AU2003297826A1 - Aspartyl protease inhibitors - Google Patents

Aspartyl protease inhibitors Download PDF

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AU2003297826A1
AU2003297826A1 AU2003297826A AU2003297826A AU2003297826A1 AU 2003297826 A1 AU2003297826 A1 AU 2003297826A1 AU 2003297826 A AU2003297826 A AU 2003297826A AU 2003297826 A AU2003297826 A AU 2003297826A AU 2003297826 A1 AU2003297826 A1 AU 2003297826A1
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alkyl
aryl
hydrogen
heteroaryl
substituted
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AU2003297826A
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Wenjin Yang
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Viracta Therapeutics Inc
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Sunesis Pharmaceuticals Inc
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Priority claimed from US10/462,127 external-priority patent/US7132568B2/en
Application filed by Sunesis Pharmaceuticals Inc filed Critical Sunesis Pharmaceuticals Inc
Publication of AU2003297826A1 publication Critical patent/AU2003297826A1/en
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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    • A61P25/00—Drugs for disorders of the nervous system
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    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/12—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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    • C07C237/14—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated and containing rings
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    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
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    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
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    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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    • C07K5/0207—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)4-C(=0), e.g. 'isosters', replacing two amino acids

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Description

WO 2005/005374 PCT/US2003/039276 ASPAR TYL PRO TEASE INHIBITORS PRIORITY CLAIM [0001] The present application claims priority to U.S. Patent Application No.: 10/462,127; filed June 16, 2003, and Patent Cooperation Treaty Application No.: PCT/USO3/18858, filed June 16, 2003; each of which claims priority to U.S. Provisional Patent Application Nos.: 60/430,693, filed December 3, 2002, and 60/389,194, filed June 17, 2002. The entire contents of each of the above-referenced applications are incorporated herein by reference. BACKGROUND OF THE INVENTION [0002] Alzheimer's Disease is a progressive dementia in which massive deposits of aggregated protein breakdown products (P3-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. [0003] As described above, a defining feature of Alzheimer's Disease which is often used during clinical diagnosis is the presence of P-amyloid plaques and neurofibrillary tangles. P-amniyloid plaques are predominantly composed of amyloid 3 peptide (A3 (or 3A4), 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 Ap3 peptide by P3-secretase and at the C-terminus by one or more y-secretases constitutes the -amyloidogenie pathway, i.e., the pathway by which AP3 is formed. It is believed that AP3 peptide accumulates as a result of this APP processing by 03 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 3-secretase WO 2005/005374 PCT/US2003/039276 cleavage site is thought to be a rate limiting step in AP3 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 J-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). [0004] 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 -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 [0005] 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: R- NH 2 1 2
R
4 R'EXIN X X'-.3,R4
R
2
R
3
R
3 (I) 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. [0006] In certain other embodiments, the invention provides pharmaceutical compositions comprising an inventive compound, wherein the compound is present in an amount effective to inhibit P-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 2 WO 2005/005374 PCT/US2003/039276 other embodiments, the additional therapeutic agent is an agent for the treatment of Alzheimer's Disease. [0007] In yet another aspect, the present invention provides methods for inhibiting P3-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 3-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 P 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 [0008] Figure 1A depicts a plasma concentration curve for an exemplary inventive compound. [0009] Figure 1 B depicts a brain concentration curve for an exemplary inventive compound. DEFINITIONS [0010] 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, 75 th 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 3 WO 2005/005374 PCT/US2003/039276 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 4 WO 2005/005374 PCT/US2003/039276 [0011] 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. [0012] 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 alkyll" 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 5 WO 2005/005374 PCT/US2003/039276 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. [0013] 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, -CH 2 -cyclopropyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, -CH 2 -cyclobutyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, cyclopentyl, -CH 2 -cyclopentyl-n, hexyl, sec-hexyl, cyclohexyl, -CH 2 -cyclohexyl moieties and the like, which again, may bear one or more substituents. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1 methyl-2-buten-l-yl, and the like. Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl and the like. [00141 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. 6 WO 2005/005374 PCT/US2003/039276 [0015] 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 NH 2 R'-, 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. [0016] 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; C1; Br; I; -OH; -NO 2 ; -CN; -CF 3 ; -CH 2
CF
3 ; -CIHC12; -CI 2 OH; CH 2
CH
2 OH; -CH 2
NH
2 ; -CH2SO 2
CH
3 ; -C(0)Rx; -CO 2 (Rx); -CON(Rx) 2 ; -OC(O)Rx; OCO 2 Rx; -OCON(Rx) 2 ; -N(Rx) 2 ; -S(0)Rx; -S(0) 2 Rx; -NRx(CO)Rx; -N(Rx)CO 2 Rx; N(Rx)S(0) 2 Rx; -N(Rx)C(=O)N(Rx) 2 ; -S(0) 2 N(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. [0017] 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 7 WO 2005/005374 PCT/US2003/039276 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. [0018] 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. [0019] 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. [0020] 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; C1; Br; I; -OH; -NO 2 ; -CN; -CF 3 ; -CH 2
CF
3 ; -CHC12; -CH 2 OH; -CH 2
CH
2 OH; CH 2
NH
2 ; -CH 2
SO
2
CH
