protease domain (residues 22-454, starting from the N- terminal methionine), followed by a short linker and C-terminal 6X His tag.
• FS-2 MOCAc-Ser-Glu-Val-Asn-Leu-
• EDANS is 5-((2-aminoethyl)amino)napthalene-l-sulfonic acid
• DABCYL is 4-((4-dimethylamino)phenyl)azo)benzoic acid
• MOCAc is 7-methoxycoumarin-4- yl) acetic acid
• DNP 2,4-dinotriphenylacetic acid.
• FS-1 and FS-2 correspond to the Swedish APP ⁇ -site sequence, flanked by either an EDANS or MOCAc fluorophore on the N-terminus and a DABCYL or DNP quenching group near the C-terminus.
• the DABCYL or DNP group quenches the EDANS or MOCAc (respectively) fluorescence by virtue of their close proximity.
• the DABCYL group quenches the EDANS fluorescence by virtue of their close proximity.
• Inhibitors were resuspended in DMSO and serially diluted in DMSO at 20x final assay concentration. Compound dilutions (5 ⁇ L) were transferred to Black non-treated 96-well microtiter plates, and resuspended in 85 ⁇ L 35.3 ⁇ M FS1 substrate in 100 mM sodium acetate buffer, pH 4.5, containing 5.9% DMSO (i.e. 10% final DMSO in assay). Following brief equilibration to room temperature, the reactions were initiated by the addition of lO ⁇ L BACE-HT (lOOnM final concentration) and brief mixing.
• K ⁇ app 's for the compounds is between 1-1000 nM.
• Ki app, s for preferced compounds is 0.1-500 nM.
• This example describes an illustrative set of cell-based assays for testing the ability of the compounds of the present invention to inhibit the secretion of the A ⁇ peptide from cells expressing high levels of the human amyloid precursor protein ("APP").
• APP human amyloid precursor protein
• a representative set of such cells include A-204 rhabdomyosarcoma cells, human embryonic kidney 293 cells transiently transfected with APP, Chinese hamster ovary cells stably transfected with APP (CHO2B7), and H4 neuroglioma cells stably transfected with APP (H4 ⁇ 695wt).
• the A-204 cells and HEK 293 cells were obtained from ATCC.
• HEK 293 transient transfections a pcDNA3 plasmid containing the human APP gene was obtained from Invitrogen, and cells were transfected with FuGENE 6 transfection reagent (Roche) following manufacturer's protocols.
• the CHO2B7 and H4 ⁇ 695wt lines were obtained from Mayo Clinic (J. Neuroscience Methods 108(2): 171-9 (2001)).
• the following media were used for the cell lines: DMEM + glucose, glutamine, sodium pyravate, pyridoxine-HCl, antibiotics, and 10% FBS (A-204 cells); DMEM + glucose, glutamine, sodium pyravate, pyridoxine-HCl, non- essential amino acids, antibiotics, and 10% FBS (HEK 293 cells); Ham's F-12 + antibiotics, 10% FBS, and 400 ⁇ g/ml Zeocin (CHO2B7 cells); and Opti-MEM (Invitrogen)+ antibiotics, 10% FBS, and 500 ⁇ g/ml geneticin(H4 ⁇ 695wt cells).
• Ih the assay, cells were pre-treated with compounds for 1-2 hours to
• Cells were plated at 2.5x10 5 cells/well (HEK293 cells in 24 well poly-D-lysine coated plate), 1.3 x 10 5 cells/well (A-204 cells) (48 well plates) or 5 x 10 4 cells/well (CHO2B7 and H4APP cells) (96 well plates) in appropriate media (500 ⁇ L per well for 24 well plates, 300 ⁇ L per well for 48 well plates, 150 ⁇ L per well for 96 well plates) and grown at 37° C and 5% CO for 16-20 h. Media was aspirated and replaced with appropriate media plus 0.1% DMSO and various concentrations of inhibitors, prepared by resuspension of the appropriate volume of a 1000X solution of inhibitor in DMSO with media on a separate plate.
• Binding was allowed to take place overnight at 4 °C, and plates were then washed 8 times and treated with 100 ⁇ L/well of 10 nM biotinylated 4G8 antibody in binding buffer (superblock in PBS plus 0.05% Tween 20) for 1 hour at room temperature. Plates were washed 8 times, treated with 100 ⁇ L/well of 1.5 ⁇ g/ Neutravidin- horseradish peroxidase conjugate (Pierce Chemicals) for 40 minutes at room temperature, washed an additional 8 times, and developed with 100 ⁇ L/well Supersignal luminescent substrate (Pierce Chemicals) for 2 minutes.
