# Patent

## Title
Aspartyl protease inhibitors

## Abstract

The present invention provides compounds having the formula:




wherein R1, R′, R2, R3, R3′, R4, X1, X2 and X3 are as defined herein, and pharmaceutical compositions thereof. The present invention also provides methods of inhibiting proteases, more specifically aspartyl proteases. In certain embodiments, compounds inhibit BACE (β-site APP-cleaving enzyme), and thus are useful in the treatment or prevention of a disease characterized by β-amyloid deposits in the brain (including, but not limited to, Alzheimer's Disease). The present invention also provides methods for preparing compounds of the invention.

## Background
PRIORITY CLAIM
The present application is a Continuation-In-Part of U.S. patent application Ser. No. 10/462,127; filed Jun. 16, 2003, which claims priority under 35 U.S.C. § 119(e) to U.S. Ser. No. 60/430,693, filed Dec. 3, 2002, and U.S. Ser. No. 60/389,194, filed Jun. 17, 2002. The present application additionally claims priority to Patent Cooperation Treaty Application No.: PCT/US03/18858, filed Jun. 16, 2003. The entire contents of each of the above-referenced applications are incorporated herein by reference.


BACKGROUND OF THE INVENTION
Alzheimer's Disease is a progressive dementia in which massive deposits of aggregated protein breakdown products (β-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.
As described above, a defining feature of Alzheimer's Disease which is often used during clinical diagnosis is the presence of β-amyloid plaques and neurofibrillary tangles. β-amyloid plaques are predominantly composed of amyloid β peptide (Aβ (or βA4), which is derived by proteolysis of the amyloid precursor protein (APP). Proteolysis of the amyloid precursor protein is effected by several enzymes called secretases. More specifically, cleavage of APP at the N-terminus of the Aβ peptide by β-secretase and at the C-terminus by one or more γ-secretases constitutes the β-amyloidogenic pathway, i.e., the pathway by which Aβ is formed. It is believed that Aβ peptide accumulates as a result of this APP processing by β-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 β-secretase cleavage site is thought to be a rate limiting step in Aβ production, and is thus believed to be a therapeutic target for Alzheimer's Disease (Sabbagh et al. Alz. Dis. Rev. 1997, 3, 1–19). Recently, an aspartyl protease (known as BACE, Asp2, Memapsin) has been identified as the enzyme responsible for processing of APP at the β-secretase cleavage site (see, for example, Vassar, et al. Science, 1999, 286, 735–741; Yan et al. Nature, 1999, 402, 533–537; Sinha et al. Nature, 1999, 402, 537–540; and Hussain et al. Mol. Cell. Neurosci. 1999, 14, 419–427).
Because it is believed that BACE plays an important role in the development and pathogenesis of Alzheimer's Disease, there has been increasing interest in the development of inhibitors of BACE as treatments (and possibly as preventative agents) for Alzheimer's Disease and other disorders caused by the accumulation of β-amyloid plaques. There remains a need, however, for the development of novel therapeutics capable of inhibiting the activity of this aspartyl protease. In particular, it would be desirable to develop therapeutics capable of selectively inhibiting BACE.
SUMMARY OF THE INVENTION
As discussed above, there remains a need for the development of novel therapeutic agents and agents useful for treating disorders mediated by aspartyl proteases. The present invention provides novel compounds having the structure:




and pharmaceutical compositions thereof, as described generally and in subclasses herein, which compounds are useful as inhibitors of aspartyl proteases, and thus are useful, for example, for the treatment of Alzheimer's Disease.

In certain other embodiments, the invention provides pharmaceutical compositions comprising an inventive compound, wherein the compound is present in an amount effective to inhibit β-secretase activity. In certain other embodiments, the invention provides pharmaceutical compositions comprising an inventive compound and optionally further comprising an additional therapeutic agent. In yet other embodiments, the additional therapeutic agent is an agent for the treatment of Alzheimer's Disease.
In yet another aspect, the present invention provides methods for inhibiting β-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. In still another aspect, the present invention provides methods for treating any disorder involving β-secretase activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention. In certain other embodiments, the invention provides a method for treating or preventing a disease characterized by β-amyloid deposits in the brain comprising administering to a patient a therapeutically effective amount of a compound of the invention.



BRIEF DESCRIPTION OF THE DRAWING
FIG. 1A depicts a plasma concentration curve for an exemplary inventive compound.
FIG. 1B depicts a brain concentration curve for an exemplary inventive compound.



DEFINITIONS
Certain compounds of the present invention, and definitions of specific functional groups are described in more detail below. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, the entire contents of which are incorporated herein by reference. Furthermore, it will be appreciated by one of ordinary skill in the art that the synthetic methods, as described herein, utilize a variety of protecting groups. 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. In preferred embodiments, 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. As detailed herein, oxygen, sulfur, nitrogen and carbon protecting groups may be utilized. For example, in certain embodiments, as detailed herein, certain exemplary oxygen protecting groups are utilized. These 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-butyldimethylsilyl ether), tribenzyl silyl ether, TBDPS (t-butyldiphenyl silyl ether), to name a few), esters (e.g., formate, acetate, benzoate (Bz), trifluoroacetate, dichloroacetate, to name a few), carbonates, cyclic acetals and ketals. In certain other exemplary embodiments, 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. Greene, T. W. and Wuts, P. G., Eds., John Wiley & Sons, New York: 1999, the entire contents of which are hereby incorporated by reference
It will be appreciated that the compounds, as described herein, may be substituted with any number of substituents or functional moieties. In general, the term “substituted” whether preceded by the term “optionally” or not, and substituents contained in formulas of this invention, refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For purposes of this invention, 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. Furthermore, this invention is not intended to be limited in any manner by the permissible 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. The term “stable”, as used herein, 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.
The term “aliphatic”, as used herein, 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. As will be appreciated by one of ordinary skill in the art, “aliphatic” is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties. Thus, as used herein, the term “alkyl” includes straight, branched and cyclic alkyl groups. An analogous convention applies to other generic terms such as “alkenyl”, “alkynyl” and the like. Furthermore, as used herein, the terms “alkyl”, “alkenyl”, “alkynyl” and the like encompass both substituted and unsubstituted groups. In certain embodiments, as used herein, “lower alkyl” is used to indicate those alkyl groups (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1–6 carbon atoms.
In certain embodiments, the alkyl, alkenyl and alkynyl groups employed in the invention contain 1–20 aliphatic carbon atoms. In certain other embodiments, 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, —CH2-cyclopropyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, —CH2-cyclobutyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, cyclopentyl, —CH2-cyclopentyl-n, hexyl, sec-hexyl, cyclohexyl, —CH2-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-1-yl, and the like. Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl and the like.
The term “alkoxy” (or “alkyloxy”), or “thioalkyl” as used herein 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. 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 alkoxy, include but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and n-hexoxy. Examples of thioalkyl include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like.
The term “alkylamino” refers to a group having the structure —NHR′ wherein R′ is alkyl, as defined herein. The term “dialkylamino” refers to a group having the structure —N(R′)2, wherein R′ is alkyl, as defined herein. The term “aminoalkyl” refers to a group having the structure NH2R′—, wherein R′ is alkyl, as defined herein. In certain embodiments, 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.
Some examples of 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; —NO2; —CN; —CF3; —CH2CF3; —CHCl2; —CH2OH; —CH2CH2OH; —CH2NH2; —CH2SO2CH3; —C(O)Rx; —CO2(Rx); —CON(Rx)2; —OC(O)Rx; —OCO2Rx; —OCON(Rx)2; —N(Rx)2; —S(O)Rx; —S(O)2Rx; —NRx(CO)Rx; —N(Rx)CO2Rx; —N(Rx)S(O)2Rx; —N(Rx)C(═O)N(Rx)2; —S(O)2N(Rx)2; wherein each occurrence of Rx independently includes, but is not limited to, aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, wherein any of the aliphatic, heteroaliphatic, alkylaryl, or alkylheteroaryl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl substituents described above and herein may be substituted or unsubstituted. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.
In general, the terms “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. It will also be appreciated that aromatic and heteroaromatic moieties, as defined herein may be attached via an alkyl or heteroalkyl moiety and thus also include -(alkyl)aromatic, -(heteroalkyl)aromatic, -(heteroalkyl)heteroaromatic, and -(heteroalkyl)heteroaromatic moieties. Thus, as used herein, the phrases “aromatic or heteroaromatic moieties” and “aromatic, heteroaromatic, -(alkyl)aromatic, -(heteroalkyl)aromatic, -(heteroalkyl)heteroaromatic, and -(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.
The term “aryl”, as used herein, 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.
The term “heteroaryl”, as used herein, 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.
It will be appreciated that aryl and heteroaryl groups (including bicyclic aryl 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; —NO2; —CN; —CF3; —CH2CF3; —CHCl2; —CH2OH; —CH2CH2OH; —CH2NH2; —CH2SO2CH3; —C(O)Rx; —CO2(Rx); —CON(Rx)2; —OC(O)Rx; —OCO2Rx; —OCON(Rx)2; —N(Rx)2; —S(O)Rx; —S(O)2Rx; —NRx(CO)Rx; —N(Rx)CO2Rx; —N(Rx)S(O)2Rx; —N(Rx)C(═O)N(Rx)2; —S(O)2N(Rx)2; wherein each occurrence of Rx independently includes, but is not limited to, aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, wherein any of the aliphatic, heteroaliphatic, alkylaryl, or alkylheteroaryl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl substituents described above and herein may be substituted or unsubstituted. Additionally, it will be appreciated, that any two adjacent groups taken together may represent a 4, 5, 6, or 7-membered cyclic, substituted or unsubstituted aliphatic or heteroaliphatic moiety. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.
The term “cycloalkyl”, as used herein, 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; —NO2; —CN; —CF3; —CH2CF3; —CHCl2; —CH2OH; —CH2CH2OH; —CH2NH2; —CH2SO2CH3; —C(O)Rx; —CO2(Rx); —CON(Rx)2; —OC(O)Rx; —OCO2Rx; —OCON(Rx)2; —N(Rx)2; —S(O)Rx; —S(O)2Rx; —NRx(CO)Rx; —N(Rx)CO2Rx; —N(Rx)S(O)2Rx; —N(Rx)C(═O)N(Rx)2; —S(O)2N(Rx)2; wherein each occurrence of Rx independently includes, but is not limited to, aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, wherein any of the aliphatic, heteroaliphatic, alkylaryl, or alkylheteroaryl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl substituents described above and herein may be substituted or unsubstituted. Additionally, it will be appreciated that 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.
The term “heteroaliphatic”, as used herein, refers to aliphatic moieties in which one or more carbon atoms in the main chain have been substituted with a heteroatom. Thus, a 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. In certain embodiments, 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; —NO2; —CN; —CF3; —CH2CF3; —CHCl2; —CH2OH; —CH2CH2OH; —CH2NH2; —CH2SO2CH3; —C(O)Rx; —CO2(Rx); —CON(Rx)2; —OC(O)Rx; —OCO2Rx; —OCON(Rx)2; —N(Rx)2; —S(O)Rx; —S(O)2Rx; —NRx(CO)Rx; —N(Rx)CO2Rx; —N(Rx)S(O)2Rx; —N(Rx)C(═O)N(Rx)2; —S(O)2N(Rx)2; wherein each occurrence of Rx independently includes, but is not limited to, aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, wherein any of the aliphatic, heteroaliphatic, alkylaryl, or alkylheteroaryl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl substituents described above and herein may be substituted or unsubstituted.
In general, the term “cycloaliphatic”, as used herein, refer 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. In certain embodiments, 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. As will be appreciated by one of ordinary skill in the art, “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, —CH2-cyclopropyl, cyclobutyl, —CH2-cyclobutyl, cyclopentyl, —CH2-cyclopentyl, cyclohexyl, —CH2-cyclohexyl, cyclohexenylethyl, cyclohexanylethyl, norborbyl moieties and the like, which again, may bear one or more substituents.
In general, the term “cycloheteroaliphatic”, as used herein, 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. The term “cycloheteroaliphatic” encompasses “heterocycloalkyl”, “heterocycle” or “heterocyclic” moieties, as defined herein.
Additionally, it will be appreciated that 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.
The terms “halo” and “halogen” as used herein refer to an atom selected from fluorine, chlorine, bromine and iodine.
The term “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.
The term “acyl”, as used herein, refers to a group having the general formula —C(═O)R, where R is an aliphatic, heteroaliphatic, heterocycle, aromatic or heteroaromatic moiety, as defined herein.
The term “heterocycloalkyl”, “heterocycle” or “heterocyclic”, as used herein, 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. In certain embodiments, the term “heterocycloalkyl”, “heterocycle” or “heterocyclic” 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 aryl or heteroaryl ring. Representative 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, and benzofused derivatives thereof. In certain embodiments, a “substituted heterocycle, or heterocycloalkyl or heterocyclic” group is utilized and as used herein, 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; —NO2; —CN; —CF3; —CH2CF3; —CHCl2; —CH2OH; —CH2CH2OH; —CH2NH2; —CH2SO2CH3; —C(O)Rx; —CO2(Rx); —CON(Rx)2; —OC(O)Rx; —OCO2Rx; —OCON(Rx)2; —N(Rx)2; —S(O)2RX; —NRx(CO)Rx; —N(Rx)CO2Rx; —N(Rx)S(O)2Rx; —N(Rx)C(═O)N(Rx)2; —S(O)2N(Rx)2; wherein each occurrence of Rx independently includes, but is not limited to, aliphatic, cycloaliphatic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl or heteroalkylheteroaryl, wherein any of the aliphatic, cycloaliphatic, heteroaliphatic, heterocyclic, alkylaryl, or alkylheteroaryl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, saturated or unsaturated, and wherein any of the aromatic, heteroaromatic, aryl or heteroaryl substitutents described above and herein may be substituted or unsubstituted. Additional examples or generally applicable substituents are illustrated by the specific embodiments shown in the Examples, which are described herein.
As used herein, the terms “aliphatic”, “heteroaliphatic”, “alkyl”, “alkenyl”, “alkynyl”, “heteroalkyl”, “heteroalkenyl”, “heteroalkynyl”, and the like encompass substituted and unsubstituted, saturated and unsaturated, and linear and branched groups. Similarly, the terms “alicyclic”, “heterocyclic”, “heterocycloalkyl”, “heterocycle” and the like encompass substituted and unsubstituted, and saturated and unsaturated groups. Additionally, the terms “cycloalkyl”, “cycloalkenyl”, “cycloalkynyl”, “heterocycloalkyl”, “heterocycloalkenyl”, “heterocycloalkynyl”, “aromatic”, “heteroaromatic”, “aryl”, “heteroaryl” and the like encompass both substituted and unsubstituted groups.
As used herein, the term “isolated”, when applied to the compounds of the present invention, 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.
The phrase, “pharmaceutically acceptable derivative”, as used herein, 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.
As used herein the term “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. For example, the term “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. a normal joint or a joint affected by disease such as rheumatoid arthritis, osteoarthritis, gout or septic arthritis). 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. Although the sample is preferably taken from a human subject, biological samples may be from any animal, plant, bacteria, virus, yeast, etc. The term animal, as used herein, 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. In certain exemplary embodiments, 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. If desired, the biological sample may be subjected to preliminary processing, including preliminary separation techniques.
DESCRIPTION OF CERTAIN PREFERRED EMBODIMENTS OF THE INVENTION
As noted above, there has been increasing interest ion recent years in the development of aspartyl protease inhibitors, particularly BACE inhibitors, as therapeutic agents for the treatment of Alzheimer's Disease and other disorders caused by the accumulation of β-amyloid plaques. It has been generally accepted by the scientific community that potential new leads for aspartyl inhibitor small molecules must comprise an aspartate binding hydroxyl group to retain aspartyl protease inhibitory activity (See for example, Ajay et al., “Designing Libraries woth CNS Activity”, J. Med. Chem., 42:4942–4951, 1999, see especially the paragraph bridging columns 1 and 2 on page 4942 of this article). 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 counterparts. In fact, the present invention shows that certain amino-containing inventive compounds possess several superior biological properties over their hydroxy-containing counterparts (e.g., increased potency in cells, increased selectivity for the BACE enzyme, and/or superior ADME properties).
Thus, 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 β amyloid deposits or plaques. In certain exemplary embodiments, the compounds are useful for the treatment of Alzheimer's Disease.
Compounds of this invention include those generally set forth above and described specifically herein, and are illustrated in part by the various classes, subgenera and species disclosed herein.
Additionally, 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.
1) General Description of Compounds of the Invention
In certain embodiments, the compounds of the invention include compounds of the general formula (I) as further defined below:




    and pharmaceutically acceptable derivatives thereof;
    wherein R′ is hydrogen or an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, or R′, taken together with R2 or a substituent present on R1, may form a cycloheteroaliphatic moiety;
    R1 is an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, or R1, taken together with R′, may form a cycloheteroaliphatic moiety;
    X1 is —C(═O)—, —S(═O)—, —C(═NH)—, —C(═S)—, —NC(═O)—, —NC(═S)—, —N—C(═N—C≡N)—, —NS(O2)—, —CHRX1A—, —SO2—, —COO—, —C(═O)C(RX1A)2—, or —SC(═O)— wherein each occurrence of RX1A is independently hydrogen, or an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety;
    R2 is an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, or R2, taken together with R′, may form a cycloheteroaliphatic moiety;
    R3 is hydrogen, halogen, or an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety;
    R3′ is hydrogen, halogen, or lower alkyl;
    R4 is hydrogen, an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, or R4, taken together with a substituent present on X2 or X3, may form a cycloaliphatic, cycloheteroaliphatic, aromatic, or heteroaromatic moiety;
    X2 is absent, —NRX2A—, —(CHRX2A)j—, —NRX2AY—, —(CHRX2A)jY— or —N(RX2A)CH(RX2A′)Y— wherein each occurrence of RX2A is independently hydrogen or an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety; each occurrence of Y is independently






wherein, for each independent occurrence of t, RX2B is hydrogen, or an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, or RX2A or one occurrence of RX2B taken together with R4 may form a cycloaliphatic, cycloheteroaliphatic, aromatic or heteroaromatic moiety, and wherein each occurrence of j and t is independently an integer from 1 to 4; and