3 ; -C(O)Rx; -CO 2 (Rx); -CON(Rx) 2 ; -OC(O)Rx; -OCO 2 Rx; OCON(Rx) 2 ; -N(Rx) 2 ; -S(O)Rx; -S(O) 2 Rx; -NRx(CO)Rx; -N(Rx)CO 2 Rx; N(Rx)S(O) 2 Rx; -N(Rx)C(=0)N(Rx) 2 ; -S(O) 2 N(Rx) 2 ; wherein each occurrence of Rx 8 WO 2005/005374 PCT/US2003/039276 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. [0021] 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; -NO 2 ; -CN; -CF 3 ; CH 2
CF
3 ; -CHC1 2 ; -CH20H; -CH 2
CH
2 OH; -CH 2
NH
2 ; -CH 2
SO
2
CH
3 ; -C(O)Rx; CO 2 (Rx); -CON(Rx) 2 ; -OC(O)Rx; -OCO 2 R; -OCON(Rx) 2 ; -N(Rx) 2 ; -S(O)Rx; S(0) 2 Rx; -NRx(CO)Rx; -N(Rx)CO 2 Rx; -N(Rx)S(O) 2 Rx; -N(Rx)C(=O)N(Rx) 2 ; S(O) 2 N(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. 9 WO 2005/005374 PCT/US2003/039276 [0022] 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; -NO 2 ; -CN; -CF 3 ; -CH 2
CF
3 ; -CHC1 2 ; -CH 2 0H; -CH 2
CH
2 OH; CH 2
NH
2 ; -CH 2
SO
2
CH
3 ; -C(O)Rx; -CO 2 (Rx); -CON(Rx) 2 ; -OC(O)Rx; -OCO 2 Rx; OCON(Rx) 2 ; -N(Rx) 2 ; -S(O)Rx; -S(O) 2 Rx; -NRx(CO)Rx; -N(Rx)CO 2 Rx; N(Rx)S(O) 2 Rx; -N(Rx)C(=O)N(Rx) 2 ; -S(O) 2 N(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. [0023] 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 10 WO 2005/005374 PCT/US2003/039276 optionally substituted with one or more functional groups. Illustrative cycloaliphatic groups thus include, but are not limited to, for example, cyclopropyl, -CH 2 cyclopropyl, cyclobutyl, -CH 2 -cyclobutyl, cyclopentyl, -CH 2 -cyclopentyl, cyclohexyl, -CH 2 -cyclohexyl, cyclohexenylethyl, cyclohexanylethyl, norborbyl moieties and the like, which again, may bear one or more substituents. [0024] 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. [0025] 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. [0026] The terms "halo" and "halogen" as used herein refer to an atom selected from fluorine, chlorine, bromine and iodine. [0027] 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. [0028] 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. [0029] 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 11 WO 2005/005374 PCT/US2003/039276 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 quatemrnized, 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;
-NO
2 ; -CN; -CF 3 ; -CH 2
CF
3 ; -CHC1 2 ; -CH 2 OH; -CH 2
CH
2 OH; -CH 2
NH
2 ; CH 2
SO
2
CH
3 ; -C(O)Rx; -CO 2 (Rx); -CON(Rx) 2 ; -OC(O)Rx; -OCO 2 Rx; -OCON(Rx) 2 ; N(Rx)2; -S(0)2Rx; -NRx(CO)Rx; -N(Rx)CO2Rx; -N(Rx)S(0)2Rx; -N(Rx)C(=O)N(Rx)2;
-S(O)
2 N(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 12 WO 2005/005374 PCT/US2003/039276 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. [0030] 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. [0031] 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. [0032] 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. 13 WO 2005/005374 PCT/US2003/039276 Certain exemplary pharmaceutical compositions and pharmaceutically acceptable derivatives will be discussed in more detail herein below. [0033] 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. [0034] 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. [00351 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 14 WO 2005/005374 PCT/US2003/039276 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 [0036] As noted above, there has been increasing interest in 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 P3-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 15 WO 2005/005374 PCT/US2003/039276 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). [0037] 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 13 amyloid deposits or plaques. In certain exemplary embodiments, the compounds are useful for the treatment of Alzheimer's Disease. [0038] 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. [0039] 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. [0040] 1) General Description of Compounds of the Invention [0041] In certain embodiments, the compounds of the invention include compounds of the general formula (I) as further defined below: R' NH 2
R.X
1 N
X
2 X 3,R 4
R
2
R
3
R
3 (I) and pharmaceutically acceptable derivatives thereof; wherein R' is hydrogen or an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, or R', taken together with R 2 or a substituent present on R 1, may form a cycloheteroaliphatic moiety;
R
1 is an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, or R 1, taken together with R', may form a cycloheteroaliphatic moiety; 16 WO 2005/005374 PCT/US2003/039276
X
1 is -C(=O)-, -S(=O)-, -C(=NH)-, -C(=S)-, -NC(=O)-, -NC(=S)-, -N-C(=N C-N)-, -NS(O 2 )-, -CHRxl
A-
, -SO 2 -, -COO-, -C(=O)C(RXA) 2 -, or -SC(=O)- wherein each occurrence of RX1A is independently hydrogen, or an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety;
R
2 is an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, or R 2 taken together with R', may form a cycloheteroaliphatic moiety;
R
3 is hydrogen, halogen, or an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety;
R
3 is hydrogen, halogen, or lower alkyl;
R
4 is hydrogen, an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, or R 4 , taken together with a substituent present on X 2 or X 3 , may form a cycloaliphatic, cycloheteroaliphatic, aromatic, or heteroaromatic moiety; X2 is absent, -NR X2A- , -(CHRX2A)j-, -NRMAY-, -(CHRA)jY - or N(RX 2 A)CH(RX2A')Y- wherein each occurrence of R x 2 A is independently hydrogen or an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety; each occurrence 0 Rx2B N of Y is independently t wherein, for each independent occurrence of t, RB is hydrogen, or an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, or R
X
A or one occurrence of R x 2 B taken together with R 4 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
X
3 is absent, -NHCO-, -NHSO2-, -NHCONH-, -NHCOO-, -CH 2 NH-, C(=O)-, -S(=O)-, -C(=NH)-, -C(=S)-, -NC(=S)N-, -N-C(=N-CEN)N-, -NS(O 2 )N-, SO 2 -, -C(=O)NR X3 A- , -C(=S)NRX 3
A
- , -COO-, -(CHRXA)k-, -0-, -CH 2
NR
X3A- , or NRx 3
A
- , wherein each occurrence of R X3A is independently hydrogen, an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, or RX 3 A taken together with R 4 may form a cycloaliphatic, cycloheteroaliphatic, aromatic or heteroaromatic moiety, and k is an integer from 1 to 3. 17 WO 2005/005374 PCT/US2003/039276 [0042] 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', R and R' are each hydrogen; R is alkyl, cycloalkylalkyl or aralkyl; X 2
-X
3
-R
4 together represents -CHReC(=O)NHCH(Rw)C(=O)NRxRY, wherein R e 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 R Y together with the nitrogen atom to which they are attached represent a 1,2,3,4 tetrahydroisoquinoline ring; and -X 1
-R
1 together represents an alkoxycarbonyl, aralkoxycarbonyl, alkanoyl, aralkanoyl, aroyl, cycloalkylcarbonyl, heterocyclylcarbonyl, heterocyclyl-alkanoyl, 6-(dibenzylcarbamoyl)-4-oxohexanoyl moiety or an acyl group of an a-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', R and R are each hydrogen; X' is -C(=O)-, -SO 2 -, N(RX)SO 2 , N(Rx)C(=O) or SC(=O), wherein Rx is hydrogen, Ci- 5 alkyl or joined together with
R
1 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 18 WO 2005/005374 PCT/US2003/039276 membered heterocycle with the nitrogen to which they are attached such as morpholinyl, piperazyl, or N-C1.