• Luminescence was measured on a Gemini XS fluorescence/luminescence plate reader, and translated into A ⁇ concentrations using an internal standard curve of known A ⁇ concentrations (A ⁇ 1-40 obtained from Oncogene).
• IC 50 's of the compounds of the present invention range from about 5X to about 15X the observed Ki app 's against the BACE enzyme as determined using the method of Example 1.
• This example describes permeability experiments using MDCK cells.
• MDCK cells derived from canine kidney, were obtained from
• This example describes pharmacokinetic experiments for determining peak plasma and peak brain concentrations using Adult Swiss Weber mice.
• the peak brain concentration determination also served as a measure for assessing whether the compounds were able to cross the blood brain barrier.
• Adult Swiss Webster mice were administered compounds via tail vein injection.
• Figure 1 A and IB are the plasma and brain concentration curves respectively for one of the compounds of the present invention (where each data point is an average concentration from three mice).
• This compound has a molecular weight of 626, has a Kj app of about 35 nM with a 125 fold selectivity over Cat D, and has an IC 5 0 in cells of about 220 nM.
• the amino compound is more potent in cells, is more selective for the BACE enzyme, and show superior ADME properties than its hydroxy counte ⁇ art.
• Plasma stability was determined by incubating the compounds in human plasma at a concentration of 1 ⁇ M at 37 °C for 0, 30 and 60 minutes.
• any available techniques can be used to make or prepare the inventive compounds or compositions including them.
• a variety of solution phase synthetic methods such as those discussed in detail below may be used.
• the inventive compounds may be prepared using any of a variety combinatorial techniques, parallel synthesis and/or solid phase synthetic methods known in the art.
• inventive compounds can be synthesized according to the methods described herein.
• the starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Company (Milwaukee, WI), Bachem (Torrance, CA), Sigma (St. Louis, MO), or are prepared by methods well known to a person of ordinary skill in the art following procedures described in such references as Fieser and Fieser 1991, “Reagents for Organic Synthesis", vols 1-17, John Wiley and Sons, New York, NY, 1991; Rodd 1989 “Chemistry of Carbon Compounds", vols.
• the starting materials, intermediates, and compounds of this invention may be isolated and purified using conventional techniques, including filtration, distillation, crystallization, chromatography, and the like. They may be characterized using conventional methods, including physical constants and spectral data.
• reaction mixtures were stirred using a magnetically driven stirrer bar.
• An inert atmosphere refers to either dry argon or dry nitrogen.
• Reactions were monitored either by thin layer chromatography, by proton nuclear magnetic resonance (NMR) or by high-pressure liquid chromatography (HPLC), of a suitably worked up sample of the reaction mixture.
• NMR proton nuclear magnetic resonance
• HPLC high-pressure liquid chromatography
• reaction mixtures were cooled to room temperature or below then quenched, when necessary, with either water or a saturated aqueous solution of ammonium chloride. Desired products were extracted by partitioning between water and a suitable water-immiscible solvent (e.g. ethyl acetate, dichloromethane, diethyl ether). The desired product containing extracts were washed appropriately with water followed by a saturated solution of brine. On occasions where the product containing extract was deemed to contain residual oxidants, the extract was washed with a 10% solution of sodium sulphite in saturated aqueous sodium bicarbonate solution, prior to the aforementioned washing procedure.
• a suitable water-immiscible solvent e.g. ethyl acetate, dichloromethane, diethyl ether
• chromatographic purification refers to flash column chromatography on silica, using a single solvent or mixed solvent as eluent. Suitably purified desired product containing elutes were combined and concentrated under reduced pressure at an appropriate temperature (generally less than 45°C) to constant mass. Final compounds were dissolved in 50%> aqueous acetonitrile, filtered and transferred to vials, then freeze-dried under high vacuum before submission for biological testing.
• a derivative of Formula I, or a pharmaceutically-acceptable derivative or salt thereof may be prepared using any of the available relevant chemical transformations, combined with protection and deprotection as desired or required. Such processes, when used to prepare a derivative of the formula I, or a pharmaceutically-acceptable salt thereof, are illustrated by the following representative examples.
• the various starting materials are either commercially available or may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described within the accompanying non-limiting Examples.
• Compound 1.2 was prepared by the treatment of (R,R)-(-)- pseudoephedrine (1 eq) and glycine methyl ester hydrochloride 1.1(1.3 eq) in tetrahydiOfuran (THF) with lithium tert-butoxide (1.4 eq) and worked up with water. EnoKzation of compound 1.2 in LiCl (3.2 eq) in THF by LHMDS (3.2 eq) and alkylation of RAX yields compound 1.3. Hydrolysis of compound 1.3 under basic condition (NaOH, H 2 O, refluxed) followed by protection of the amine gives compound 1.4.