    X3 is absent, —NHCO—, —NHSO2—, —NHCONH—, —NHCOO—, —CH2NH—, —C(═O)—, —S(═O)—, —C(═NH)—, —C(═S)—, —NC(═S)N—, —N—C(═N—C≡N)N—, —NS(O2)N—, —SO2—, —C(═O)NRX3A—, —C(═S)NRX3A—, —COO—, —(CHRX3A)k—, —O—, —CH2NRX3A—, or —NRX3A—, wherein each occurrence of RX3A is independently hydrogen, an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, or RX3A taken together with R4 may form a cycloaliphatic, cycloheteroaliphatic, aromatic or heteroaromatic moiety, and k is an integer from 1 to 3.


In certain embodiments of compounds described directly above and compounds as described in certain classes and subclasses herein, one or more of the following groups do not occur simultaneously as defined:

    (i) R′, R3 and R3′ are each hydrogen; R2 is alkyl, cycloalkylalkyl or aralkyl; —X2—X3—R4 together represents —CHReC(═O)NHCH(Rw)C(═O)NRxRy, wherein Re is hydrogen or alkyl, Rw is alkyl, and one of Rx or Ry represents hydrogen and the other represents hydrogen, alkyl, aryl, aralkyl, 1-alkoxycarbonyl-2-phenylethyl, 1-alkoxycarbonyl-2-(imidazol-4-yl)ethyl, 2-(imidazol-1-yl)ethyl, indanyl, heterocyclyl-alkyl, carboxyalkyl, alkoxycarbonylalkyl, aryloxycarbonylalkyl, aralkoxycarbonylalkyl or a group of the formula -A-N(Ra)(Rb) in which A represents alkylene and Ra and Rb each represents alkyl or Ra and Rb together represent a pentamethylene group in which one methylene group can be replaced by NH, N-alkyl, N-alkanoyl, N-aralkoxycarbonyl, O, S, SO, or SO2; or Rx and Ry together with the nitrogen atom to which they are attached represent a 1,2,3,4-tetrahydroisoquinoline ring; and —X1—R1 together represents an alkoxycarbonyl, aralkoxycarbonyl, alkanoyl, aralkanoyl, aroyl, cycloalkylcarbonyl, heterocyclylcarbonyl, heterocyclyl-alkanoyl, 6-(dibenzylcarbamoyl)-4-oxohexanoyl moiety or an acyl group of an α-amino acid in which the amino group is substituted by an alkoxycarbonyl, aralkoxycarbonyl, diaralkylcarbamoyl, diaralkylalkanoyl, or aralkanoyl moiety;
    wherein the term “aroyl” refers to an acyl group derived from from an arylcarboxylic acid such as benzoyl, 1-naphthoyl, 2-naphthoyl, etc., and the term “aralkanoyl” refers to an acyl group derived from an aryl-substituted alkanecarboxylic acid;
    whereby the term “aryl” alone or in each of the aralkyl, aryloxycarbonylalkyl, aralkoxycarbonylalkyl or N-aralkoxycarbonyl moieties refers to a phenyl or naphthyl group optionally substituted with one or emore substituents selected from alkyl, hydroxy, alkoxy and halogen;
    (ii) R′, R3 and R3′ are each hydrogen; X1 is —C(═O)—, —SO2—, N(Rx)SO2, N(Rx)C(═O) or SC(═O), wherein Rx is hydrogen, C1-5alkyl or joined together with R1 either directly to form a 5–7 membered heterocycle such as pyrrolidinyl or piperidinyl, or through a heteroatom selected from N, O and S, to form a 6-membered heterocycle with the nitrogen to which they are attached such as morpholinyl, piperazyl, or N—C1-3alkyl-piperazyl; R1 is a substituted or unsubstituted C1-6alkyl, a 5–6 membered heterocycle or a 6–10 carbon atoms aryl moiety substituted with C1-4alkyl, C1-3alkoxy, hydroxy, halogen, N(Ra)2, C(═O)ORa, —C(═O)N(Ra)2, —SO2N(Ra)2, CH2N(Ra)2, N(Ra)C(═O)Ra or N(Ra)SO2Ra; R2 is ORa, N(Ra)2, C1-4alkenyl-Rc or —[CRbRc]nRc; and —X2—X3—R4 together represent —CH(Rd)C(═O)NHCH(Re)C(═O)—Y—[CRfRg]mRg, wherein m is an integer from 0 to 5, Y is O or NH, Rd and Re are independently hydrogen, ORa, N(Ra)2, C1-4alkenyl-Rc or —[CRbRc]nRc wherein n is an integer from 0 to 5, Ra is hydrogen or C1-4alkyl, Rb is hydrogen, hydroxy or C1-4alkyl and Rc is hydrogen, substituted or unsubstituted aryl, 5- or 6-membered heterocycle, C1-6alkyl or C1-6alkenyl, C3-7cycloalkyl, 5- to 7-membered carbocyclic or 7- to 10-membered bicyclic carbocyclic ring, benzofuryl, indolyl, azabicyclo C7-11cycloalkyl or benzopiperidinyl; Rf is hydrogen, substituted or unsubstituted C1-6alkyl or (CH2CH2O)pCH3 or (CH2CH2O)pH wherein p is an integer from 0 to 5, and Rg is hydrogen, or substituted or unsubstituted aryl, heterocycle, 5- to 7-membered carbocyclic or 7- to 10-membered bicyclic carbocyclic ring;
    (iii) R′, R3 and R3′ are each hydrogen; X1 is —C(═O)—, —SO2—, N(Rx)SO2, N(Rx)C(═O) or SC(═O), wherein Rx is hydrogen, C1-5alkyl or joined together with R1 either directly to form a 5–7 membered heterocycle such as pyrrolidinyl or piperidinyl, or through a heteroatom selected from N, O and S, to form a 6-membered heterocycle with the nitrogen to which they are attached such as morpholinyl, piperazyl, or N—C1-3alkyl-piperazyl; R1 is a substituted or unsubstituted C1-6alkyl, a 5–6 membered heterocycle or a 6–10 carbon atoms aryl moiety substituted with C1-4alkyl, C1-3alkoxy, hydroxy, halogen, N(Ra)2, C(═O)ORa, —C(═O)N(Ra)2, —SO2N(Ra)2, CH2N(Ra)2, N(Ra)C(═O)Ra or N(Ra)SO2Ra; R2 is ORa, N(Ra)2, C1-4alkenyl-Rc or —[CRbRc]nRc; and —X2—X3—R4 together represent —CH(Rd)C(═O)—Y—[CRfRg]mRg, wherein m is an integer from 0 to 5, Y is O or NH, Rd is hydrogen, ORa, N(Ra)2, C1-4alkenyl-Rc or —[CRbRc]nRc; wherein n is an integer from 0 to 5, Ra is hydrogen or C1-4alkyl, Rb is hydrogen, hydroxy or C1-4alkyl and Rc is hydrogen, substituted or unsubstituted aryl, 5- or 6-membered heterocycle, C1-6alkyl or C1-6alkenyl, C3-7cycloalkyl, 5- to 7-membered carbocyclic or 7- to 10-membered bicyclic carbocyclic ring, benzofuryl, indolyl, azabicyclo C7-11cycloalkyl or benzopiperidinyl; Rf is hydrogen, substituted or unsubstituted C1-6alkyl or (CH2CH2O)pCH3 or (CH2CH2O)pH wherein p is an integer from 0 to 5, and Rg is hydrogen, or substituted or unsubstituted aryl, heterocycle, 5- to 7-membered carbocyclic or 7- to 10-membered bicyclic carbocyclic ring;
    (iv) R′ and R3′ are each hydrogen; X1 is —C(═O)—, —SO2—, N(Rx)SO2, N(Rx)C(═O) or SC(═O), wherein Rx is hydrogen, C1-5alkyl or joined together with R1 either directly to form a 5–7 membered heterocycle such as pyrrolidinyl or piperidinyl, or through a heteroatom selected from N, O and S, to form a 6-membered heterocycle with the nitrogen to which they are attached such as morpholinyl, piperazyl, or N—C1-3alkyl-piperazyl; R1 is a substituted or unsubstituted C1-6alkyl, a 5–6 membered heterocycle or a 6–10 carbon atoms aryl moiety substituted with C1-4alkyl, C1-3alkoxy, hydroxy, halogen, N(Ra)2, C(═O)ORa, —C(═O)N(Ra)2, —SO2N(Ra)2, CH2N(Ra)2, N(Ra)C(═O)Ra or N(Ra)SO2Ra; R2 is ORa, N(Ra)2, C1-4alkenyl-Rc or —[CRbRc]nRc; R3 is hydrogen, ORa, N(Ra)2, C1-4alkenyl-Rc or —[CRbRc]nRc; and —X2—X3—R4 together represent —CH(Rd)C(═O)NHCH(Re)C(═O)—Y—[CRfRg]mRg, wherein m is an integer from 0 to 5, Y is O or NH, Rd and Re are independently hydrogen, ORa, N(Ra)2, C1-4alkenyl-Rc or —[CRbRc]nRc wherein n is an integer from 0 to 5, Ra is hydrogen or C1-4alkyl, Rb is hydrogen, hydroxy or C1-4alkyl and Rc is hydrogen, substituted or unsubstituted aryl, 5- or 6-membered heterocycle, C1-6alkyl or C1-6alkenyl, C3-7cycloalkyl, 5- to 7-membered carbocyclic or 7- to 10-membered bicyclic carbocyclic ring, benzofuryl, indolyl, azabicyclo C7-11cycloalkyl or benzopiperidinyl; Rf is hydrogen, substituted or unsubstituted C1-6alkyl or (CH2CH2O)pCH3 or (CH2CH2O)pH wherein p is an integer from 0 to 5, and Rg is hydrogen, or substituted or unsubstituted aryl, heterocycle, 5- to 7-membered carbocyclic or 7- to 10-membered bicyclic carbocyclic ring;
    (v) R′ and R3′ are each hydrogen; X1 is —C(═O)—, —SO2—, N(Rx)SO2, N(Rx)C(═O) or SC(═O), wherein Rx is hydrogen, C1-5alkyl or joined together with R1 either directly to form a 5–7 membered heterocycle such as pyrrolidinyl or piperidinyl, or through a heteroatom selected from N, O and S, to form a 6-membered heterocycle with the nitrogen to which they are attached such as morpholinyl, piperazyl, or N—C1-3alkyl-piperazyl; R1 is a substituted or unsubstituted C1-6alkyl, a 5–6 membered heterocycle or a 6–10 carbon atoms aryl moiety substituted with C1-4alkyl, C1-3alkoxy, hydroxy, halogen, N(Ra)2, C(═O)ORa, —C(═O)N(Ra)2, —SO2N(Ra)2, CH2N(Ra)2, N(Ra)C(═O)Ra or N(Ra)SO2Ra; R2 is ORa, N(Ra)2, C1-4alkenyl-Rc or —[CRbRc]nRc; R3 is hydrogen, ORa, N(Ra)2, C1-4alkenyl-Rc or —[CRbRc]nRc; and —X2—X3—R4 together represent —CH(Rd)C(═O)—Y—[CRfRg]mRg, wherein m is an integer from 0 to 5, Y is O or NH, Rd is hydrogen, ORa, N(Ra)2, C1-4alkenyl-Rc or —[CRbRc]nRc; wherein n is an integer from 0 to 5, Ra is hydrogen or C1-4alkyl, Rb is hydrogen, hydroxy or C1-4alkyl and Rc is hydrogen, substituted or unsubstituted aryl, 5- or 6-membered heterocycle, C1-6alkyl or C1-6alkenyl, C3-7cycloalkyl, 5- to 7-membered carbocyclic or 7- to 10-membered bicyclic carbocyclic ring, benzofuryl, indolyl, azabicyclo C7-11cycloalkyl or benzopiperidinyl; Rf is hydrogen, substituted or unsubstituted C1-6alkyl or (CH2CH2O)pCH3 or (CH2CH2O)pH wherein p is an integer from 0 to 5, and Rg is hydrogen, or substituted or unsubstituted aryl, heterocycle, 5- to 7-membered carbocyclic or 7- to 10-membered bicyclic carbocyclic ring; and
    (vi) R′, R3 and R3′ are each hydrogen; R2 is C1-6alkyl, C2-6alkenyl, C3-7cycloalkyl, aryl, heteroaryl, T-C1-6alkyl, T-C2-6alkenyl, wherein T is aryl, heteroaryl or C3-7cycloalkyl; R1—X1 together represent W wherein W is Rx, RxCO, RxOCO, RxOCH(Ry)CO, RxNHCH(Ry)CO, RxSCH(Ry)CO, RxSO2, RxSO or an amino acid with a blocked or unblocked amino terminus, wherein Rx and Ry are each independently hydrogen, C1-6alkyl, C3-7cycloalkyl, aryl, heteroaryl, T-C1-6alkyl or T-(CH2)nCH(T)(CH2)n wherein n is an integer from 1 to 4; and —X2—X3—R4 together represent —CH(Ra)C(═X)CHRbRc, wherein X is (OH,H) or O; Ra is hydrogen, C1-6alkyl, C2-6alkenyl, C3-7cycloalkyl, aryl, heteroaryl, T-C1-6alkyl or T-C2-6alkenyl; Rb is hydrogen or OH; and Rc is Y, (CHRw)n—Y or ═CRz(CHRw)n—Y, wherein Y is hydrogen, OH, —NRwRq, aryl, heteroaryl or CO-Z, n is an integer from 1 to 4, Z is OH, —NRwRq, ORw or an amino acid with a blocked or unblocked carboxy terminus, Rq is H, C1-6alkyl or arylC1-6alykl, and Rz and Rw are each independently hydrogen, C1-6alkyl, C3-7cycloalkyl, aryl, heteroaryl, T-C1-6alkyl or T-C2-6alkenyl. In certain embodiments, compounds specifically and/or generically disclosed in European Application No.: EP 0 316 965 (which is incorporated herein by reference) are excluded.