3 alkyl-piperazyl; R' is a substituted or unsubstituted C1.
6 alkyl, a 5-6 membered heterocycle or a 6-10 carbon atoms aryl moiety substituted with CI.
4 alkyl, C1- 3 alkoxy, hydroxy, halogen, N(Ra) 2 , C(=O)ORa, C(=O)N(Ra) 2 , -SO 2 N(Ra) 2 , CH 2 N(Ra) 2 , N(Ra)C(=O)Ra or N(Ra)SO 2 Ra; R 2 is ORa, N(Ra) 2 , CI- 4 alkenyl-R e or -[CRbRe]nRc; and -X 2
-X
3
-R
4 together represent CH(Rd)C(=O)NHCH(Re)C(=O)-Y-[CRfRg]mR g, wherein m is an integer from 0 to 5, Y is O or NH, Rd and Re are independently hydrogen, ORa, N(Ra) 2 , CI-4alkenyl-Rc or -[CRbRc]nRc wherein n is an integer from 0 to 5, Ra is hydrogen or C14alkyl, Rb is hydrogen, hydroxy or C1- 4 alkyl and R is hydrogen, substituted or unsubstituted aryl, 5- or 6-membered heterocycle, CI- 6 alkyl or Cp.
6 alkenyl, C 3 _7cycloalkyl, 5- to 7 membered carbocyclic or 7- to 10-membered bicyclic carbocyclic ring, benzofuryl, indolyl, azabicyclo C 7
.
11 cycloalkyl or benzopiperidinyl; R f is hydrogen, substituted or unsubstituted CI- 6 alkyl or (CH 2
CH
2 0)pCH 3 or (CH 2
CH
2 0)pH wherein p is an integer from 0 to 5, and R9 is hydrogen, or substituted or unsubstituted aryl, heterocycle, 5- to 7-membered carbocyclic or 7- to 10-membered bicyclic carbocyclic ring; (iii) R', R 3 and R 3 ' are each hydrogen; X 1 is -C(=O)
-
, -SO 2 -, N(RX)SO 2 , N(R)C(=0) or SC(=0) , wherein Rx is hydrogen, C 1 -salkyl or joined together with
R
1 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-CI_ 3 alkyl-piperazyl; R' is a substituted or unsubstituted C1- 6 alkyl, a 5-6 membered heterocycle or a 6-10 carbon atoms aryl moiety substituted with C 1 4 alkyl, CI_ 3 alkoxy, hydroxy, halogen, N(Ra) 2 , C(=O)ORa, C(=0)N(Ra) 2 , -SO 2 N(Ra) 2 , CH 2 N(Ra) 2 , N(Ra)C(=O)Ra or N(Ra)SO 2 Ra; R 2 is ORa, N(Ra) 2 , C 14 alkenyl-R or -[CRbR]nR; and -X 2
-X
3
-R
4 together represent CH(Rd)C(=O)-Y-[CRRg]mRg, wherein m is an integer from 0 to 5, Y is O or NH, Rd is hydrogen, ORa, N(Ra) 2 , Cl-4alkenyl-Rc or -[CRbR]nRc; wherein n is an integer from 0 to 5, Ra is hydrogen or C 14 alkyl, Rb is hydrogen, hydroxy or C14alkyl and Rc is hydrogen, substituted or unsubstituted aryl, 5- or 6-membered heterocycle, Cl 6 alkyl or C 1
-
6 alkenyl, C 3
.-
7 cycloalkyl, 5- to 7-membered carbocyclic or 7- to 10 19 WO 2005/005374 PCT/US2003/039276 membered bicyclic carbocyclic ring, benzofuryl, indolyl, azabicyclo C 7
.
11 cycloalkyl or benzopiperidinyl; R f is hydrogen, substituted or unsubstituted C 1
.-
6 alkyl or
(CH
2
CH
2 0)pCH 3 or (CH 2 CH2O)pH wherein p is an integer from 0 to 5, and R is hydrogen, or substituted or unsubstituted aryl, heterocycle, 5- to 7-membered carbocyclic or 7- to 10-membered bicyclic carbocyclic ring; (iv) R' and R 3 are each hydrogen; X 1 is -C(=O)-, -SO 2 -, N(RX)SO 2 , N(Rx)C(=0) or SC(=O), wherein R x is hydrogen, CI.-salkyl or joined together with R' 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-C 1
.
3 alkyl-piperazyl; R 1 is a substituted or unsubstituted C1- 6 alkyl, a 5-6 membered heterocycle or a 6-10 carbon atoms aryl moiety substituted with C1 4 alkyl, C 1
.