• Methyl ester 3.1 is prepared by esterf ⁇ cation of the corresponding compound 1.4 (Example 6).
• the ketophosphonate 3.2 is made from methyl ester 3.1 by Claisen condensation with litho-dimethyl methylphosphonate.
• the Wadsworth- Emmons reaction of ketophosphonate 3.2 with ethyl pyravate affords olefin 3.3, which is followed by the reduction by NaBH 4 to afford lactone 3.4.
• Hydrogenation of lactone 3.4 followed by reduction of LAH yields diol 3.6.
• the protection of primary alcohol gives TBS ether 3.7.
• the mesylation of 3.7 follow by the addition of sodium azide to the mesylate affords compound 1.
• Method 1 To a mixture of compound 5.10 and 2-amino-N-benzyl-3-methyl- butyramide in DMF, EDC/HOBt/ DIEA was added. The resulting solution was stirred at room temperature overnight. IN HCI (2 mL) was added, followed by addition of EtOAc (80 mL). After stirring for 10 minutes, the organic layer was separated, washed with brine and dried over MgSO 4 . After removal of solvents, the residue was purified by column chromatography to afford compound 5.11.
• Method 2 To a mixture of compound 5.10 and 2-amino-N-benzyl-3-methyl-butyramide in CH 2 C1 2 , HATU/DIEA was added.
• Boc' - N a A solution of dimethyl methylphosphonate 6.1 (34.1 g, 215.4 mmol) in THF (250 mL) in a nitrogen atmosphere was cooled to -78 °C and then was added 2.0 M solution of butyllithium (107 mL, 215.4 mmol) via canula in 20 minutes. The solution was stirred at -78 °C for 20 minutes, and a THF (150 mL) solution of N- boc-L-phenylalanine methyl ester (10.0 g, 35.8 mmol) was slowly added via dropping funnel. The mixture was stirred at -78 °C for 1 hour. The reaction was then quenched with 10% AcOH (250 mL) and warmed to room temperature.
• Lactone 6.4 (3.5 g, 11.0 mmol) was dissolved in THF (300 mL), and to this solution 10% Pd/C (350 mg) was added. The mixture was stirred under an atmosphere of H 2 (balloon) for 5 hours, followed by filtration and concentration in vacuo, to provide product 6.5 (3.5 g, 99%) as white solid.
• R B is a substituted or unsubstituted aliphatic or aromatic moiety.
• Exemplary esters and their corresponding products are shown in Table 2. [0315] Table 2
• RQ is substituted or unsubstituted aliphatic or aromatic moiety.
• These compounds are prepared according to Example 10 except for using acids of the formula RcCOOH as a reagent instead of N,N-dipropyl-isophthalamic acid in step i and using 4-fluoroanaline instead of 2-amino-N-benzyl-3-methyl-butyramide in step k.
• acids of the formula RcCOOH as a reagent instead of N,N-dipropyl-isophthalamic acid in step i and using 4-fluoroanaline instead of 2-amino-N-benzyl-3-methyl-butyramide in step k.
• Table 3 Table 3
• R D and R E are each independently substituted or unsubstituted aliphatic or aromatic moieties.
• R F , R G , and R H are each independently substituted or unsubstituted aliphatic or aromatic. These compounds are prepared according to Scheme 9 and the procedure below.
• R F is substituted or unsubstituted aliphatic or aromatic moiety.
• Amino acid 12.2 is treated with benzyl amine and a coupling reagent such as HATU, to give 12.3.
• Compound 12.3 is reduced by a reducing reagent such as LAH to give amine 12.4.
• Compound 12.4 is treated with acid to afford diamine 12.5, which follow by condensation with an oxalic acid derivative gives the dioxopiperazine 12.6.
• Treatment of 12.6 with NaH and alkyl halide gives compound 12.7.
• R M is substituted or unsubstituted aliphatic or aromatic moiety.
• R N , R O , Rp, and RQ are each independently substituted or unsubstituted aliphatic or aromatic moiety.
• EXAMPLE 32 This example describes the synthesis of compounds of the formula wherein R R and Rs are each independently substituted or unsubstituted aliphatic or aromatic moiety, or R R and Rs together form a substituted or unsubstituted cycloaliphatic or aromatic moiety. These compounds are prepared according to Scheme 15 and the procedure below.
• Rj is substituted or unsubstituted aliphatic or aromatic moiety.
• These compounds are prepared according to Example 10 except for using amines of the formula H NR ⁇ instead of 2-amino-N-benzyl-3-methyl-butyramide in step k.

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