In certain embodiments, the present invention defines particular classes of compounds which are of special interest. For example, one class of compounds of special interest includes those compounds of formula (I) having the stereochemistry shown in Formula (IA):




Another class of compounds of special interest includes those compounds of formula (IA) wherein, X2 is absent and the compound has the Formula (IB):




Another class of compounds of special interest includes those compounds of formula (IA) wherein X3 is absent and the compound has the Formula (IC):




Another class of compounds of special interest includes those compounds of formula (IA) wherein X2 and X3 are each absent and the compound has the Formula (ID):




Another class of compounds of special interest includes those compounds of formula (IA) wherein R3′ is hydrogen, X2 is CHMe and the compound has the Formula (IE):




Another class of compounds of special interest includes those compounds of formula (IA) wherein R3′ is hydrogen, X3 is absent, X2 is —CH(Me)Y— where Y is




and the compound has the Formula (IF):





Another class of compounds of special interest includes those compounds of formula (I) wherein R′ and R3′ are each hydrogen, X2 is CHMe and X3 is —C(═O)NH—, and the compound has the Formula (II):




Another class of compounds of special interest includes those compounds of formula (I) wherein X1 is —C(═O)—, R′ is hydrogen, X2 and X3 are each absent, and the compound has the Formula (III):




Another class of compounds of special interest includes those compounds of formula (I) wherein X1 is —C(═O)—, R′ and R3′ are each hydrogen, X2 is —CHMe, and the compound has the Formula (IV):




Another class of compounds of special interest includes those compounds of formula (I) wherein R′ and R3′ are each hydrogen, X2 is —NRX2A, and the compound has the Formula (V):




Another class of compounds of special interest includes those compounds of formula (V) above having the stereochemistry as shown in Formula (VA):




Another class of compounds of special interest includes those compounds of formula (I) wherein R′ and R3′ are each hydrogen, X1 is —C(═O)—, X2 is —NH—, and the compound has the Formula (VI):




Another class of compounds of special interest includes those compounds of Formula (I) wherein X1 is —C(═O)— and the compound has the structure as shown in Formula (VII):




Another class of compounds of special interest includes those compounds of formula (I) wherein X1 is CHRX1A and the compound has the structure as shown in Formula (VIII):




Another class of compounds of special interest includes those compounds of formula (I) wherein X1 is CH2, X2 is CHRX2A, X3 is —C(═O)NRX3A, and the compound has the Formula (IX):




Another class of compounds of special interest includes those compounds of formula (IX) wherein RX2A is methyl and the compound has the Formula (IXA):




Another class of compounds of special interest includes those compounds of formula (I) wherein X1 is —C(═O)—, X2 is CHRX2A, X3 is —CH2NRX3A, and the compound has the Formula (X):




Another class of compounds of special interest includes those compounds of formula (X) wherein RX2A is methyl and the compound has the Formula (XA):




In certain other exemplary embodiments, for each of the classes of compounds as described above, R3 is hydrogen; R2 is substituted or unsubstituted lower alkyl, lower alkylamino, lower heteroaryl, —(CH2)cycloalkyl, —(CH2)heterocycloalkyl, —(CH2)aryl, —(CH2)heteroaryl, optionally substituted with one or more occurrences of R2A, wherein R2A is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, —OR2B, —SR2B, —N(R2B)2, —SO2N(R2B)2, —C(═O)N(R2B)2, halogen, —CN, —NO2, —C(═O)OR2B, —N(R2B)C(═O)R2C, wherein each occcurrence of R2B and R2C is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl; R1 is alkyl, alkenyl, heteroalkyl, heteroalkenyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or -(heteroalkyl)heteroaryl, wherein R1 is optionally substituted with one or more occurrences of R1A, wherein R1A is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, —OR1B, —SR1B, —N(R1B)2, —SO2N(R1B)2, —C(═O)N(R1B)2, halogen, —CN, —NO2, —C(═O)OR1B, N(R1B)C(═O)R1C; or or R1B and R1C, taken together with the atoms to which they are attached, form a substituted or unsubstituted heterocyclic moiety; wherein each occcurrence of R1B and R1C is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl; and R4 is alkyl, alkenyl, heteroalkyl, heteroalkenyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl -(heteroalkyl)aryl, or -(heteroalkyl)heteroaryl, optionally substituted with one or more occurrences of R4A, wherein R4A is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, —OR4B, —SR4B, N(R4B)2, —SO2N(R4B)2, —C(═O)N(R4B)2, halogen, —CN, —NO2, —C(═O)OR4B, —N(R4B)C(═O)R4C, wherein each occcurrence of R4B and R4C is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl.
A number of important subclasses of each of the foregoing classes deserve separate mention; these subclasses include subclasses of the foregoing classes in which:
i) R1 is substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl or alkenyl;
ii) R1 is substituted or unsubstituted aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or heterocyclic;
iii) R1 is one of:







    wherein R1A is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, —OR1B, —SR1B, —N(R1B)2, —SO2N(R1B)2, —C(═O)N(R1B)2, halogen, —CN, —NO2, —C(═O)OR1B, N(R1B)C(═O)R1C or —N(R1B)SO2R1C; wherein each occcurrence of R1B and R1C is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl; or R1B and R1C, taken together with the atoms to which they are attached, form a substituted or unsubstituted heterocyclic moiety; R1D is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, acyl or a nitrogen protecting group; wherein n and p are each independently integers from 0 to 3 and r is an integer from 1 to 6; 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;


iv) R1 is one of:




    wherein n, p, R1A and R1D are as defined in iii) above;


v) R1 is one of:







    wherein n, p, R1A and R1B are as defined in iii) above; R1D is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl; -(alkyl)heteroaryl or acyl; R1E and R1F are each independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, —C(═O)R1C or —SO2R1C, where R1C is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl; or R1E and R1F taken together form a 5–8 membered heterocyclic ring; or R1E and one occurrence of R1A, taken together, form a substituted or unsubstituted, saturated or unsaturated heterocyclic ring;




    vi) R1 is:






    wherein n is 1–2; p is 0–1; R1A is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, —OR1B, —SR1B, —N(R1B)2, —SO2N(R1B)2, —C(═O)N(R1B)2, halogen, —CN, —NO2, —C(═O)OR1B, —N(R1B)C(═O)R1C or —N(R1B)SO2R1C, wherein each occcurrence of R1B and R1C is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl; or R1B and R1C, taken together with the atoms to which they are attached, form a substituted or unsubstituted heterocyclic moiety; R1D and R1E are each independently hydrogen or lower alkyl; or R1D and R1E taken together form a 5–8 membered heterocyclic ring; or R1E and one occurrence of R1A, taken together, form a substituted or unsubstituted, saturated or unsaturated heterocyclic ring;


vii) R1 is:




    wherein a is 0 or 1; n is from 0–4; and R1A and R1D are as defined in vii) above;


viii) R1 is:




    wherein R1A is hydrogen, halogen, —CN, —NO2, lower alkyl, lower heteroalkyl, -(alkyl)aryl, -(alkyl)heteroaryl, —OR1B or —N(R1B)SO2R1C; wherein each occcurrence of R1B and R1C 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;


ix) R1 is:




    wherein R1A is as defined in viii) above; and R1D is hydrogen or lower alkyl;


x) R1 is:




    wherein n is 1–2; p is 0–1; R1A is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, —OR1B, —SR1B, —N(R1B)2, —SO2N(R1B)2, —C(═O)N(R1B)2, halogen, —CN, —NO2, —C(═O)OR1B, —N(R1B)C(═O)R1C or —N(R1B)SO2R1C, wherein each occcurrence of R1B and R1C is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl; or R1B and R1C, taken together with the atoms to which they are attached, form a substituted or unsubstituted heterocyclic moiety; R1D and R1E are each independently hydrogen or lower alkyl; or R1D and R1E taken together form a 5–8 membered heterocyclic ring; or R1E and one occurrence of R1A, taken together, form a substituted or unsubstituted, saturated or unsaturated heterocyclic ring;


xi) R1 is:




    wherein R1A is hydrogen, halogen, —CN, —NO2, lower alkyl, lower heteroalkyl, -(alkyl)aryl, -(alkyl)heteroaryl, —OR1B or —N(R1B)SO2R1C; wherein each occcurrence of R1B and R1C 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;


xii) R1 is:




    wherein R1A is as defined in x) above; and R1D is hydrogen or lower alkyl;


xiii) compounds of subsets vi)–xii) wherein R1A is methyl, methoxy or halide;
xiv) compounds of subsets vi)–xii) wherein R1A is methyl, methoxy or F;
xv) compounds of subsets vi)–xii) wherein R1A is methyl;
xvi) compounds of subsets viii) and xii) wherein R1B is hydrogen, methyl or ethyl;
xvii) R1 is:




    wherein R1A and R1B are each independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl;


xviii) compounds of subset xvii) wherein R1A and R1B are each independently cyclic or acyclic lower alkyl;
xix) compounds of subset xvii) wherein R1A and R1B are each independently methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, sec-butyl, isopentyl or cyclopropyl;
xx) R1 is:




    wherein R1A is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl; R1E and R1F are each independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, —C(═O)R1C or —SO2R1C, where R1C is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl; or R1E and R1F taken together form a 5–8 membered heterocyclic ring;


xxi) compounds of subset xx) wherein R1A is substituted or unsubstituted, linear or branched, cyclic or acyclic lower alkyl; R1E is lower alkyl; and R1F is —SO2R1D wherein R1D is lower alkyl;
xxii) compounds of subset xx) wherein R1A is substituted or unsubstituted, linear or branched, cyclic or acyclic lower alkyl; R1E and R1F, taken together with the nitrogen atom to which they are attached, form a 5- or 6-membered cyclic sulfonamide moiety;
xxiii) R1 is one of:






















xxiv) R1 is one of:
















xxv) R1 is one of:







xxvi) R2 is lower alkyl, —CH2NR2AR2B or —(CH2)phenyl, wherein the phenyl group is optionally substituted with one or more occurrences of R2C, wherein R2C is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, —OR2D, —SR2, —N(R2D)2, —SO2N(R2D)2, —C(═O)N(R2D)2, halogen, —CN, —NO2, —C(═O)OR2D, —N(R2D)C(═O)R2E, wherein each occcurrence of R2D and R2E is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl; and wherein R2A and R2B 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;
xxvii) R2 is lower alkyl, —CH2NR2AR2B or —(CH2)phenyl, wherein the phenyl group is optionally substituted with one or more occurrences of R2C, wherein R2C is hydrogen, alkyl, alkoxy or halogen; and wherein R2A and R2B 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;
xxviii) R2 is one of:







    wherein R2A is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, —OR2B, —SR2B, —N(R2B)2, —SO2N(R2B)2, —C(═O)N(R2B)2, halogen, —CN, —NO2, —C(═O)OR2B, —N(R2B)C(═O)R2C, wherein each occcurrence of R2B and R2C is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, wherein q and s are each independently integers from 0 to 3 and u is an integer from 1 to 6; 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;


xxix) R2 is one of:




    wherein each occcurrence of R2A 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;


xxx) compounds of subset xxix) wherein X is chlorine or fluorine;
xxxi) compounds of subset xxix) wherein each occurrence of X is fluorine;
xxxii) compounds of subset xxix) wherein R2A is methyl;
xxxiii) R2 is one of:







xxxiv) R2 is one of:







xxxv) R2 is one of:




xxxvi) R2 is one of:




xxxvii) R3 is hydrogen or halogen;
xxxviii) R3 is hydrogen or F;
xxxix) R3 is hydrogen;
xl) R3′ is hydrogen, methyl or halogen;
xli) R3′ is hydrogen, methyl or F;
xlii) R3′ is hydrogen;
xliii) one of R3 and R3′ is halogen;
xliv) R3 and R3′ are each independently hydrogen or F;
xlv) R3 and R3′ are each F;
xlvi) R3 and R3′ are each hydrogen;
xlvii) X1 is —C(═O)—;
xlviii) X1 is CHRX1A and RX1A is hydrogen or linear or branched substituted or unsubstituted alkyl;
xlix) X1 is CH2;
l) X2 is CHRX2A and RX2A is hydrogen or linear or branched substituted or unsubstituted alkyl or -alkyl(aryl);
li) X2 is CHRX2A and RX2A is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, benzyl or phenethyl;
lii) X2 is CHRX2A and RX2A is methyl, ethyl, propyl, isopropyl or phenethyl;
liii) X2 is CHMe
liv) X2 is —NRX2A— and RX2A is hydrogen or linear or branched substituted or unsubstituted alkyl;
lv) X2 is —NRX2A— and RX2A is C1–C3 alkyl;
lvi) X2 is NH;
lvii) X2 is NHY where Y is




where each occurrence RX2B is independently 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;

lviii) X2 is —CH(Me)Y— where Y is




where each occurrence RX2B 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;

lix) X2 is absent;
lx) X3 is (CHRX3A)k, —CH2NH—, —C(═O)NH—, or —SO2—, wherein each occurrence of RX3A is independently hydrogen, an aliphatic, heteroaliphatic, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or -(heteroalkyl)heteroaryl moiety, and k is an integer from 1 to 3 and each of the foregoing aryl, heteroaryl, -(alkyl)aryl and -(alkyl)heteroaryl moieties may be substituted or unsusbtituted;
lxi) X3 is absent;
lxii) X3 is —C(═O)NH—;
lxiii) X3 is CHRX3A, X2 is —NRX2A— and RX2A and RX3A are each independently hydrogen or linear or branched substituted or unsubstituted alkyl;
lxiv) X3 is CHRX3A and X2 is NH; wherein RX3A is hydrogen or linear or branched substituted or unsubstituted alkyl;
lxv) X3 is CH2 and X2 is NH;
lxvi) X2 and X3 are each absent;
lxvii) X2 is CHRX2A and X3 is CH2NH; wherein RX2A is hydrogen or linear or branched substituted or unsubstituted alkyl;
lxviii) X2 is CHRX2A and X3 is —C(═O)NH—; wherein RX2A is hydrogen or linear or branched substituted or unsubstituted alkyl or -alkyl(aryl);
lxix) R4 is substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl, phenyl or —(CH2)phenyl, wherein the phenyl group is optionally substituted with one or more occurrences of R4A, wherein R4A is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, —OR4B, —SR4B, —N(R4B)2, —SO2N(R4B)2, —C(═O)N(R4B)2, halogen, —CN, —NO2, —C(═O)OR4B, —N(R4B)C(═O)R4C or —N(R4B)SO2R4C; wherein each occcurrence of R4B and R4C is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteoraryl, -(alkyl)aryl or -(alkyl)heteroaryl;
lxx) R4 is substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl, phenyl or —(CH2)phenyl, wherein the phenyl group is optionally substituted with one or more occurrences of R4A, wherein R4A is hydrogen, hydroxyl, alkyl, alkoxy or halogen;
lxxi) R4 is one of:







    wherein each occurrence of R4A is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, —OR4B, —SR4B, —N(R4B)2, —SO2N(R4B)2, —C(═O)N(R4B)2, halogen, —CN, —NO2, —C(═O)OR4B, —N(R4B)C(═O)R4C, wherein each occcurrence of R4B and R4C is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, wherein v and w are each independently integers from 0 to 3 and x is an integer from 1 to 6; 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;


lxxii) R4 is hydrogen;
lxxiii) R4 is methyl, ethyl, propyl or one of:




    wherein each occcurrence of R4A is independently hydrogen, lower alkyl or C(═O)OR4B, wherein R4B is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl; each occurrence of X is independently a halogen; w is an integer from 0 to 3 and x is an integer from 1 to 6; 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;


lxxiv) compounds of subset lxxiii) wherein w is 1;
lxxv) compounds of subset lxxiii) wherein w is 0;
lxxvi) compounds of subset lxxiii) wherein x is 1, 3 or 4;
lxxvii) compounds of subset lxxiii) wherein X is chlorine or fluorine;
lxxviii) compounds of subset lxxiii) wherein each occurrence of X is fluorine;
lxxix) compounds of subset lxxiii) wherein R4A is methyl;
lxxx) R4 is methyl, ethyl, propyl, isopropyl or one of:




    wherein R4A is hydrogen, hydroxyl, lower alkyl, lower alkoxy, halogen, C(═O)OR4B, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, wherein R4B is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteoraryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl;


lxxxi) R4 is methyl, ethyl, propyl, isopropyl or one of:




lxxxii) R4 is one of:




lxxxiii) R4 is methyl, ethyl, propyl, isopropyl or one of:




lxxxiv) R4 is methyl, ethyl, propyl or one of:




lxxxv) R′, R3 and R3′ are each hydrogen, X1 is —C(═O)—, X3 is —C(═O)NH—, R1 is as described in subset xxiii, R2 is as described in subset xxxiv, X2 is as described in subset li, and R4 is as described in subset lxxxiii;
lxxxvi) R′, R3 and R3′ are each hydrogen, X1 is —C(═O)—, X3 is —C(═O)NH—, R1 is as described in subset xxiv, R2 is as described in subset xxxv, X2 is as described in subset lii, and R4 is as described in subset lxxxiv; and/or
lxxxvii) R′, R3 and R3′ are each hydrogen, X1 is —C(═O)—, X3 is —C(═O)NH—, R1 is as described in subset xxiv, R2 is as described in subset xxxvi, X2 is as described in subset lii, R4 is as described in subset lxxxiv.
It will be appreciated that for each of the classes and subclasses described above and herein, 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 reader will also appreciate that all possible combinations of the variables described in i)- through lxxxvii) above (e.g., R′, R1, X1, R2, R3, R3′, X2, X3 and R4, among others) are considered part of the invention. Thus, the invention encompasses any and all compounds of formula I generated by taking any possible permutation of variables R′, R1, X1, R2, R3, R3′, X2, X3 and R4, and other variables/substituents (e.g., RX1A, RX2A, Y, RX3A, R4A, etc.) as further defined for R′, R1, X1, R2, R3, R3′, X2, X3 and R4, described in i)- through lxxxvii) above.
For example, an exemplary combination of variables described in i)- through lxxxvii) above includes those compounds of Formula I wherein:

    R′ is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl;
    R1 is alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl;
    X1 is —C(═O)—, —S(═O)—, —C(═NH)—, —C(═S)—, —NC(═O)—, —NC(═S)—, —N—C(═N—C≡N)—, —NS(O2)—, —CHRX1A—, —SO2—, —COO—, —C(═O)C(RX1A)2—, or —SC(═O)— wherein each occurrence of RX1A is independently hydrogen, or an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety;
    R2 is alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl;
    R3 is hydrogen, halogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl;
    R3′ is hydrogen, halogen, or lower alkyl;
    R4 is alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl;
    X2 is absent, —NRX2A—, —(CHRX2A)j—, —NRX2AY—, or —(CHRX2A)jY— wherein each occurrence of RX2A is independently hydrogen or an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, each occurrence of Y is independently






wherein, for each independent occurrence of t, RX2B is hydrogen, or an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, and wherein each occurrence of j and t is independently an integer from 1 to 4; and

    X3 is absent, —NHCO—, —NHSO2—, —NHCONH—, —NHCOO—, —CH2NH—, —C(═O)—, —S(═O)—, —C(═NH)—, —C(═S)—, —NC(═S)N—, —N—C(═N—C≡N)N—, —NS(O2)N—, —SO2—, —CONRX3A—, —COO—, —(CHRX3A)k—, —O—, or —NRX3A—, wherein each occurrence of RX3A is independently hydrogen, an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, and k is an integer from 1 to 3.


Other exemplary combinations are illustrated by compounds of the following subgroups I and II:
I. Compounds Having the Structure (and Pharmaceutically Acceptable Derivatives Thereof):




    wherein R1, R2, R3, R3′, X2, X3 and R4 are as defined generally and in classes and subclasses herein.
    In certain embodiments,






has one of the following structures:





    wherein R3 is hydrogen, halogen or an aliphatic, heteroaliphatic, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or -heteroalkyl)heteroaryl moiety;
    R4 is an aliphatic, heteroaliphatic, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or -heteroalkyl)heteroaryl moiety, or R4, taken together with RX2A′ or a substituent present on Y or X3, may form a cycloaliphatic, cycloheteroaliphatic, aryl, or heteroaryl moiety;
    RX2A is hydrogen or an aliphatic, heteroaliphatic, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or -heteroalkyl)heteroaryl moiety;
    RX2A′ is hydrogen, or an aliphatic, heteroaliphatic, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or -(heteroalkyl)heteroaryl moiety, or RX2A′ taken together with R4 may form a cycloaliphatic, cycloheteroaliphatic, aryl or heteroaryl moiety;
    Y is independently absent or is






     wherein, for each independent occurrence of t, RX2B is hydrogen, or an aliphatic, heteroaliphatic, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or -heteroalkyl)heteroaryl moiety, or one occurrence of RX2B taken together with R4 may form a cycloaliphatic, cycloheteroaliphatic, aryl or heteroaryl moiety; t is an integer from 1 to 4; and
    X3 is absent, —NHCO—, —NHSO2—, —NHCONH—, —NHCOO—, —CH2NH—, —C(═O)—, —S(═O)—, —C(═NH)—, —C(═S)—, —NC(═S)N—, —N—C(═N—C≡N)N—, —NS(O2)N—, —SO2—, —C(═O)NRX3A—, —C(═S)NRX3A—, —COO—, (CHRX3A)k, —O—, —CH2NRX3A—, or —NRX3A, wherein each occurrence of RX3A is independently hydrogen, an aliphatic, heteroaliphatic, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or -heteroalkyl)heteroaryl moiety, or RX3A taken together with R4 may form a cycloaliphatic, cycloheteroaliphatic, aryl or heteroaryl moiety, and k is an integer from 1 to 3.


In certain embodiments,




has one of the following structures:





In certain embodiments,




has one of the following structures:





    wherein R3, R4, RX2A, RX2A′, RX2B and t are as defined above and in classes and subclasses herein.


In certain embodiments,




has one of the following structures:





    wherein R3 and R4 are as defined above and in classes and subclasses herein.


II. Compounds Having the Structure (and Pharmaceutically Acceptable Derivatives Thereof):




    wherein R1, R2, RX2A and R4 are as defined generally and in classes and subclasses herein.


In certain embodiments for compounds as described in subgroups I–II above, R1 is a substituted or unsubstituted aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or heterocyclic moiety. In certain exemplary embodiments, R1 has one of the following structures:







In certain embodiments, for compounds as described in subgroups I–II above, R2 has one of the following structures:




In certain embodiments, for compounds as described in subgroup I above, R3 is halogen. In certain exemplary embodiments, R3 is F. In certain other embodiments, R3 is hydrogen.
In certain embodiments for compounds as described in subgroups I and II above, R4 is substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl, phenyl or —(CH2)phenyl, wherein the phenyl group is optionally substituted with one or more occurrences of R4A, wherein R4A is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or —(alkyl)heteroaryl, —OR4B, —SR4B, —N(R4B)2, —SO2N(R4B)2, —C(═O)N(R4B)2, halogen, —CN, —NO2, —C(═O)OR4B, —N(R4B)C(═O)R4C, wherein each occcurrence of R4B and R4C is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, -(heteroalkyl)heteroaryl. In certain other exemplary embodiments, R4 is substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl, phenyl or —(CH2)phenyl, wherein the phenyl group is optionally substituted with one or more occurrences of R4A, wherein R4A is hydrogen, hydroxyl, alkyl, alkoxy or halogen. In certain exemplary embodiments, R4 has one of the following structures:




In certain exemplary embodiments, for compounds as described in subgroups I and II above, RX2A is a substituted or unsubstituted, linear or branched lower alkyl moiety. In certain other exemplary embodiments, RX2A is methyl, ethyl, propyl, isopropyl or phenethyl.
It will also be appreciated that for each of the subgroups I–II described above, a variety of other subclasses are of special interest, including, but not limited to those classes described above i)–lxxxvii) and classes, subclasses and species of compounds described above and in the examples herein.
Some of the foregoing compounds can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., stereoisomers and/or diastereomers. Thus, inventive compounds and pharmaceutical compositions thereof may be in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers. In certain embodiments, the compounds of the invention are enantiopure compounds. In certain other embodiments, mixtures of stereoisomers or diastereomers are provided.
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. In addition to the above-mentioned compounds per se, 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. For example, 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. Thus, the present invention encompasses inventive compounds, their derivatives, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them.
2) Synthetic Overview:
The practitioner has a a well-established literature of peptide chemistry to draw upon, in combination with the information contained herein, for guidance on synthetic strategies, protecting groups, and other materials and methods useful for the synthesis of the compounds of this invention, including compounds containing the various R′, R1, R2, R3, R3′ and R4 substituents and X1, X2 and X3 moieties.
The various patent documents and other references cited herein provide helpful background information on preparing compounds similar to the inventive compounds described herein or relevant intermediates, as well as information on formulation, uses, and administration of such compounds which may be of interest.
Moreover, the practitioner is directed to the specific guidance and examples provided in this document relating to various exemplary compounds and intermediates thereof.
As described above, the present invention provides novel compounds, specifically compounds having the following general structure:




    and pharmaceutically acceptable derivatives thereof,
    wherein R1, R2, R3, R3′, R′, X1, X2, X3 and R4 are as defined generally above and in classes and subclasses herein.


It will be appreciated that for compounds as generally described above, certain classes of compounds are of special interest. For example, one class of compounds of special interest includes those compounds wherein the compound has the stereochemistry as shown in Formula (IA):




In yet another aspect of the invention, methods for producing intermediates useful for the preparation of compounds of formulae (I) and (IA) are provided, embodiments of said methods being depicted generally in Schemes A and A1:








Alternatively, substituent R3′ may be introduced at a later stage in the synthesis, as depicted for example in Schemes A2 and A3:








In certain embodiments, the inventive method comprises

    i) providing a compound having the structure:






    wherein R′, R2, R3, R3′ and X2 are as defined generally above and in classes and subclasses herein,
    RP1 is a nitrogen protecting group;
    A is absent, —NHCO—, —NHSO2—, —NHCONH—, —NHCOO—, —CH2NH—, —C(═O)—, —S(═O)—, —C(═NH)—, —C(═S)—, —NC(═S)N—, —N—C(═N—C≡N)N—, —NS(O2)N—, —SO2—, —C(═O)NR5—, —C(═S)NR5—, —COO—, —(CHR5)r, —O—, —CH2NR5— or —NR5—, wherein each occurrence of R5 is independently hydrogen, an aliphatic, heteroaliphatic, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or -heteroalkyl)heteroaryl moiety, and k is an integer from 1 to 3; and
    B is a protecting group, or an aliphatic, heteroaliphatic, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl moiety, or is —VRC, wherein V is —O—, —NRD—, —C(═O)—, —S(═O)— or —SO2—, wherein each occurrence of RC and RD is independently hydrogen, a protecting group or an aliphatic, heteroaliphatic, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl moiety;
    ii) reacting the compound of step (i) under suitable conditions to generate a compound having the structure:






    wherein U is —NHRP2 or —N3, wherein RP2 is a nitrogen protecting group;
    iii) reacting the compound of step (ii) with suitable reagents to generate a compound having the structure:






    iv) reacting the compound of step (iii) with suitable reagents to generate the free amine having the structure:






    wherein R′, R1, R2, R3, R3′, R4, X1, X2 and X3 are as defined generally above and in classes and subclasses herein.


In certain embodiments, the present invention encompasses methods for the preparation of compounds having the general formula (IA), and classes and subclasses herein.




In certain embodiments, the method comprises:

    i) providing a compound having the structure:






    wherein R′, R2, R3, R3′ and X2 are as defined above,
    RP1 is a nitrogen protecting group;
    A is absent, —NHCO—, —NHSO2—, —NHCONH—, —NHCOO—, —CH2NH—, —C(═O)—, —S(═O)—, —C(═NH)—, —C(═S)—, —NC(═S)N—, —N—C(═N—C≡N)N—, —NS(O2)N—, —SO2—, —C(═O)NR5—, —C(═S)NR5—, —COO—, —(CHR5)r—, —O—, —CH2NR5— or —NR5—, wherein each occurrence of R5 is independently hydrogen, an aliphatic, heteroaliphatic, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or -heteroalkyl)heteroaryl moiety, and k is an integer from 1 to 3; and
    B is a protecting group, or an aliphatic, heteroaliphatic, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl moiety, or is —VRC, wherein V is —O—, —NRD—, —C(═O)—, S(═O) or —SO2—, wherein each occurrence of RC and RD is independently hydrogen, a protecting group or an aliphatic, heteroaliphatic, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl moiety;
    ii) reacting the compound of step (i) under suitable conditions to generate a compound having the structure:






    wherein U is —NHRP2 or —N3, wherein RP2 is a nitrogen protecting group;
    iii) reacting the compound of step (ii) with suitable reagents to generate a compound having the structure:






    iv) reacting the compound of step (iii) with suitable reagents to generate the free amine having the structure (IA):






    wherein R′, R1, R2, R3, R3′, R4, X1, X2 and X3 are as defined generally above and in classes and subclasses herein.


In yet another aspect of the invention, methods for producing intermediates useful for the preparation of compounds of formulas (I′) and (I′A) are provided, embodiments of said methods being depicted generally in Schemes A4 and A5:








In certain embodiments, the inventive method comprises

    i) providing a compound having the structure:






    wherein R2, R3, and X2 are as defined above,
    RP1 is a nitrogen protecting group;
    A is absent, —NHCO—, —NHSO2—, —NHCONH—, —NHCOO—, —CH2NH—, —C(═O)—, —S(═O)—, —C(═NH)—, —C(═S)—, —NC(═S)N—, —N—C(═N—C≡N)N—, —NS(O2)N—, —SO2—, —C(═O)NR5—, —C(═S)NR5—, —COO—, —(CHR5)r—, —O—, —CH2NR5— or —NR5—, wherein each occurrence of R5 is independently hydrogen, an aliphatic, heteroaliphatic, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or -heteroalkyl)heteroaryl moiety, and k is an integer from 1 to 3; and
    B is a protecting group, or an aliphatic, heteroaliphatic, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl moiety, or is —VRC, wherein V is —O—, —NRD—, —C(═O)—, —S(═O)— or —SO2—, wherein each occurrence of RC and RD is independently hydrogen, a protecting group or an aliphatic, heteroaliphatic, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl moiety;
    ii) reacting the compound of step (i) under suitable conditions to generate a compound having the structure:






    wherein U is —NHRP2 or —N3, wherein RP2 is a nitrogen protecting group;
    iii) reacting the compound of step (ii) with suitable reagents to generate a compound having the structure:






    iv) reacting the compound of step (iii) with suitable reagents to generate the free amine having the structure:






    wherein R1, R2, R3, R4, X1, X2 and X3 are as defined generally above and in classes and subclasses herein.


In certain embodiments, the present invention encompasses methods for the preparation of compounds having the general formula (I′A), and classes and subclasses herein.




In certain embodiments, the method comprises:

    i) providing a compound having the structure:






    wherein R2, R3, and X2 are as defined above,
    RP1 is a nitrogen protecting group;
    A is absent, —NHCO—, —NHSO2—, —NHCONH—, —NHCOO—, —CH2NH—, —C(═O)—, —S(═O)—, —C(═NH)—, —C(═S)—, —NC(═S)N—, —N—C(═N—C≡N)N—, —NS(O2)N—, —SO2—, —C(═O)NR5—, —C(═S)NR5—, —COO—, —(CHR5)r—, —O—, —CH2NR5— or —NR5—, wherein each occurrence of R5 is independently hydrogen, an aliphatic, heteroaliphatic, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or -(heteroalkyl)heteroaryl moiety, and k is an integer from 1 to 3; and
    B is a protecting group, or an aliphatic, heteroaliphatic, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl moiety, or is —VRC, wherein V is —O—, —NRD—, —C(═O)—, —S(═O)— or —SO2—, wherein each occurrence of RC and RD is independently hydrogen, a protecting group or an aliphatic, heteroaliphatic, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl moiety;
    ii) reacting the compound of step (i) under suitable conditions to generate a compound having the structure:






    wherein U is —NHRP2 or —N3, wherein RP2 is a nitrogen protecting group;
    iii) reacting the compound of step (ii) with suitable reagents to generate a compound having the structure:






    iv) reacting the compound of step (iii) with suitable reagents to generate the free amine having the structure (I′A):






    wherein R1, R2, R3, R4, X1, X2 and X3 are as defined generally above and in classes and subclasses herein.


In certain exemplary embodiments, compounds (and methods of synthesis thereof) are provided wherein the compounds have the general formula (I′′A) as shown in Scheme B below:




    wherein each of R1, X1, RP1, R2, X3, and R4 are as defined above and RP3 is an oxygen protecting group.