3 alkoxy, hydroxy, halogen, N(Ra) 2 , C(=O)ORa , C(=O)N(Ra) 2 , -SO 2 N(Ra) 2 , CH 2 N(Ra) 2 , N(Ra)C(=O)Ra or N(Ra)SO 2 Ra; R 2 is ORa, N(Ra) 2 , CI- 4 alkenyl-R or -[CRbRo]nR; R is hydrogen, ORa, N(Ra) 2 , Cl- 4 alkenyl-R or -[CRbR]nRe; and -X 2
-X
3
-R
4 together represent -CH(Rd)C(=O)NHCH(Re)C(=O) Y-[CR'R]mR g, 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- 4 alkenyl-R' or -[CRbR]nRc wherein n is an integer from 0 to 5, R a is hydrogen or C 1
-
4 alkyl, Rb is hydrogen, hydroxy or C 1 . 4 alkyl and Re is hydrogen, substituted or unsubstituted aryl, 5- or 6-membered heterocycle, C 1
.
6 alkyl or CI_ 6 alkenyl, C 3
.
7 cycloalkyl, 5- to 7-membered carbocyclic or 7- to 10-membered bicyclic carbocyclic ring, benzofuryl, indolyl, azabicyclo C7 licycloalkyl or benzopiperidinyl; R f is hydrogen, substituted or unsubstituted C1 6 alkyl or (CH 2
CH
2 0)pCH 3 or (CH 2
CH
2 0)pH wherein p is an integer from 0 to 5, and RI is hydrogen, or substituted or unsubstituted aryl, heterocycle, 5- to 7 membered carbocyclic or 7- to 10-membered bicyclic carbocyclic ring; (v) R' and R 3 are each hydrogen; X 1 is -C(=O)-, -SO 2 -, N(RX)SO 2 , N(R)C(=0) or SC(=O), wherein Rx is hydrogen, C 1
-
5 alkyl or joined together with
R
1 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-C 1
-
3 alkyl-piperazyl; R 1 is a substituted or unsubstituted 20 WO 2005/005374 PCT/US2003/039276
CI.
6 alkyl, a 5-6 membered heterocycle or a 6-10 carbon atoms aryl moiety substituted with CI- 4 alkyl, C 1 3 alkoxy, hydroxy, halogen, N(Ra) 2 , C(=0)ORa, C(=O)N(Ra) 2 , -SO 2 N(Ra) 2 , CH 2 N(Ra) 2 , N(Ra)C(=O)Ra or N(Ra)SO 2 R; R 2 is ORa, N(Ra) 2 , C-4alkenyl-RC or -[CRbR]nR; R is hydrogen, ORa, N(Ra) 2 , C1- 4 alkenyl-R or -[CRbRc]nRc; and --X-X 3
-R
4 together represent -CH(Rd)C(=O)-Y-[CR'R]mR g, wherein m is an integer from 0 to 5, Y is O or NH, Rd is hydrogen, ORa, N(Ra) 2 , C 1
.
4 alkenyl-Rc or -[CRbR]nR; wherein n is an integer from 0 to 5, Ra is hydrogen or
C
1
-
4 alkyl, Rb is hydrogen, hydroxy or CI- 4 alkyl and R is hydrogen, substituted or unsubstituted aryl, 5- or 6-membered heterocycle, CI.- 6 alkyl or C 1
.
6 alkenyl, C 3
.
7 cycloalkyl, 5- to 7-membered. carbocyclic or 7- to 10-membered bicyclic carbocyclic ring, benzofuryl, indolyl, azabicyclo C7-11cycloalkyl or benzopiperidinyl; R is hydrogen, substituted or unsubstituted C1- 6 alkyl or
(CH
2
CH
2 0)pCH 3 or (CH 2
CH
2 0)pH wherein p is an integer from 0 to 5, and R is hydrogen, or substituted or unsubstituted aryl, heterocycle, 5- to 7-membered carbocyclic or 7- to 10-membered bicyclic carbocyclie ring; and (vi) R', R 3 and R are each hydrogen; R is C1- 6 alkyl, C 2
-
6 alkenyl, C 3 7 cycloalkyl, aryl, heteroaryl, T-CI- 6 alkyl, T-C 2
-
6 alkenyl, wherein T is aryl, heteroaryl or C 3
-
7 cycloalkyl; R 1
-X
x together represent W wherein W is Rx, RxCO, RxOCO, RxOCH(RY)CO, RXNHCH(RY)CO, RXSCH(RY)CO, RxSO 2 , RxSO or an amino acid with a blocked or unblocked amino terminus, wherein Rx and R y are each independently hydrogen, CI- 6 alkyl, C 3
.-
7 cycloalkyl, aryl, heteroaryl, T-CI.
6 alkyl or T
(CH
2
),CH(T)(CH
2 )n wherein n is an integer from 1 to 4; and -X2-X -R 4 together represent -CH(Ra)C(=X)CHRbR c , wherein X is (OH,H) or O; Ra is hydrogen, C.
6 alkyl, C 2
-
6 alkenyl, C 3
-
7 cycloalkyl, aryl, heteroaryl, T-Cl- 6 alkyl or T-C 2
-
6 alkenyl; Rb is hydrogen or OH; and R is Y, (CHRw)n-Y or =CRz(CHR)n-Y, wherein Y is hydrogen, OH, -NRR q, aryl, heteroaryl or CO-Z, n is an integer from 1 to 4, Z is OH, -NRWR q, ORw or an amino acid with a blocked or unblocked carboxy terminus,
R
q is H, CI_ 6 alkyl or arylCi- 6 alykl, and Rz and Rw are each independently hydrogen, Ci- 6 alkyl, C 3 7 cycloalkyl, aryl, heteroaryl, T-CI.- 6 alkyl or T-C 2
.-
6 alkenyl. [0043] In certain embodiments, the present invention defines particular classes of compounds which are of special interest. For example, one class of compounds 21 WO 2005/005374 PCT/US2003/039276 of special interest includes those compounds of formula (I) having the stereochemistry shown in Formula (IA): R' NH 2 ~4 R XX R4
SR
3 R A (I) [0044] Another class of compounds of special interest includes those compounds of formula (IA) wherein, X 2 is absent and the compound has the Formula (IB): R- NH 2
REX
1 N X " R 4 R2
R
3 R (I") [0045] Another class of compounds of special interest includes those compounds of formula (IA) wherein X 3 is absent and the compound has the Formula R- NH 2 X RE'XIN X R 4 R2 R 3 R
(I
c) [0046] Another class of compounds of special interest includes those compounds of formula (IA) wherein X 2 and X 3 are each absent and the compound has the Formula (ID): R' NH 2 REVyN- R4 R
R
3 (ID) [0047] Another class of compounds of special interest includes those compounds of formula (IA) wherein R 3 ' is hydrogen, X 2 is CHMe and the compound has the Formula (IE): R' NH 2 x - x 3 . R2 R (IE) 22 WO 2005/005374 PCT/US2003/039276 [0048] Another class of compounds of special interest includes those compounds of formula (I
A
) wherein R 3 ' is hydrogen, X 3 is absent, X 2 is -CH(Me)Y 0 RX2B N where Y is 2 and the compound has the Formula (IF): R" NH 2 H R1X1 1N_ U R4 R R (I) [0049] Another class of compounds of special interest includes those compounds of formula (I) wherein R' and R 3 ' are each hydrogen, X 2 is CHMe and
X
3 is -C(=O)NH-, and the compound has the Formula (II): HIj NH 2 H
R
1 1V N, REX "NN'R4 R R 3 0 (11) [00501 Another class of compounds of special interest includes those compounds of formula (I) wherein X 1 is -C(=O)-, R" is hydrogen, X 2 and X 3 are each absent, and the compound has the Formula (III): H NH 2
R
1 N R 4 0 R2 R 3
R
3 '. (III) [0051] Another class of compounds of special interest includes those compounds of formula (I) wherein X' is -C(=O)-, R' and R 3 ' are each hydrogen, X 2 is -CHMe, and the compound has the Formula (IV): R1 N-_, 2 x3'R4 S NH2 R (IV) [0052] Another class of compounds of special interest includes those compounds of formula (I) wherein R' and R 3 are each hydrogen, X 2 is -NR x 2A- , and the compound has the Formula (V): 23 WO 2005/005374 PCT/US2003/039276 SNH 2
RX
2 A
R
1 YN I R4 R -, x 1 N N1 . I - N -X 3 '. 1 R2
R
3 (VT) [0053] Another class of compounds of special interest includes those compounds of formula (V) above having the stereochemistry as shown in Formula (VA): - NH 2
RX
2 A Rk 1 IN N'X ,R 4 X . I 2 R 3 (VA) [0054] Another class of compounds of special interest includes those compounds of formula (I) wherein R' and R 3 ' are each hydrogen, X 1 is -C(=O)-, X 2 is -NH-, and the compound has the Formula (VI): H
NH
2 H R1 N NI X3 R 4 S R2 R (VI) [0055] Another class of compounds of special interest includes those compounds of Formula (I) wherein X' is -C(=O)- and the compound has the structure as shown in Formula (VII): R' NH 2 RI N X 2
R
4 R N3 o R 2
RR
3 (VII) [0056] Another class of compounds of special interest includes those compounds of formula (I) wherein X 1 is CHRXlA and the compound has the structure as shown in Formula (VIII): R' NH 2 Rly N-_ X2 R 4 RX1A R2 R 3
R
3 ' (VIII) 24 WO 2005/005374 PCT/US2003/039276 [0057] Another class of compounds of special interest includes those compounds of formula (I) wherein X 1 is CH 2 , X 2 is CHR x 2 A, X 3 is -C(=O)NR 3 A and the compound has the Formula (IX): R' NH 2 RX2A RX3A RIN N'R4 2 RO " (IX) [0058] Another class of compounds of special interest includes those compounds of formula (IX) wherein R x 2 A is methyl and the compound has the Formula (IXA): R'
NH
2 RX3A RQN N-R4 RR RZ2
R
3 O
(IX
A
) [0059] Another class of compounds of special interest includes those compounds of formula (I) wherein X 1 is -C(=O)-, X 2 is CHR X2 A, X 3 is -CH 2 NRx 3 A and the compound has the Formula (X): R' NH 2 RX2A RX 3 A R N N'R4 O R2 R3 (X) [0060] Another class of compounds of special interest includes those compounds of formula (X) wherein R x 2 A is methyl and the compound has the Formula (XA): R' NH 2 RX3A RI N NR 4 O R2
R
3
(X
A
) [0061] In certain other exemplary embodiments, for each of the classes of compounds as described above, R 3 is hydrogen; R 2 is substituted or unsubstituted lower alkyl, lower alkylamino, lower heteroaryl, -(CH 2 )cycloalkyl,
(CH