It will be appreciated that in certain embodiments, as depicted in Scheme B, 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 —X1—R1) is also effected. Finally, reaction with a suitable reagent to generate —X3—R4 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.
Additionally, it will appreciated that compounds having the general structures depicted above, wherein X3 is SO2 can be effected using the methodology generally described herein and also methodology described in U.S. Pat. No. 5,585,397, the entire contents of which are hereby incorporated by reference.
Numerous suitable prodrug moieties, and information concerning their selection, synthesis and use are well known in the art. Examples of prodrug moieties of interest include, among others, prodrug moieties that can be attached to primary or secondary amine-containing functionalities. For instance, prodrug moieties of interest include those that can be attached to group —NH2. Examples of such prodrug moieties include the following:




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.
3) Pharmaceutical Compositions
As discussed above, certain of the compounds as described herein exhibit activity generally as inhibitors of aspartyl proteases and more specifically as inhibitors of β-secretase enzyme activity, and have the ability to halt or reduce the production of Aβ from APP and reduce or eliminate the formation of β-amyloid deposits in the brain. Thus, the compounds are useful for treating humans or animals suffering from a condition characterized by a pathological form of β-amyloid peptide, such as β-amyloid plaques, and for helping to prevent or delay the onset of such a condition. Thus, in certain embodiments, 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. single and recurrent lobal hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, and diffuse Lewy body type Alzheimer's disease. The compounds and compositions of the invention are particularly useful for treating or preventing Alzheimer's disease. When treating or preventing these diseases, the compounds of the invention can either be used individually or in combination.
Accordingly, in another aspect of the present invention, pharmaceutical 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. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents. Alternatively, 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. For example, 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 β-amyloid peptide. It will also be appreciated that certain of the compounds of present invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof. According to the present invention, 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.
As used herein, 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 art. 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. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting a free base or free acid function with a suitable reagent, as described generally below. For example, a free base function can be reacted with a suitable acid. Furthermore, where the compounds of the invention carry an acidic moiety, 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. Other pharmaceutically acceptable 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, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative 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, lower alkyl sulfonate and aryl sulfonate.
Additionally, as used herein, the term “pharmaceutically acceptable 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. Examples of particular esters include formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
Furthermore, the term “pharmaceutically acceptable prodrugs” as used herein 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. The term “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.
As described above, 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. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as 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. Some examples of 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; pyrogen free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, 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. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
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. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, 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.
In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension or crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption 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 drug 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.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, 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) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk 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. In the case of capsules, tablets and pills, 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. Additionally, 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. Absorption 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.
It will also be appreciated that 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. For example, 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. Exemplary 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 Aβ peptide or administration of anti-Aβ peptide antibodies; statins; and direct or indirect neurotropic agents such as Cerebrolysin®V, AIT-082 (Emilieu, 2000, Arch. Neurol. 57:454), and other neurotropic agents of the future. 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). In certain embodiments, the pharmaceutical compositions of the present invention further comprises one or more additional therapeutically active ingredients (e.g., palliative). For purposes of the invention, 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. For example, palliative treatment encompasses painkillers, antinausea medications and anti-sickness drugs.
4) Research Uses, Pharmaceutical Uses and Methods of Treatment
Research Uses
According to the present invention, the inventive compounds may be assayed in any of the available assays known in the art for identifying compounds having protease inhibitory activity. For example, the assay may be cellular or non-cellular, in vivo or in vitro, high- or low-throughput format, etc.
In certain exemplary embodiments, compounds of this invention were assayed for their ability to inhibit aspartyl proteases, more specifically BACE.
Thus, in one aspect, compounds of this invention which are of particular interest include those which:

    are inhibitors of aspartyl proteases;
    exhibit the ability to inhibit BACE (β-secretase enzyme activity);
    exhibit the ability to inhibit Aβ peptide production;
    exhibit the ability to halt or reduce the production of Aβ from APP and reduces or eliminates the formation of β-amyloid deposits in the brain;
    are useful for treating mammals (e.g., humans) or animals suffering from a condition characterized by a pathological form of β-amyloid peptide, such as β-amyloid plaques, and for helping to prevent or delay the onset of such a condition;
    exhibit a favorable therapeutic profile (e.g., safety, efficacy, and stability).


In certain embodiments, compounds of the invention are aspartyl protease inhibitors. In certain exemplary embodiments, inventive compounds are selective BACE inhibitors. In certain exemplary embodiments, inventive compounds have BACEKiapp≦10 μM. In certain other embodiments, inventive compounds have BACEKiapp≦7.5 μM. In certain other embodiments, inventive compounds have BACEKiapp≦5 μM. In certain other embodiments, inventive compounds have BACEKiapp≦2.5 μM. In certain other embodiments, inventive compounds have BACEKiapp≦1 μM. In certain other embodiments, inventive compounds have BACEKiapp≦750 nM. In certain other embodiments, inventive compounds have BACEKiapp≦500 nM. In certain other embodiments, inventive compounds have BACEKiapp≦250 nM. In certain other embodiments, inventive compounds have BACEKiapp≦100 nM. In certain other embodiments, inventive compounds have BACEKiapp≦80 nM. In certain other embodiments, inventive compounds have BACEKiapp≦60 nM. In certain other embodiments, inventive compounds have BACEKiapp≦50 nM. In certain other embodiments, inventive compounds have BACEKiapp≦30 nM. In certain other embodiments, inventive compounds have BACEKiapp≦20 nM. In certain other embodiments, inventive compounds have BACEKiapp≦10 nM.
In certain embodiments, CatDKiapp for compounds of the invention is ≧2 fold greater than BACEKiapp. In certain other embodiments, CatDKiapp for compounds of the invention is ≧3 fold greater than BACEKiapp. In certain other embodiments, CatDKiapp for compounds of the invention is ≧4 fold greater than BACEKiapp. In certain other embodiments, CatDKiapp for compounds of the invention is ≧5 fold greater than BACEKiapp. In certain embodiments, CatDKiapp for compounds of the invention is ≧7.5 fold greater than BACEKiapp. In certain embodiments, CatDKiapp for compounds of the invention is ≧10 fold greater than BACEKiapp. In certain embodiments, CatDKiapp for compounds of the invention is ≧25 fold greater than BACEKiapp. In certain embodiments, CatDKiapp for compounds of the invention is ≧50 fold greater than BACEKiapp. In certain embodiments, CatDKiapp for compounds of the invention is ≧75 fold greater than BACEKiapp. In certain embodiments, CatDKiapp for compounds of the invention is ≧100 fold greater than BACEKiapp. In certain embodiments, CatDKiapp for compounds of the invention is ≧150 fold greater than BACEKiapp. In certain embodiments, CatDKiapp for compounds of the invention is ≧200 fold greater than BACEKiapp. In certain embodiments, CatDKiapp for compounds of the invention is ≧250 fold greater than BACEKiapp. In certain embodiments, CatDKiapp for compounds of the invention is ≧300 fold greater than BACEKiapp. In certain embodiments, CatDKiapp for compounds of the invention is ≧500 fold greater than BACEKiapp. In certain embodiments, CatDKiapp for compounds of the invention is ≧1000 fold greater than BACEKiapp.
In certain exemplary embodiments, inventive compounds have CellIC50 values ≦10 μM. In certain other embodiments, inventive compounds have CellIC50 values ≦7.5 μM. In certain other embodiments, inventive compounds have CellIC50 values ≦5 μM. In certain other embodiments, inventive compounds have CellIC50 values ≦2.5 μM. In certain other embodiments, inventive compounds have CellIC50 values ≦1 μM. In certain other embodiments, inventive compounds have CellIC50 values ≦750 nM. In certain other embodiments, inventive compounds have CellIC50 values ≦500 nM. In certain other embodiments, inventive compounds have CellIC50 values ≦250 nM. In certain other embodiments, inventive compounds have CellIC50 values ≦100 nM. In certain other embodiments, inventive compounds have CellIC50 values ≦80 nM. In certain other embodiments, inventive compounds have CellIC50 values ≦60 nM. In certain other embodiments, inventive compounds have CellIC50 values ≦50 nM. In certain other embodiments, inventive compounds have CellIC50 values ≦30 nM. In certain other embodiments, inventive compounds have CellIC50 values ≦20 nM. In certain other embodiments, inventive compounds have CellIC50 values ≦10 nM.
Pharmaceutical Uses and Methods of Treatment
As discussed above, without wishing to be bound by any particular theory, certain of the compounds as described herein exhibit activity generally as inhibitors of aspartyl proteases and more specifically as inhibitors of β-secretase enzyme activity. In certain embodiments compounds exhibit the ability to halt or reduce the production of Aβ from APP and reduce or eliminate the formation of β-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 β-amyloid peptide, such as β-amyloid plaques, and for helping to prevent or delay the onset of such a condition (e.g., Alzheimer's Disease). Thus, in certain embodiments, 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. single and recurrent lobal hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, and diffuse Lewy body type Alzheimer's disease. The compounds and compositions of the invention are particularly useful for treating or preventing Alzheimer's disease. When treating or preventing these diseases, the compounds of the invention can either be used individually or in combination.
In certain embodiments, 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.
As described in more detail herein, in certain embodiments, compounds of the invention are useful as inhibitors of aspartyl proteases. Generally, 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 β-secretase enzyme activity and A β peptide production. Thus, in certain embodiments, the present invention provides compounds useful for the treatment of disorders mediated by a pathological form of β-amyloid peptide, such as , amyloid plaques, and for helping to prevent or delay the onset of such a condition.
Thus, in certain embodiments, 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. single and recurrent lobal hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, and diffuse Lewy body type Alzheimer's disease. The compounds and compositions of the invention are particularly useful for treating or preventing Alzheimer's disease. When treating or preventing these diseases, the compounds of the invention can either be used individually or in combination.
Thus, as described above, in another aspect of the invention, a method for the treatment of disorders useful for the treatment (or prevention) of disorders mediated by a pathological form of β-amyloid peptide, such as β amyloid plaques, is provided comprising administering a therapeutically effective amount of a compound of Formula (I) or (IA), or any classes and subclasses of these compounds as described herein, to a subject in need thereof. It will be appreciated that 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 β-amyloid peptide, such as β amyloid plaques. Thus, the expression “effective amount” as used herein, refers to a sufficient amount of agent to inhibit the production of A β 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. The expression “dosage unit form” as used herein 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 incorporated herein by reference in its entirety).
Another aspect of the invention relates to a method for inhibiting β-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.
Furthermore, after formulation with an appropriate pharmaceutically acceptable carrier in a desired dosage, the pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, 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. In certain embodiments, 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.
TREATMENT KIT
In other embodiments, the present invention relates to a kit for conveniently and effectively carrying out the methods in accordance with the present invention. In general, 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. Such 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. If desired, 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. Alternatively, placebo dosages, or calcium dietary supplements, either in a form similar to or distinct from the dosages of the pharmaceutical compositions, 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.
EQUIVALENTS
The representative examples that follow are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples which follow and the references to the scientific and patent literature cited herein. It should further be appreciated that the contents of those cited references are incorporated herein by reference to help illustrate the state of the art.
The following examples contain important additional information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and the equivalents thereof.
EXEMPLIFICATION
The compounds of this invention and their preparation can be understood further by the examples that illustrate some of the processes by which these compounds are prepared or used. It will be appreciated, however, that these examples do not limit the invention. Variations of the invention, now known or further developed, are considered to fall within the scope of the present invention as described herein and as hereinafter claimed.
EXAMPLE 1
This example describes the enzyme assay for determining the apparent Ki of the compounds of the present invention.
The BACE enzyme used for inhibition analyses, BACE-HT, was produced from baculovirus-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 6×His tag.
Compounds were tested for their ability to inhibit BACE hydrolysis of the internally quenched fluorescent substrate, FS-1 (Ermolieff et al., Biochemistry 39:12450–12456 (2000)):

    FS1: NH2-Arg-Glu(EDANS)-Glu-Val-Asn-Leu-↓-Asp-Ala-Glu-Phe-Lys(DABCYL)-Arg-COOH
    FS-2: MOCAc-Ser-Glu-Val-Asn-Leu-↓-Asp-Ala-Glu-Phe-Lys(DNP)-Arg-Arg-COOH

where EDANS is 5-((2-aminoethyl)amino)napthalene-1-sulfonic acid; DABCYL is 4-((4-dimethylamino)phenyl)azo)benzoic acid; MOCAc is 7-methoxycoumarin-4-yl) acetic acid; and DNP is 2,4-dinotriphenylacetic acid.



FS-1 and FS-2 correspond to the Swedish APP β-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. In the intact state, the DABCYL or DNP group quenches the EDANS or MOCAc (respectively) fluorescence by virtue of their close proximity. In the intact state, the DABCYL group quenches the EDANS fluorescence by virtue of their close proximity. Upon cleavage at the site indicated by the arrow by BACE, the quenching is relieved and fluorescence is observed using λexcitation=350 nm and λemission=490 nm or λexcitation=328 nm and λemission=440 nm (MOCAc). For determination of apparent inhibition constant (Kiapp) for various inhibitors, the initial rates of FS-1 hydrolysis in the presence of various concentrations of inhibitors were measured and fit to the Morrison equation (Williams and Morrison, Methods Enzymol. 63: 437–467 (1979)):




  v
  =
  
    
      v
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                    app
                  
                
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where v is the initial rate measured in the presence of [I]0, the inhibitor concentration, using an enzyme concentration [E]0. v0 is the initial rate measured in the absence of inhibitor.

Inhibitors were resuspended in DMSO and serially diluted in DMSO at 20× final assay concentration. Compound dilutions (5 μL) were transferred to Black non-treated 96-well microtiter plates, and resuspended in 85 μL 35.3 μM 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 10 μL BACE-HT (100 nM final concentration) and brief mixing. The increase in EDANS fluorescence over time was monitored on a Gemini XS fluorometric plate reader using Softmax pro software. Initial rates were fit to the Morrison equation and Kiapp's determined using Graphpad Prism software. A representative range of Kiapp's for the compounds is between 1–1000 nM. The range of Kiapp's for preferred compounds is 0.1–500 nM.
EXAMPLE 2
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 Aβ peptide from cells expressing high levels of the human amyloid precursor protein (“APP”).
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 β695 wt). The A-204 cells and HEK 293 cells were obtained from ATCC. For 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 β695 wt 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 pyruvate, pyridoxine-HCl, antibiotics, and 10% FBS (A-204 cells); DMEM+glucose, glutamine, sodium pyruvate, pyridoxine-HCl, non-essential amino acids, antibiotics, and 10% FBS (HEK 293 cells); Ham's F-12+antibiotics, 10% FBS, and 400 μg/ml Zeocin (CHO2B7 cells); and Opti-MEM (Invitrogen)+antibiotics, 10% FBS, and 500 μg/ml geneticin (H4 β695 wt cells).
In the assay, cells were pre-treated with compounds for 1–2 hours to “wash out” any Aβ in the secretory pathway prior to incubation with compounds for the conditioning period required to generate detectable concentrations of Aβ. The production of secreted Aβ in cultured cells was monitored by sandwich ELISA, using the anti-Aβ monoclonal antibodies 6E10 and 4G8 (Signet Laboratories). The antibody 6E10 (specific to amino acids 1–17 of Aβ) was immobilized to the plate and used for capture, and a biotinylated version of the antibody 4G8 (specific to amino acids 17–24 of Aβ) was used for detection, via subsequent treatment with Neutravidin-horseradish peroxidase conjugate and development with luminescent substrate.
Cells were plated at 2.5×105 cells/well (HEK293 cells in 24 well poly-D-lysine coated plate), 1.3×105 cells/well (A-204 cells) (48 well plates) or 5×104 cells/well (CHO2B7 and H4APP cells) (96 well plates) in appropriate media (500 μL per well for 24 well plates, 300 μL per well for 48 well plates, 150 μL per well for 96 well plates) and grown at 37° C. and 5% CO2 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 1000× solution of inhibitor in DMSO with media on a separate plate. Cells and inhibitors were incubated for 1–2 hours, followed by aspiration of the media and replacement with fresh media solutions having the same concentrations of inhibitors. After a 4–24 hour incubation period (depending on cell type), conditioned media were collected and 100 μL of each sample applied to wells of Nunc Maxisorp white 96-well plates that had been previously coated with 10 μg/mL 6E10 antibody in 50 mM Na2CO3, (pH 9.0) overnight at 4° C., blocked with Superblock in PBS (Pierce Chemicals; PBS=10 mM sodium phosphate+150 mM NaCl, pH 7.4) for 1 hour at room temperature, and washed 3 times in wash buffer (PBS plus 0.05% Tween 20). Binding was allowed to take place overnight at 4° C., and plates were then washed 8 times and treated with 100 μL/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 μL/well of 1.5 μg/Neutravidin-horseradish peroxidase conjugate (Pierce Chemicals) for 40 minutes at room temperature, washed an additional 8 times, and developed with 100 μL/well Supersignal luminescent substrate (Pierce Chemicals) for 2 minutes. Luminescence was measured on a Gemini XS fluorescence/luminescence plate reader, and translated into Aβ concentrations using an internal standard curve of known Aβ concentrations (Aβ 1–40 obtained from Oncogene). In general, IC50's of the compounds of the present invention range from about 5× to about 15× the observed Kiapp's against the BACE enzyme as determined using the method of Example 1.
EXAMPLE 3
This example describes permeability experiments using MDCK cells.
MDCK cells, derived from canine kidney, were obtained from American Type Culture Collection (ATCC, Rockville, Md.). Cells were cultured in DMEM medium supplemented with 10% fetal bovine serum, 1 mM sodium pyruvate and 0.01 mg/ml gentamicin. Cells were maintained in a humidified atmosphere with 5% CO2 at 37° C. For transport studies, cells were plated at a density of 50×103 cells/cm2 on 0.4 μm pore size TranswellTM polyester membranes (Corning, Corning, N.Y.). Culture medium was replaced every two days until a tight cell monolayer was formed as measured by preliminary R123 permeability measurements. Compounds, 10 μM, were placed in either the apical or basolateral compartment and the amount of drug in the opposite chamber was measured using LC/MS/MS or fluorometry. The permeability coefficient was calculated using the following equation:

Papp=(1/AC0)dQ/dt

where A=surface area of the cell monolayers, C0 is the initial concentration and dQ/dt represents the amount of drug flux in a specified time.