2 )heterocycloalkyl, -(CH 2 )aryl, -(CH 2 )heteroaryl, optionally substituted with one or more occurrences of R 2 A, wherein R 2 A is hydrogen, alkyl, heteroalkyl, aryl, 25 WO 2005/005374 PCT/US2003/039276 heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -OR 2 B, -SR 2 B, -N(R 2
B)
2 , -SO 2
N(R
2
B)
2 , C(=O)N(R 2
B)
2 , halogen, -CN, -NO 2 , -C(=O)OR 2 B, -N(R 2
B)C(=O)R
2c , wherein each occurrence of R 2 B and R 2 c is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl; R' is alkyl, alkenyl, heteroalkyl, heteroalkenyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, (heteroalkyl)aryl, or -(heteroalkyl)heteroaryl, wherein R' is optionally substituted with one or more occurrences of RIA, wherein R 1 A is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -ORlB, -SR'l, -N(RIB) 2 , SO 2
N(RB)
2 , -C(=O)N(R B)2 , halogen, -CN, -NO2, -C(=O)ORI B , -N(RIB)C(=O)RC; or or R'B and R 1 c, taken together with the atoms to which they are attached, form a substituted or unsubstituted heterocyclic moiety; wherein each occcurrence of RB and Ri c is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, (alkyl)aryl or -(alkyl)heteroaryl; and R 4 is alkyl, alkenyl, heteroalkyl, heteroalkenyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl -(heteroalkyl)aryl, or (heteroalkyl)heteroaryl, optionally substituted with one or more occurrences of R 4 A, wherein R 4 A is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, (alkyl)heteroaryl, -OR 4 B, -SR 4 B, -N(R 4
B)
2 , -SO 2
N(R
4
B)
2 , -C(=O)N(R 4
B)
2 , halogen, CN, -NO 2 , -C(=O)OR 4 B, -N(R 4
B)C(=O)R
4c , wherein each occcurrence of R 4B and
R
4c is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, (alkyl)aryl or -(alkyl)heteroaryl. [0062] A number of important subclasses of each of the foregoing classes deserve separate mention; these subclasses include subclasses of the foregoing classes in which: [0063] i) R 1 is substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl or alkenyl; [0064] ii) R is substituted or unsubstituted aryl, heteroaryl, -(alkyl)aryl, (alkyl)heteroaryl or heterocyclic; [0065] iii) R 1 is one of: 26 WO 2005/005374 PCT/US2003/039276 (R1A) (R1A)n (R1A) " (R1A)n (RA(1A) (RA) N (R1A)n (R1A ( R1D O : (R S P S s P HN N 0 N P 0 P H H H A (R1A O (R1A O n N 0 N r (R 1A H 4C Rf S R O R N =OO (RlA) / (RA), (RA) (R1An N H\ 0 NA A NAr-S=RTDN0 wherein R 1 A is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, (alkyl)heteroaryl, -OR, -SR, -N(RB) 2 , -SO 2 N(R)2, -C )N(RB) 2 , halogen, CN, -NO 2 , -C(=O)ORB, N(R1B)C(=O)Ric or -N(RIB)SO 2 RC; wherein each occurrence of RIB and Ri c is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl; or RiB and Ric, taken together with the atoms to which they are attached, form a substituted or unsubstituted heterocyclic moiety; R 1 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; [0066] iv) R is one of: 27 WO 2005/005374 PCT/US2003/039276 (R(A)R 00 0 Y0 (R1A)
R
1 D S O 0 N ID-N NR( (R1A)n (R1A)n " R 0 ID R1D XsO R O 'N N N N wherein n, p, R 1 A and RID are as defined in iii) above; [0067] v) R' is one of: RiF ~ RF4O\ pc (R1A)n (R A) n (R1A)n (R A)n | 0 0 RF R1E RIF NR 1 E (RIA)n NT RIE N - R1BR R1F S R N - )P o-\( IA CRlA) 0 0 IF () R1D- 00RN RRNS RN R0 RD R 1 RID /S \N R1, N-=O R ~o No' wherein n, p, R1A and RIB are as defined in iii) above; R1D is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl; -(alkyl)heteroaryl or acyl; RE and RIF are each independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -C(=O)Ric or -SO 2 Ric, where Ric is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or (alkyl)heteroaryl; or R 1 E and RIF taken together form a 5-8 membered heterocyclic ring; or R 1E and one occurrence of RIA, taken together, form a substituted or unsubstituted, saturated or unsaturated heterocyclic ring; [0068] vi) R 1 is: (R1A)n R1DIE 28 28 WO 2005/005374 PCT/US2003/039276 wherein n is 1-2; p is 0-1; R 1 A is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -ORlB, -SR", -N(R') 2 , -SO 2 N(R ")2, C(=O)N(R1B) 2 , halogen, -CN, -NO 2 , -C(=O)OR 1 ", -N(RB)C(=O)Rc or N(R B)SO 2 Rlc, wherein each occcurrence of R'B and Ric is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or (alkyl)heteroaryl; or R IB and Ric, taken together with the atoms to which they are attached, form a substituted or unsubstituted heterocyclic moiety; RID and RI E are each independently hydrogen or lower alkyl; or R 1 D and R1 E taken together form a 5 8 membered heterocyclic ring; or R IE and one occurrence of RIA, taken together, form a substituted or unsubstituted, saturated or unsaturated heterocyclic ring; [0069] vii) R' is: R1A aI 0 wherein a is 0 or 1; n is from 0-4; and R 1A and R 1D are as defined in vii) above; [0070] viii) R 1 is: R1A 0 wherein R1A is hydrogen, halogen, -CN, -NO 2 , lower alkyl, lower heteroalkyl, -(alkyl)aryl, -(alkyl)heteroaryl, -OR 13 or -N(RiB)SO 2 RiC; wherein each occcurrence of RiB and Ric is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl; whereby each of the foregoing alkyl and heteroalkyl moieties may be linear or branched, substituted or unsubstituted, cyclic or acylic, and each of the foregoing aryl, heteroaryl, (alkyl)aryl and -(alkyl)heteroaryl moieties may be substituted or unsusbtituted; [0071] ix) R' is: 29 WO 2005/005374 PCT/US2003/039276 R1A RlD SN N 0 wherein R 1 A is as defined in viii) above; and R 1 D is hydrogen or lower alkyl; [0072] x) R' is: (RD A) wherein n is 1-2; p is 0-1; R 1 A is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -OR , -SR , -N(R1B)2, -SO 2 N(R1B )2,
C(=O)N(RIB)
2 , halogen, -CN, -NO 2 , -C(=O)OR ", -N(R )C(=O)Ri c or N(RIB)SO 2 Ric, wherein each occcurrence of RIB and R lc is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or (alkyl)heteroaryl; or RIB and Ri c , taken together with the atoms to which they are attached, form a substituted or unsubstituted heterocyclic moiety; RID and R 1 E are each independently hydrogen or lower alkyl; or R 1 D and R 1 E taken together form a 5 8 membered heterocyclic ring; or R 1 E and one occurrence of RIA, taken together, form a substituted or unsubstituted, saturated or unsaturated heterocyclic ring; [0073] xi) R 1 is: R1A N, 0 0 wherein R 1A is hydrogen, halogen, -CN, -NO 2 , lower alkyl, lower heteroalkyl, -(alkyl)aryl, -(alkyl)heteroaryl, -ORlB or -N(R iB)SO 2 RC; wherein each occcurrence of RIB and Ric is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl; whereby each of the foregoing alkyl and heteroalkyl moieties may be linear or branched, substituted or unsubstituted, cyclic or acylic, and each of the foregoing aryl, heteroaryl, (alkyl)aryl and -(alkyl)heteroaryl moieties may be substituted or unsusbtituted; [0074] xii) R 1 is: 30 WO 2005/005374 PCT/US2003/039276 R1A RIDN N wherein R1A is as defined in x) above; and RID is hydrogen or lower alkyl; [0075] xiii) compounds of subsets vi)-xii) wherein R 1 A is methyl, methoxy or halide; [0076] xiv) compounds of subsets vi)-xii) wherein R 1A is methyl, methoxy or F; [0077] xv) compounds of subsets vi)-xii) wherein R1 A is methyl; [0078] xvi) compounds of subsets viii) and xii) wherein RIB is hydrogen, methyl or ethyl; [0079] xvii) R 1 is: ORIA RiBO / wherein RIA and RIB are each independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl; [0080] xviii) compounds of subset xvii) wherein RIA and RIB are each independently cyclic or acyclic lower alkyl; [0081] xix) compounds of subset xvii) wherein R1A and RIB are each independently methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, sec-butyl, isopentyl or cyclopropyl; [00821 xx) R 1 is: RINFR1E 1N' R1AO I wherein R 1 A is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, (alkyl)aryl or -(alkyl)heteroaryl; RIE and R 1 F are each independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, C(=O)R c or -SO 2
R
c , where Ric is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl; or R 1 E and R 1 F taken together form a 5 8 membered heterocyclic ring; 31 WO 2005/005374 PCT/US2003/039276 [0083] xxi) compounds of subset xx) wherein RIA is substituted or unsubstituted, linear or branched, cyclic or acyclic lower alkyl; R 1 E is lower alkyl; and RIF is -SO 2 RID wherein R 1 D is lower alkyl; [0084] xxii) compounds of subset xx) wherein RIA is substituted or unsubstituted, linear or branched, cyclic or acyclic lower alkyl; RIE and RF, taken together with the nitrogen atom to which they are attached, form a 5- or 6-membered cyclic sulfonamide moiety; [0085] xxiii) R 1 is one of: OMeO ,-, N I N_ 0 0 0 o
O
e OMe N N N O8-N N N N N N 0 OMe Nr I -- _ N H 0 0 OMe OMe OMe OMe e 17 0 0 0 0 oo c,/- o o, .. N.- o N -S-N" o' 'N o0' 0 00 ON N N N N N 'N H 0 oo 0 0 s N~-N [0086] xxiv) R 1 is one of: 32 WO 2005/005374 PCT/US2003/039276 OMe N N N 000 0 OMe OMeMe N. NI NN 0 0 0 OMe OMe O~e 0 0 0~ NN.SN-N 0- 4 F - H NN OFN N 0 H o~o0 0 ,,/N S"N - -\ [0087] xxv) R 1 is one of: O F N 00 00 O H 0 0 [0088] xxvi) R 2 is lower alkyl, -CH2NR2AR 2B or -(CH2)phenyl, wherein the phenyl group is optionally substituted with one or more occurrences of R 2C, wherein
R
2c is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or (alkyl)heteroaryl, -OR 2
D
,
-SR
2
D
, -N(R2D)2, -SO2N(R2D)2, -C(=O)N(R2D)2, halogen, CN, -NO2, -C(=O)OR 2D, -N(R2D)C(=O)R 2E, wherein each occcurrence of R 2D and
R
2 E is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, (alkyl)aryl or -(alkyl)heteroaryl; and wherein R 2A and R 2B 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 33 WO 2005/005374 PCT/US2003/039276 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; [0089] xxvii) R 2 is lower alkyl, -CH 2
NR
2
AR
2 B or -(CH 2 )phenyl, wherein the phenyl group is optionally substituted with one or more occurrences of R 2c , wherein
R
2c is hydrogen, alkyl, alkoxy or halogen; and wherein R 2A and R 2B are each independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl; whereby each of the foregoing alkyl and heteroalkyl moieties may be linear or branched, substituted or unsubstituted, cyclic or acylic, and each of the foregoing aryl, heteroaryl, -(alkyl)aryl and -(alkyl)heteroaryl moieties may be substituted or unsusbtituted; [0090] xxviii) R 2 is one of: N (R2A (R 2 A)qR )q (R)q s (S 2A N S
(R
2 A (R 2 A (2A) (R N 00 0 S0
(R
2 A s (R 2 A) (R 2 A) (R N S IS S S
(R
2 A)q (R 2 A)q
(R
2 A) N (R2A ( R 2 A O/ ) ~ HIN N SN N S H H H TN ~ (R 2 A)q , (R 2 A)q