EXAMPLE 4
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. Plasma and brain tissue were collected at 0, 0.5, 1, 2, 3, 4, and 8 hrs. Blood was collected via cardiac puncture. Subsequently, animals were perfused intra-cardially with ice-cold saline; the brain was homogenized in 10 volumes of ice-cold Tris-buffered saline (20 mM Tris, 137 mM NaCl, pH 7.6) and was then frozen at −20° C. Following extraction, compound concentrations in plasma and brain homogenates were measured by LC/MS/MS. Peak plasma and brain concentrations (Cmax) and time to achieve these concentrations (Tmax) were measured directly from concentration versus time profiles. Descriptive pharmacokinetic parameters were calculated using the WinNonlin software package (Pharsight Inc., Mountain View Calif.). FIGS. 1A and 1B 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 Kiapp of about 35 nM with a 125 fold selectivity over Cat D, and has an IC50 in cells of about 220 nM.
EXAMPLE 5
This example compares the biological properties of a hydroxy-containing compound with an amino-containing compound. The two compounds are of the structure




where R is either OH or NH2. In a surprising and unexpected finding, the amino-containing compound possesses several superior biological properties over its hydroxy-containing counterpart.

As it can be seen in the following Table, the amino compound is more potent in cells, is more selective for-the BACE enzyme, and show superior ADME properties than its hydroxy counterpart.

















Cat
% recovery


Compound
BACE Ki
IC50 (H4 cells)
D Ki
liver microsomes







R = OH
150 nM
2000 nM
 20 nM
 0% at 60 minutes


R = NH2
180 nM
 740 nM
610 nM
43% at 60 minutes









Although both compounds show similar activity against the BACE enzyme (180 nM versus 150 nM), the amino compound is significantly more potent in cells (740 nM versus 2000 nM). Moreover, the amino compound displays over a three fold preference for BACE over Cat D. In contrast, the hydroxy counterpart displays a 7.5 fold preference for Cat D over BACE. In addition, although both the amino and hydroxy compounds were stable in human plasma (100% recovery at 1 hour), the amino compound is much more stable in liver microsomes than its hydroxy counterpart.
These trends appear to be a general phenomenon and have been observed in several scaffolds in addition to one exemplified above.
The Ki for BACE and the IC50 determinations were performed as described in Examples 1 and 2 respectively.
The Ki determination for Cat D was performed using the assay conditions derived from Haque et al., J. Med. Chem. 42: 1428–1440 (1999) and the following substrate:

    DABCYL-GLu-Arg-Nle-Phe-Leu-Ser-Phe-Pro-EDANS where Nle is norleucine and DABCYL and EDANS are as previously defined.


Plasma stability was determined by incubating the compounds in human plasma at a concentration of 1 μM at 37° C. for 0, 30 and 60 minutes. Reactions were stopped by addition of acetonitrile. Protein was precipitated by centrifugation (3000 rpm×10 min) then supernatants were analyzed for remaining parent compound by LC/MS/MS.
Metabolic stability was determined by incubating the compounds with human liver microsomes (100 μg/ml) in 100 mM Tris buffer pH 7.4 for 5 minutes at 37° C. Metabolic reactions were started by addition of NADPH to give a final concentration of 1 μM. Reactions were stopped after 30 and 60 minutes by addition of acetonitrile. Protein was precipitated by centrifugation (3000 rpm×10 min) then supernatants were analyzed for remaining parent compound by LC/MS/MS.
General Description of Synthetic Strategy:
According to the present invention, any available techniques can be used to make or prepare the inventive compounds or compositions including them. For example, a variety of solution phase synthetic methods such as those discussed in detail below may be used. Alternatively or additionally, 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.
It will be appreciated as described below, that a variety of 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, Wis.), Bachem (Torrance, Calif.), 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, N.Y., 1991; Rodd 1989 “Chemistry of Carbon Compounds”, vols. 1–5 and supps, Elsevier Science Publishers, 1989; “Organic Reactions”, vols 1–40, John Wiley and Sons, New York, N.Y., 1991; March 2001, “Advanced Organic Chemistry”, 5th ed. John Wiley and Sons, New York, N.Y.; and Larock 1989, “Comprehensive Organic Transformations”, VCH Publishers. These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these schemes can be made and will be suggested to a person of ordinary skill in the art having regard to this disclosure.
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.
General Reaction Procedures:
Unless mentioned specifically, 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.
General Work Up Procedures:
Unless mentioned specifically, 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. On occasions where the product containing extract was deemed to contain residual acids, the extract was washed with saturated aqueous sodium bicarbonate solution, prior to the aforementioned washing procedure (except in those cases where the desired product itself had acidic character). On occasions where the product containing extract was deemed to contain residual bases, the extract was washed with 10% aqueous citric acid solution, prior to the aforementioned washing procedure (except in those cases where the desired product itself had basic character). Post washing, the desired product containing extracts were dried over anhydrous magnesium sulphate, and then filtered. The crude products were then isolated by removal of solvent(s) by rotary evaporation under reduced pressure, at an appropriate temperature (generally less than 45° C.).
General Purification Procedures:
Unless mentioned specifically, 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.
Synthesis of Exemplary Compounds:
The practitioner has a well-established literature of amino acid and peptide chemistry to draw upon, in combination with the information contained in the many examples which follow, for guidance on synthetic strategies, protecting groups, and other materials and methods useful for the synthesis of the compounds of this invention, including compounds containing the various R1, R2 and R3 substituents and X1, X2 and X3 moieties. Described generally below, are procedures and general guidance for the synthesis of compounds as described generally and in subclasses and species herein. In addition, synthetic guidance for the synthesis of amino acid derivatives and peptide analogues (and protease inhibitors more generally) can be found in U.S. Pat. Nos. 5,585,397; 5,916,438 and 5,413,999; U.S. application Ser. No. 10/462,127 filed Jun. 16, 2003 and Published PCT application WO 02/02505, the entire contents of which are hereby incorporated by reference. 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.
Unless otherwise indicated, starting materials are either commercially available, as indicated or are obtained through laboratory synthesis by anyone reasonably familiar with the art.
EXAMPLE 6
This example describes the synthesis of amino acids and amino-acid like compounds of the formula




where P is a protecting group and RA is substituted or unsubstituted aliphatic or aromatic moiety. These compounds were made as described in J. Org. Chem. 64: 3322 (1999) and described by Scheme 1.





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 tetrahydrofuran (THF) with lithium tert-butoxide (1.4 eq) and worked up with water. Enolization 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, H2O, refluxed) followed by protection of the amine gives compound 1.4.
EXAMPLE 7
This example describes the synthesis of compounds of the formula




where RA is as defined in Example 6. These compounds were prepared according to Scheme 2 and the procedure below.




Compound 2.1 is prepared by the procedure described J. Am. Chem. Soc. 122: 3522 (2000) starting with the corresponding N-protected compound made by Example 6 or purchased from commercial sources. Reduction of lactone 2.1 by lithium aluminum hydride (“LAH”) yields the corresponding diol 2.2, which was followed by the protection of the primary alcohol by tert-butyl-dimethyl silyl chloride (“TBSCl”; 1 eq), imidazole in CH2Cl2 to afford compound 2.3. Oxidation of the secondary alcohol by Dess-Martin periodinane to ketone 2.4, and reduction of ketone 2.4 by NaBH4 afford alcohol 2.5. The mesylate 2.6 is obtained by the treatment of alcohol 2.5 with mesyl chloride. The addition of sodium azide to the mesylate 2.6 affords compound 1.
EXAMPLE 8
An alternate procedure to prepare compound 1 is described in Scheme 3 and the procedure below.




Methyl ester 3.1 is prepared by esterfication 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 pyruvate affords olefin 3.3, which is followed by the reduction by NaBH4 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.
EXAMPLE 9
Another alternate procedure to prepare compound 1 is described in Scheme 4 and the procedure below.




Compound 4.2 and 4.3 are prepared by the procedure described J. Org. Chem. 56: 4823 (1991), starting with the corresponding compound 1.4 (Example 6). Reduction of ketone 4.3 by NaBH4, followed by hydrogenation gives the corresponding diol 4.4. The protection of the primary alcohol by TBSCl (1 eq), imidazole in CH2Cl2 affords compound 4.5. Mesylation of 4.5 followed by the addition of sodium azide to the mesylate 4.6 affords compound 1.
EXAMPLE 10
This example describes the synthesis of




which was prepared according to Scheme 5 and the procedure below.







    a) Compound 5.1 ([3-Methyl-1-(4-methyl-5-oxo-tetrahydro-furan-2-yl)-butyl]-carbamic acid tert-butyl ester) was prepared by the procedure described in J. Am. Chem. Soc. 122: 3522 (2000).
    b) A solution of LiAlH4 (40 mL, 1 M in THF) was added dropwise to 5.7 g of compound 5.1 in 40 ml of THF at 0° C. The reaction solution was warmed to room temperature, stirred for 1.5 hours and cooled to 0° C. A solution of 15% NaHSO4 in water was added dropwise to the reaction mixture until no further precipitate was formed (6 ml of NaHSO4). The reaction mixture was filtered, and concentrated, and the product 5.2 (5.4 g, 93% yield) was used for next reaction without further purification. LCMS: 290 (M+1).
    c) TBSCl(2.82 g, 18.8 mmol) was added to the solution of diol 5.2 (5.4 g, 18.8 mmol) and imidazole (2.6 g, 38.2 mmol) in 30 ml of CH2Cl2. After 30 minutes of stirring, the solvent was removed under reduced pressure. The reaction mixture was purified by column chromatography (40% ether/hexanes) to afford 6.5 g (88% yield) of compound 5.3. LCMS: 404(M+1). 1H NMR(CDCl3)δ: 4.7(1H, broad s), 3.72(1H, m), 3.6–3.4(3H, m), 3.2(1H, broad s), 1.93 (1H, m), 1.7–1.55 (2H, m), 1.45(10H, m), 1.35–1.25 (2H, m), 0.95–0.85 (18H, m), 0.04 (6H, s).
    d) A solution of Dess-Martin periodatate (5.5 g, 13 mmol in 5.5 mL CH2Cl2) was added to a solution of compound 5.3 (3.5 g, 8.68 mmol) in 30 mL of CH2Cl2. After stirring for 15 minutes, the reaction mixture was purified by column (20% ether/hexanes) to afford compound 5.4 (3.2 g, 91%). LCMS: 402(M+1).
    e) To a solution of ketone 5.4 (3.2 g, 8.0 mmol) in 50 mL of MeOH, NaBH4 (0.3 g) was added at −78° C. The reaction mixture was stirred for 10 minutes at −30° C., and was concentrated under reduced pressure. The reaction mixture was then extracted by ether (3×50 mL) water (50 mL) and washed with brine (50 mL), and then concentrated to afford compound 5.5 (2.6 g, 81% yield) as 20:1 ratio of syn and anti isomer (determined by 1H NMR). LCMS: 404(M+1).
    f) Mesyl chloride (1.1 g, 9.7 mmol) was added to the solution of alcohol 5.5 (2.6 g, 6.5 mmol) and triethylamine (2 mL) in chloroform (20 mL) at 0° C. The resulting mixture was stirred for 60 minutes, then purified by column chromatography (20% ether/hexanes) to afford mesylate 5.6 (2.5 g, 80%). LCMS: 482 (M+1).
    g) Sodium azide (3.4 g) was added to a solution of mesylate 5.6 (2.5 g) in dimethylformamide (“DMF”; 20 mL). The reaction mixture was stirred for overnight at 75° C. and extracted (ether 5×50 mL/Water 50 mL). The combined organic solution was dried, concentrated and purified by column chromatography (10%, ether/haxanes) to afford desired product 5.7 (1.05 g, 55%), which used as common intermediate LCMS: 429(M+1) 1H NMR (CDCl3)δ: 4.43(1H, broad), 3.77(1H, m), 3.63 (1H, m), 3.49(2H, m), 1.85 (1H, m), 1.7–1.6 (2H, m), 1.45(10H, m), 1.35–1.25 (2H, m), 1.0–0.88(18H, m), 0.05(6H, s) and syn isomer (0.19 g).
    h) A solution of 4N HCl in dioxane was added to a solution of compound 5.7 in MeOH. After stirring at room temperature for 60 minutes, the volatiles were removed by reduced pressure to afford compound 5.8, which was without further purification.
    i) Method 1: To a mixture of compound 5.8 and N,N-dipropyl-isophthalamic acid in DMF, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (“EDC”)/1-hydroxybenzotriazole hydrate(“HOBt”)/diisopropylethylamine (“DIEA”) was added. The resulting solution was stirred at room temperature overnight. 1N HCl (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 MgSO4. After removal of solvents, the residue was purified by column chromatography to afford compound 5.9. Method 2: To a mixture of compound 5.8 and N,N-dipropyl-isophthalamic acid in CH2Cl2, 2-(1H-azabenzotriazole-1-yl)-1,3,3-tetramethyluronium hexafluorophosphate(“HATU”)/DIEA was added. The resulting mixture was stirred at room temperature for 2 hours. The volatiles were removed by reduced pressure and purified by column chromatography to afford compound 5.9.
    j) Compound 5.9 was oxidized by Jone's reagent, after worked up and purified by column to give acid 5.10. LCMS: 460(M+1) 1H NMR(CD3OD)δ: 7.92(1H, d), 7.80(1H, s), 7.5–7.6(2H, m), 4.33(1H, m), 3.59(1H, m), 3.51(2H, t), 3.22 (3H, t), 2.70 (1H, m), 1.98(1H, m), 1.80–1.35 (8H, m), 1.20(3H, t), 1.06–0.9(9H, m), 0.75(3H, t).
    k) 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. 1N HCl (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 MgSO4. 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 CH2Cl2, HATU/DIEA was added. The resulting mixture was stirred at room temperature for 2 hours, the volatiles were removed by reduced pressure and purified by column chromatography to afford compound 5.11.
    l) Method 1: Compound 5.11 is treated with 1M PhMe3 in THF, and the resulting mixture is stirred for several hours until compound 5.11 is consumed. The reaction mixture is concentrated and 1N HCl is added. The resulting mixture is stirred overnight after which 20% NaOH(aq) is added dropwise until the pH of the solution reaches 12–13. Method 2: Hydrogenation of compound 5.11 by 10% Pd—C in MeOH yields compound 5.12 which is purified by preparative HPLC.


EXAMPLE 11
This example describes the synthesis of




which was prepared according to Scheme 6 and the procedure below.








    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. The solution was extracted with EtOAc, and the combined organic extracts were washed with saturated aqueous NaHCO3 and brine and then dried over MgSO4. Solvents were evaporated and the excess dimethyl methylphosphonate was removed by rotary evaporator under high vacuum in a 90° C. water bath. The resulted oily product 6.2 containing 5–10% dimethyl methylphosphonate (shown by 1H NMR) was used without purification. 1H NMR (400 MHz, CDCl3) δ ppm 1.29 (m, 6H) 1.35 (s, 9H) 2.92 (dd, J=14.24, 8.39 Hz, 1H) 3.03 (dd, J=22.38, 13.73 Hz, 1H) 3.22 (m, 2H) 4.10 (m, 4H) 4.55 (d, J=5.59 Hz, 1H) 5.38 (d, J=7.88 Hz, 1H) 7.20 (m, 5H); MS: 422 (MNa+)
    b) A solution of the crude phosphonate 6.2 above (16.8 g, ca. 35.8 mmol) in THF (100 mL) in a nitrogen atmosphere was cooled to 0° C. and then was added 1.6 M solution of butyllithium (22.4 mL, 35.8 mmol) via syringe in 10 minutes. The solution was stirred at 0° C. for 30 minutes, and ethyl pyruvate (7.1 mL, 63.2 mmol) was added slowly. Stirring was continued at 0° C. for 1 hour and at room temperature overnight. The reaction was quenched with saturated aqueous NH4Cl (100 mL) and diluted with EtOAc (400 mL). The organic layer was separated, washed with brine and then dried over MgSO4. Solvents were evaporated and the residue was purified by column chromatography (silica gel, Hexane-EtOAc 5:1) to give oily pure product 6.3 (9.0 g, 70% starting from 1). 1H NMR (400 MHz, ACETONE-D6) δ ppm 1.24 (t, J=7.12 Hz, 3H) 1.33 (s, 9H) 2.00 (d, J=1.27 Hz, 3H) 2.86 (m, 1H) 3.19 (dd, J=13.99, 5.09 Hz, 1H) 4.18 (q, J=7.12 Hz, 2H) 4.53 (m, 1H) 6.13 (d, J=7.88 Hz, 1H) 6.51 (d, J=1.27 Hz, 1H) 7.22 (m, 5H); MS: 384 (MNa+).
    c) To a solution of compound 6.3 (8.4 g, 23.2 mmol) in MeOH (200 mL) cooled to −78° C. was added sodium borohydride (1.7 g, 46.4 mmol). The mixture was stirred and warmed to −15° C. in 3 hours, and then kept at the same temperature overnight. 1N aqueous HCl (100 mL) was added to the cold reaction mixture, and the volatiles were removed by rotary evaporator. The resulted mixture was extracted with EtOAc. The combined extracts were washed with saturated aqueous NaHCO3 and brine and dried over MgSO4. After removal of solvents, the residue was purified by column chromatography (silica gel, Hexane-EtOAc 3:1) to give pure product 6.4 (4.3 g, 58%) and its 5-epimer (3.0 g, 41%) both as white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.36 (s, 9H) 1.88 (s, 3H) 2.80 (d, J=6.61 Hz, 2H) 4.05 (m, 1H) 4.68 (d, J=8.39 Hz, 1H) 4.92 (s, 1H) 6.91 (s, 1H) 7.23 (m, 5H); MS: 340 (Na+).
    d) 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 H2 (balloon) for 5 hours, followed by filtration and concentration in vacuo, to provide product 6.5 (3.5 g, 99%) as white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.26 (d, J=7.12 Hz, 3H) 1.35 (s, 9H) 1.71 (m, 1H) 2.42 (m, 1H) 2.64 (m, 1H) 2.87 (m, 1H) 3.01 (m, 1H) 3.92 (m, 1H) 4.25 (m, 1H) 4.46 (m, 1H) 7.24 (m, 5H); MS: 342 (MNa+).
    e) To a solution of compound 6.5 (3.5 g, 11.0 mmol) in THF (50 mL) cooled to 0° C. was added 0.5 M LiAlH4 in DME (22.0 mL, 11.0 mmol). The mixture was stirred at 0° C. for 0.5 hours and warmed to room temperature. Stirring was continued until TLC indicated the reduction was completed. The mixture was cooled to 0° C. and 1N NaHSO4 (30 mL) was added slowly. After stirring for 30 minutes at room temperature, the mixture was extracted with EtOAc. The combined extracts were washed with saturated aqueous NaHCO3 and brine and dried over MgSO4. After removal of solvents, the residue was purified by column chromatography (silica gel, Hexane-EtOAc 1:1) to yield pure product 6.6 (2.7 g, 76%) as white solid. 1H NMR (400 MHz, CDCl3) δ ppm 0.82 (d, J=6.61 Hz, 3H) 1.19 (s, 9H) 1.26 (m, 1H) 1.41 (m, 1H) 1.75 (m, J=15.13, 5.72 Hz, 1H) 2.46 (dd, J=13.61, 10.05 Hz, 1H) 2.93 (dd, J=13.73, 3.05 Hz, 1H) 3.30 (m, 2H) 3.50 (m, 2H) 7.10 (m, 5H); MS: 324 (MH+).
    f) To a solution of compound 6.6 (1.0 g, 3.10 mmol) in DCM (15 mL) was added imidazole (422 mg, 6.20 mmol) and TBSCl (578 mg, 3.72 mmol) sequentially at 0° C. After stirring at 0° C. for 1 hour, H2O (10 mL) was added to quench the reaction. The organic layer was separated and the aqueous layer was extracted with DCM. The combined DCM solution was washed with H2O and dried over MgSO4. After removal of solvents, the residue was purified by column chromatography (silica gel, Hexane-EtOAc 3:1) to afford pure product 6.7 (1.34 g, 98%) as white solid. 1H NMR (400 MHz, CDCl3) δ ppm 0.08 (s, 6H) 0.87 (d, J=6.87 Hz, 3H) 0.91 (s, 9H) 1.32 (s, 9H) 1.49 (m, J=6.36 Hz, 2H) 1.80 (m, 1H) 2.77 (m, 1H) 2.89 (m, 1H) 3.40 (m, 1H) 3.58 (dd, J=10.05, 4.20 Hz, 1H) 3.68 (s, 1H) 3.81 (s, 1H) 4.18 (m, J=12.33, 4.96 Hz, 1H) 4.78 (d, J=8.65 Hz, 1H) 7.21 (m, 5H); MS: 438 (MH+), 460 (MNa+).
    g) To a solution of compound 6.7 (1.2 g, 2.75 mmol) in chloroform (10 mL) was added triethylamine (0.8 mL, 5.5 mmol) and methanesulfonyl chloride (“MsCl”; 0.32 mL, 4.12 mmol) sequentially at 0° C. After stirring at 0° C. for 1 hour, 1 N HCl (5 mL) was added to quench the reaction. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined CH2Cl2 solution was washed with H2O and dried over MgSO4. After removal of solvents, the residue was purified by column chromatography (silica gel, Hexane-EtOAc 3:1) to afford pure product 6.8 (1.34 g, 95%) as colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 0.04 (s, 6H) 0.88 (m, 12H) 1.32 (s, 9H) 1.37 (m, 1H) 1.79 (m, 1H) 1.95 (m, 1H) 2.66 (dd, J=13.22, 10.68 Hz, 1H) 2.90 (dd, J=14.24, 4.83 Hz, 1H) 3.03 (s, 3H) 3.40 (m, 1H) 3.52 (m, 1H) 4.16 (s, 1H) 4.87 (d, J=8.65 Hz, 1H) 4.96 (d, J=9.16 Hz, 1H) 7.23 (m, 5H); MS: 515 (MNa+).
    h) Mesylate 6.8 (1.34 g, 2.60 mmol) was dissolved in anhydrous DMF (300 mL). To this stirred solution was added NaN3 (2.50 g, 39.0 mmol). The mixture was heated to 60° C. with an oil bath and stirred at this temperature for 8 hours. The solvent was evaporated in vacuo and then H2O (20 mL) was added to dissolve the solid. The solution was extracted with ether, and the combined extracts were dried over MgSO4. After removal of solvents, the residue was purified by column chromatography (silica gel, Hexane-EtOAc 10:1) to afford pure product 6.9 (0.72 g, 60%) as colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm −0.05 (s, 3H) −0.03 (s, 3H) 0.74 (d, J=6.87 Hz, 3H) 0.84 (s, 9H) 1.39 (s, 9H) 1.43 (m, 1H) 1.63 (m, 1H) 1.73 (m, 1H) 2.75 (dd, J=13.61, 8.77 Hz, 1H) 2.92 (m, 1H) 3.37 (m, 2H) 3.53 (t, J=7.12 Hz, 1H) 3.91 (q, J=8.22 Hz, 1H) 4.65 (d, J=9.66 Hz, 1H) 7.25 (m, 5H); MS: 485 (MNa+).
    i) Azide 6.9 (109 mg, 0.24 mmol) was treated with 4N HCl in dioxane (5 mL). After stirring for 1 hour, the mixture was concentrated in vacuo and the resulted crude product 6.10 was used for the next step without purification. To a solution of the crude compound 6.10 in DMF (1 mL) was added N,N-dipropyl-isophthalamic acid (58 mg, 0.24 mmol), diisopropylethylamine (0.3 mL, 1.42 mmol), HOBt (54 mg, 0.35 mmol) and EDC (68 mg, 0.35 mmol) sequentially. The mixture was stirred at room temperature for 8 hours. 1N HCl (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 MgSO4. After removal of solvents, the residue was purified by column chromatography (silica gel, DCM-MeOH 19:1) to afford pure product 6.11 (113 mg, 81% starting from 6.9) as colorless oil. 1H NMR (400 MHz, CD3OD) δ ppm 0.60 (t, J=7.12 Hz, 3H) 0.81 (d, J=6.61 Hz, 3H) 0.89 (t, J=7.25 Hz, 3H) 1.32 (m, 1H) 1.43 (m, 2H) 1.64 (m, 3H) 1.75 (m, 1H) 2.84 (m, 1H) 2.94 (m, 1H) 3.06 (m, 2H) 3.32 (m, 4H) 3.61 (m, 1H) 4.41 (m, 1H) 7.06 (m, 1H) 7.16 (q, J=7.46 Hz, 4H) 7.40 (m, 2H) 7.55 (s, 1H) 7.67 (d, J=7.12 Hz, 1H); MS: 480 (MH+).
    j) To a solution of compound 6.11 (57 mg, 0,12 mmol) in acetone (1 mL) was added Jones' reagent (2.7M, 88 mM, 0,24 mmol). After stirring at room temperature for 20 minutes, iPrOH (40 mL) was added. Stirring was continued for 10 minutes and the reaction mixture was diluted with acetone (20 mL), followed by filtration over celite. The solution was dried (Na2SO4) and concentrated. The resulted crude product 6.12 was used for next step without purification.
    k) To a DMF (0.5 mL) solution of the crude acid 6.12 was added 2-amino-N-benzyl-3-methyl-butyramide (20 mg, 0.075 mmol), diisopropylethylamine (0.1 mL, 0.45 mmol) and HATU (38 mg, 0.10 mmol) sequentially. The mixture was stirred at room temperature for 2 hours, and then purified by HPLC to provide pure product 6.13 (26 mg, 76% starting from compound 6.11) as white solid. 1H NMR (400 MHz, METHANOL-D) δ ppm 0.57 (t, J=7.25 Hz, 3H) 0.76 (m, 6H) 0.87 (t, J=7.25 Hz, 4H) 0.98 (d, J=6.61 Hz, 3H) 1.41 (m, 3H) 1.59 (m, 2H) 1.90 (m, 2H) 2.66 (m, 1H) 2.79 (dd, J=13.73, 9.66 Hz, 1H) 2.94 (dd, J=13.99, 5.60 Hz, 1H) 3.03 (m, 2H) 3.22 (s, 1H) 3.36 (m, 3H) 3.99 (d, J=7.63 Hz, 1H) 4.25 (s, 2H) 4.40 (s, 1H) 7.10 (m, 10H) 7.38 (q, J=7.97 Hz, 2H) 7.53 (s, 1H) 7.65 (d, J=6.87 Hz, 1H); MS: 682 (MH+).
    l) To a solution of compound 6.13 (19 mg, 0.0279 mmol) in MeOH (5 mL) 10% Pd—C (6 mg) was added. The mixture was stirred under an atmosphere of H2 for 30 minutes, followed by filtration and concentration. The resulting crude product was purified by preparative TLC to afford pure product 6.14 (16 mg, 88%) as white solid. 1H NMR (400 MHz, METHANOL-D) δ ppm 0.61 (t, J=7.25 Hz, 3H) 0.76 (d, J=6.61 Hz, 6H) 0.88 (m, 4H) 0.98 (d, J=6.87 Hz, 3H) 1.28 (m, 1H) 1.42 (m, 2H) 1.62 (m, 2H) 1.79 (m, 1H) 1.91 (m, 1H) 2.65 (dd, J=14.62, 6.23 Hz, 1H) 2.75 (m, 2H) 2.91 (m, 1H) 3.07 (m, 2H) 3.37 (m, 2H) 4.00 (d, J=7.38 Hz, 1H) 4.27 (m, 2H) 7.05 (t, J=7.12 Hz, 1H) 7.16 (m, 9H) 7.40 (m, 2H) 7.58 (s, 1H) 7.71 (d, J=7.38 Hz, 1H); MS: 656 (MH+).


EXAMPLE 12
The example describes the synthesis of compounds of the formula




These compounds are prepared according the procedure of Example 10 or Example 11 except for using other amino acids and amino acid like compound of the formula




as a reagent instead of





(Example 10) or





(Example 11). Illustrative examples of amino acids and amino acid like compounds and their corresponding products are shown in Table 1.









TABLE 1





Reagent
Product


























 












 












 












 












 












 












 












 












 












 












 












 












 



















EXAMPLE 13
This example describes the synthesis of




which was prepared according to Example 10 except for using 4-fluoroaniline instead of 2-amino-N-benzyl-3-methyl-butyramide in step k. MS (M+1) 527.

EXAMPLE 14
The example describes the synthesis of compounds of the formula




These compounds are prepared according to Example 13 except for using amino acids and amino acid-like compounds of the formula




instead of





Exemplary amino acids and amino acid-like compounds are shown in Table 1.

EXAMPLE 15
This example describes the synthesis of




which is prepared according to Example 10 except for using isopropylamine instead of 2-amino-N-benzyl-3-methyl-butyramide in step k when n=0 and for using isobutylamine instead of 2-amino-N-benzyl-3-methyl-butyramide in step k when n=1.

EXAMPLE 16
The example describes the synthesis of compounds of the formula




These compounds are prepared according to Example 15 except for using amino acids and amino acid-like compounds of the formula




instead of





EXAMPLE 17
This example describes the synthesis of




which was prepared according to Example 10 except for using cyclopropylamine instead of 2-amino-N-benzyl-3-methyl-butyramide in step k when n=0 and cyclopropyl-methyl amine instead 2-amino-N-benzyl-3-methyl-butyramide in step k when n=1.

Example 18
This example describes the synthesis of compounds of the formula




These compounds are prepared according to Example 17 except for using amino acids and amino acid-like compounds of the formula




instead of





Example 19
This example describes the synthesis of




which was prepared according to Example 10 except for 2-methyl-butylamine instead of 2-amino-N-benzyl-3-methyl-butyramide in step k.

EXAMPLE 20
The example describes the synthesis of compounds of the formula




These compounds are prepared according to Example 19 except for using amino acids and amino acid-like compounds of the formula




instead of





EXAMPLE 21
This example describes the synthesis of




which is prepared according to Example 11 except for using 3-benzyloxy-2-oxo propanic acid methyl ester, which is prepared from 3-hydroxyl-2-oxo propanic acid instead of ethyl pyruvate in the step b, and 4-fluoroaniline instead of 2-amino-N-benzyl-3-methyl-butyramine in the step j.

EXAMPLE 22
This example describes the synthesis of compounds of the formula




wherein RB is a substituted or unsubstituted aliphatic or aromatic moiety. These compounds are prepared according to Example 21 except for using 2-oxo-acid esters of the formula ROC(═O)C(═O)RB (wherein R is lower alkyl and RB is as defined above) instead of 3-benzyloxy-2-oxo-propanic acid methyl ester. Exemplary esters and their corresponding products are shown in Table 2.









TABLE 2





Ester
Product

















 












 



















EXAMPLE 23
The example describes the synthesis of compounds of the formula




where RC 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. Illustrative examples of acids and their corresponding products are shown in Table 3.









TABLE 3





RCCOOH
Product

















 












 












 












 












 



















EXAMPLE 24
This example describes the synthesis of the compounds of the formula




which are prepared according to Scheme 7 and the procedure below.





The Compounds-7.1 are prepared according to Example 16. These compounds are then reacted with phenyl chloroformate and DIEA to yield compounds 7.2. In certain embodiments, compounds 7.2 can be used as prodrug forms of their corresponding compounds 7.1.
EXAMPLE 25
This example describes the synthesis of compounds of the formula




wherein RD and RE are each independently substituted or unsubstituted aliphatic or aromatic moieties. These compounds are prepared according to Scheme 8 and the procedure below.





Compound 8.2 is treated with NaH in DMF, and halide RDX (1 eq) is added to the reaction mixture to yield aryl ether 8.3. Compound 8.3 is then treated with NaH in DMF, and halide REX (1 eq) is added. The reaction mixture is hydrolized (LiOH, H2O/THF) to give acid 8.1. Compounds 8.1, acids of the formula RCCOOH, are used to make additional compounds of the invention. Table 4 shows exemplary compounds 8.1's.









TABLE 4





RDX
REX
RCCOOH





















 
















 
















 






CH3I






 
















 
















 
















 
















 
















 























EXAMPLE 26
This example describes the synthesis of compounds of the formula




wherein RF, RG, and RH are each independently substituted or unsubstituted aliphatic or aromatic. These compounds are prepared according to Scheme 9 and the procedure below.





Mitsunobu reaction of compound 9.2 and the corresponding alcohol gives aryl ether 9.3. Hydrogenation of 9.3 reduces nitro group to aniline 9.4, which is followed by treatment of sulfonyl chloride to give the corresponding sulfonamide 9.5. Alkylation of sulfonamide 9.5 with halide (NaH, RHX, 1 eq) gives 9.6, followed by basic hydrolysis (LiOH, H2O/THF/MeOH) to give acid 9.1. Compounds 9.1, acids of the formula RCCOOH, are used to make additional compounds of the invention. Table 5 shows exemplary compounds 9.1's.










TABLE 5





RFX
RGSO2Cl
RHX
RCCOOH











MeSO2Cl










 






MeSO2Cl
NT






 






MeSO2Cl










 


CH3I
MeSO2Cl
CH3I






 






MeSO2Cl
CH3I






 






MeSO2Cl
CH3I






 






MeSO2Cl
CH3I






 






MeSO2Cl
CH3I






 






MeSO2Cl
CH3I






 






MeSO2Cl
CH3I






 






PhSO2Cl










 






PhSO2Cl










 


CH3I
PhSO2Cl
CH3I






 






PhSO2Cl
CH3I






 






PhSO2Cl
CH3I






 






PhSO2Cl
CH3I






 






PhSO2Cl
CH3I






 






PhSO2Cl
CH3I






 






PhSO2Cl
CH3I













EXAMPLE 27
This example describes the synthesis of compounds of the formula




wherein RF is substituted or unsubstituted aliphatic or aromatic moiety. These compounds are prepared according to Scheme 10 and the procedure below.





Aniline 9.4 (Example 35) is treated which sulfonyl chloride to yield sulfonamide 10.2, which is followed by the treatment of NaH to afford cyclic sulfonamide 10.3. Basic hydrolysis (LiOH, H2O/THF/MeOH) of compound 10.3 gives acid 10.1. Compounds 10.1, acids of the formula RCCOOH, are used to make additional compounds of the invention. Table 6 shows exemplary compounds 10.1's.










TABLE 6







RF
RCCOOH




















 














 














 














 














 














 














 





















EXAMPLE 28
This example describes the preparation of compounds of the formula




wherein RI, RJ, and RK are each independently substituted or unsubstituted aliphatic or aromatic moiety. These compounds are prepared according to Scheme 11 and the procedure below.





The treatment of diamine 11.2 with sulfamine a under refluxing pyridine affords sulfamine 11.3, which is followed by alkylation of a-halo alkyl ester to give compound 11.4. Basic hydrolysis (LiOH, H2O/THF/MeOH) of ester gives acid 11.1. Compounds 11.1, acids of the formula RCCOOH, are used to make additional compounds of the invention. Table 7 shows exemplary compounds 11.1's.









TABLE 7





XCRIRJCOOCH3
RKNHCH2CH2NH2
RCCOOH





















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 























EXAMPLE 29
This example describes the synthesis of compounds of the formula




wherein RI, RJ, and RL are each independently substituted or unsubstituted aliphatic or aromatic moiety. These compounds are prepared according to Scheme 12 and the procedure below.





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. Removal of benzyl group by hydrogenation to give 12.8, which is alkylated with an a-halo alkyl ester to give compound 12.9. Hydrolysis of 12.9 affords acid 12.1.
Compounds 12.1, acids of the formula RCCOOH, are used to make additional compounds of the invention. Table 8 shows exemplary compounds 12.1's.









TABLE 8





XCRIRJCOOMe
RLX
RCCOOH











BuBr






 






PrBr






 
















 
















 
















 
















 
















 
















 






BuBr






 






PrBr






 
















 
















 
















 
















 
















 
















 






BuBr






 






PrBr






 
















 
















 
















 
















 
















 
















 






BuBr






 






PrBr






 
















 
















 
















 
















 
















 























EXAMPLE 30
This example describes the synthesis of compounds of the formula




wherein RM is substituted or unsubstituted aliphatic or aromatic moiety. These compounds are prepared according to Scheme 13 and the procedure below.





Mitsunobu reaction of 13.2 gives the corresponding aryl ether 13.3, which is followed by the alkylation with halide (NaH, RMX, 1 eq) to afford aryl diether 13.4. Basic hydrolysis (LiOH, H2O/THF/MeOH) of 13.4 gives acid 13.1. Compounds 13.1, acids of the formula RCCOOH, are used to make additional compounds of the invention. Table 9 shows exemplary compounds 13.1's.










TABLE 9







RMX
RCCOOH




















 














 














 














 














 





















EXAMPLE 31
This example describes the synthesis of compounds of the formula




wherein RN, RO, RP, and RQ are each independently substituted or unsubstituted aliphatic or aromatic moiety. These compounds are prepared according to Scheme 14 and the procedure below.





The treatment of aniline 14.2 with sulfonyl chloride gives the corresponding sulfonamide 14.3, which is follow by alkylation with halide to give 14.4. The basic hydrolysis of 14.4 affords the mono-acid 14.5, follow by amide coupling with corresponding amine to give 14.6. Basic hydrolysis (LiOH, H2O/THF/MeOH) of 14.6 gives acid 14.1. Compounds 14.1, acids of the formula RCCOOH, are used to make additional compounds of the invention. Table 10 shows exemplary compounds 14.1's.










TABLE 10





RPNHRQ
RNSO2Cl
ROX
RCCOOH











MeSO2Cl










 






MeSO2Cl










 






PhSO2Cl










 






MeSO2Cl










 






MeSO2Cl










 






PhSO2Cl










 






MeSO2Cl










 






MeSO2Cl










 






PhSO2Cl










 






MeSO2Cl










 






MeSO2Cl










 






PhSO2Cl

















EXAMPLE 32
This example describes the synthesis of compounds of the formula




wherein RR and RS are each independently substituted or unsubstituted aliphatic or aromatic moiety, or RR and RS together form a substituted or unsubstituted cycloaliphatic or aromatic moiety. These compounds are prepared according to Scheme 15 and the procedure below.





Esterfication of di-acid 15.2 with TMSCH2N2 gives the corresponding di-methyl ester 15.3. Basic hydrolysis (LiOH, 1 eq) of compound 15.3 yields mono-acid 15.4 which is then coupled with RRNHRS to yield compound 15.5. The basic hydrolysis (LiOH, H2O/THF/MeOH) of 15.5 gives acid 15.1. Compound 15.1, an acid of the formula RCCOOH, are used to make additional compounds of the invention. Table 11 shows exemplary compounds 15.1's.









TABLE 11





RRNHRS




RCCOOH





















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 
















 























EXAMPLE 33
This example describes the synthesis of compounds of the formula




These compounds are prepared according to Example 23 except for using




as a reagent instead of





EXAMPLE 34
This example describes the synthesis of compounds of the formula




which are prepared according to Example 13 except for using acids of the formula RCCOOH as a reagent instead of N,N-dipropyl-isophthalamic acid.

EXAMPLE 35
This example describes the synthesis of compounds of the formula




These compounds are prepared according to Example 34 except for using




as a reagent instead of





EXAMPLE 36
This example describes the synthesis of




where RT is substituted or unsubstituted aliphatic or aromatic moiety. These compounds are prepared according to Example 10 except for using amines of the formula H2NRT instead of 2-amino-N-benzyl-3-methyl-butyramide in step k.

EXAMPLE 37
This example describes the synthesis of compounds of the formula




These compound are prepared according to Example 36 except for using acids of the formula RCCOOH as a reagent instead of N,N-dipropyl-isophthalamic acid.
EXAMPLE 38
This example describes the synthesis of compounds of the formula




These compounds are prepared according to Example 37 except for using




as a reagent instead of





EXAMPLE 39
This example describes the synthesis of compounds of the formula




where RU is substituted or unsubstituted alkyl. These compounds are made according to Scheme 16 and the procedure below.





Compound 16.1 is prepared by amide coupling of compound 1.4 with N,O-dimethylhydroxylamine. Reaction of Weinreb amide 16.1 with Grignard reagent RUMgX yields ketone 16.2 which is then reduced to alcohol 16.3. Mesylation of compound 16.3 followed by the addition of azide replacement yields compound 16.4 which is deprotected to yield amine 16.5. Amide coupling of compound 16.5 and acid RCCOOH with amide coupling reagents yields compound 16.6 which is reduced to make product 16.7.

## Claims

1. An isolated compound having the structure:



or pharmaceutically acceptable derivative thereof;
wherein R1 is an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, or R1, taken together with R′, may form a cycloheteroaliphatic moiety;
R2 is an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, or R2, taken together with R′, may form a cycloheteroaliphatic moiety;
R4 is hydrogen, an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, or R4, taken together with a substituent present on X2 or X3, may form a cycloaliphatic, cycloheteroaliphatic, aromatic, or heteroaromatic moiety; and
RX2A is hydrogen or an aliphatic, heteroaliphatic, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or -(heteroalkyl)heteroaryl moiety;
wherein at least one of R1, R2, RX2A and R4 comprises a cycloheteroaliphatic or heteroaromatic moiety.

2. The compound of claim 1, wherein RX2A is a substituted or unsubstituted, linear or branched lower alkyl moiety.

3. The compound of claim 2, wherein RX2A is methyl, ethyl, propyl, isopropyl or phenethyl.

4. The compound of claim 1, wherein R1 has one of the following structures:






wherein R1A is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, —OR1B, —SR1B, —N(R1B)2, —SO2N(R1B)2, —C(═O)N(R1B)2, halogen, —CN, —NO2, —C(═O)OR1B, N(R1B)C(═O)R1C or —N(R1B)SO2R1C; wherein each occcurrence of R1B and R1C is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl; or R1B and R1C, taken together with the atoms to which they are attached, form a substituted or unsubstituted heterocyclic moiety; R1D is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, acyl or a nitrogen protecting group; wherein n and p are each independently integers from 0 to 3 and r is an integer from 1 to 6; 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.

5. The compound of claim 4, wherein R1 has one of the following structures:

6. The compound of claim 4, wherein R1 has one of the following structures:



wherein R1D is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl; -(alkyl)heteroaryl or acyl; R1E and R1F are each independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, —C(═O)R1C or —SO2R1C, where R1C is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl; or R1E and R1F taken together form a 5–8 membered heterocyclic ring; or R1E and one occurrence of R1A, taken together, form a substituted or unsubstituted, saturated or unsaturated heterocyclic ring.

7. The compound of claim 4, wherein R1 has one of the following structures:

8. The compound of claim 4, wherein R1 has one of the following structures:

9. The compound of claim 4, wherein R1 has one of the following structures:

10. The compound of claim 1, wherein R2 is lower alkyl, —CH2NR2AR2B or —(CH2)phenyl, wherein the phenyl group is optionally substituted with one or more occurrences of R2C, wherein R2C is hydrogen, alkyl, alkoxy or halogen; and wherein R2A and R2B 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.

11. The compound of claim 10, wherein R2 has one of the following structures:






wherein R2A is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, —OR2B, —SR2B, —N(R2B)2, —SO2N(R2B)2, —C(═O)N(R2B)2, halogen, —CN, —NO2, —C(═O)OR2B, —N(R2B)C(═O)R2C, wherein each occcurrence of R2B and R2C is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, wherein q and s are each independently integers from 0 to 3 and u is an integer from 1 to 6; 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.

12. The compound of claim 10, wherein R2 has one of the following structures:



wherein each occcurrence of R2A 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.

13. The compound of claim 10, wherein each occurrence of X is independenly chlorine or fluorine and R2A is methyl.

14. The compound of claim 10, wherein R2 has one of the following structures:

15. The compound of claim 10, wherein R2 has one of the following structures:

16. The compound of claim 1, wherein R4 is substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl, phenyl or —(CH2)phenyl, wherein the phenyl group is optionally substituted with one or more occurrences of R4A, wherein R4A is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, —OR4B, —SR4B, —N(R4B)2, —SO2N(R4B)2, —C(═O)N(R4B)2, halogen, —CN, —NO2, —C(═O)OR4B, —N(R4B)C(═O)R4C, wherein each occcurrence of R4B and R4C is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, -(heteroalkyl)heteroaryl.

17. The compound of claim 16, wherein R4 is substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl, phenyl or —(CH2)phenyl, wherein the phenyl group is optionally substituted with one or more occurrences of R4A, wherein R4A is hydrogen, hydroxyl, alkyl, alkoxy or halogen.

18. The compound of claim 16, wherein R4 has one of the following structures:






wherein each occurrence of R4A is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, —OR4B, —SR4B, —N(R4B)2, —SO2N(R4B)2, —C(═O)N(R4B)2, halogen, —CN, —NO2, —C(═O)OR4B, —N(R4B)C(═O)R4C, wherein each occcurrence of R4B and R4C is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, wherein v and w are each independently integers from 0 to 3 and x is an integer from 1 to 6; 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.

19. The compound of claim 16, wherein R4 is methyl, ethyl, propyl or one of:



wherein each occcurrence of R4A is independently hydrogen, lower alkyl or C(═O)OR4B, wherein R4B is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl; each occurrence of X is independently a halogen; w is an integer from 0 to 3 and x is an integer from 1 to 6; 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.

20. The compound of claim 19, wherein each occurrence of X is independenly chlorine or fluorine and R4A is methyl.

21. The compound of claim 16, wherein R4 is methyl, ethyl, propyl or one of:



wherein R4A is hydrogen, hydroxyl, lower alkyl, lower alkoxy, halogen, C(═O)OR4B, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, wherein R4B is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteoraryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl.

22. The compound of claim 16, wherein R4 is methyl, ethyl, propyl, isopropyl or one of:

23. The compound of claim 16, wherein R4 has one of the following structures:

24. The compound of claim 1, wherein:
R1 has one of the following structures:













R2 is lower alkyl, —CH2NR2AR2B or —(CH2)phenyl, wherein the phenyl group is optionally substituted with one or more occurrences of R2C, wherein R2C is hydrogen, alkyl, alkoxy or halogen; and wherein R2A and R2B 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;
R4 is substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl, phenyl or —(CH2)phenyl, wherein the phenyl group is optionally substituted with one or more occurrences of R4A, wherein R4A is hydrogen, hydroxyl, alkyl, alkoxy or halogen; and
RX2A is a substituted or unsubstituted, linear or branched lower alkyl moiety.

25. A pharmaceutical composition comprising a compound of claim 1, and a pharmaceutically acceptable carrier or diluent, optionally further comprising an additional therapeutic agent.

26. The pharmaceutical composition of claim 25, wherein the compound is present in an amount effective to inhibit β-secretase activity.

27. The pharmaceutical composition of claim 25, wherein the additional therapeutic agent is an agent for the treatment of Alzheimer's Disease.

28. A method for treating a disease characterized by β-amyloid deposits in the brain comprising administering to a patient a therapeutically effective amount of a compound of claim 1.

29. The method of claim 28, wherein the disease is Alzheimer's disease MCI (mild cognitive impairment), Down's syndrome, Hereditary Cerebral Hemmorhage with Amyloidosis of the Dutch-Type, cerebral amyloid angiopathy, other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, and diffuse Lewy body type Alzheimer's disease.