(R
2 A)q H (R2A)q ] (R2A)q O NN(R2A)T- S U wherein R 2 A is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or (alkyl)heteroaryl, -OR
B
, -SR 2B , -N(R 2
B)
2 , -SO 2
N(R
2
B)
2 , -C(=O)N(R 2
B)
2 , halogen, CN, -NO 2 , -C(=O)OR
B
, -N(R2B)C(=O)R2C, wherein each occcurrence of R 2 B and R c is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, (alkyl)aryl or -(alkyl)heteroaryl, wherein q and s are each independently integers 34 WO 2005/005374 PCT/US2003/039276 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; [00911 xxix) R 2 is one of: ~ -X X x 0A- ra0w SSM NNN wherein each occcurrence of R 2 A is independently hydrogen or lower alkyl; each occurrence of X is independently a halogen; s is an integer from 0 to 3 and u is an integer from 1 to 6; whereby each of the foregoing alkyl moieties may be linear or branched, substituted or unsubstituted and cyclic or acylic; [0092] xxx) compounds of subset xxix) wherein X is chlorine or fluorine; [0093] xxxi) compounds of subset xxix) wherein each occurrence of X is fluorine; [0094] xxxii) compounds of subset xxix) wherein R 2 A is methyl; [0095] xxxiii) R 2 is one of: 35 WO 2005/005374 PCT/US2003/039276 T- NI Cl F FMe -OMe F NN [0096] xxxiv) R 2 is one of: F F F F -F FF FF F -OMe -- c - ^ .OMe 2 [0097] xxxy) R 2 is One of -I
OFI
F C 0\/ ~- -0\ FF [0098] xxxvi) R 2 is one of: 36 WO 2005/005374 PCT/US2003/039276 F -FF F S S [0099] xxxvii) R 3 is hydrogen or halogen; [0100] xxxviii) R 3 is hydrogen or F; [0101] xxxix) R 3 is hydrogen; [0102] xl) R3' is hydrogen, methyl or halogen; [0103] xli) R3' is hydrogen, methyl or F; [0104] xlii) R is hydrogen; [0105] xliii) one of R 3 and R' is halogen; [0106] xliv) R 3 and R 3 are each independently hydrogen or F; [0107] xlv) R 3 and R 3' are each F; [0108] xlvi) R 3 and R 3 are each hydrogen; [0109] xlvii) X 1 is -C(=O)-; [0110] xlviii) X 1 is CHRX1A and RX1A is hydrogen or linear or branched substituted or unsubstituted alkyl; [0111] xlix) X 1 is CH 2 ; [0112] 1) X 2 is CHR x2A and R A is hydrogen or linear or branched substituted or unsubstituted alkyl or -alkyl(aryl); [0113] li) X 2 is CHR x 2A and R x2 A is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, benzyl or phenethyl; [0114] lii) X 2 is CHR x A and RE A is methyl, ethyl, propyl, isopropyl or phenethyl; [0115] liii) X 2 is CHMe [0116] liv) X 2 is -NR x 2A- and R X2A is hydrogen or linear or branched substituted or unsubstituted alkyl; [0117] lv) X 2 is -NR x2A- and R x 2 A is C1-C3 alkyl; [0118] lvi) X 2 is NH; 37 WO 2005/005374 PCT/US2003/039276 0 R x2B N [0119] lvii) X 2 is NHY where Y is H 2 where each occurrence R x a B 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; 0 RX2B [0120] lviii) X 2 is -CH(Me)Y- where Y is NH 2 where each occurrence R x2s is hydrogen, or an aliphatic, heteroaliphatic, aryl, heteroaryl, (alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or -(heteroalkyl)heteroaryl moiety; whereby each of the foregoing aliphatic and heteroaliphatic moieties may be linear or branched, substituted or unsubstituted, cyclic or acylic, saturated or unsaturated, and each of the foregoing aryl, heteroaryl, -(alkyl)aryl and -(alkyl)heteroaryl moieties may be substituted or unsusbtituted; [0121] lix) X 2 is absent; [01221 lx) X 3 is (CHRxA)k, -CH 2 NH-, -C(=O)NH-, or -SO 2 -, wherein each occurrence of R X3 A 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; [0123] ixi) X 3 is absent; [0124] lxii) X 3 is -C(=O)NH-; [0125] lxiii) X 3 is CHR X3A , X 2 is -NR X2A - and R 2A and R X3A are each independently hydrogen or linear or branched substituted or unsubstituted alkyl; [0126] lxiv) X 3 is CHRX 3 A and X 2 is NH; wherein RX 3 A is hydrogen or linear or branched substituted or unsubstituted alkyl; 38 WO 2005/005374 PCT/US2003/039276 [0127] lxv) X 3 is CH 2 and X 2 is NH; [0128] lxvi) X 2 and X 3 are each absent; 10129] lxvii) X 2 is CHR x A and X 3 is CH 2 NI-H; wherein R x A is hydrogen or linear or branched substituted or unsubstituted alkyl; [0130] lxviii) X 2 is CHR x 2 A and X' is -C(=O)NH-; wherein RX2A is hydrogen or linear or branched substituted or unsubstituted alkyl or -alkyl(aryl); [0131] lxix) R 4 is substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl, phenyl or -(CH 2 )phenyl, wherein the phenyl group is optionally substituted with one or more occurrences of R 4 A, wherein R 4 A is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -OR 4B , -SR 4 B, N(R 4
B)
2 , -SO 2
N(R
4
B)
2 , -C(=O)N(R 4
B)
2 , halogen, -CN, -NO 2 , -C(=O)OR 4B N(R 4
B)C(=O)R
4 c or -N(R 4
B)SO
2
R
4 C; wherein each occcurrence of R 4B and R 4 c is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteoraryl, -(alkyl)aryl or -(alkyl)heteroaryl; [0132] lxx) R 4 is substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl, phenyl or -(CH 2 )phenyl, wherein the phenyl group is optionally substituted with one or more occurrences of R 4A , wherein R 4 A is hydrogen, hydroxyl, alkyl, alkoxy or halogen; [0133] lxxi) R 4 is one of: 39 WO 2005/005374 PCT/US2003/039276 (RA -( 4A(4) R )
(R
4 A (R 4 A) (R 4 A) (R 4Ar
(R
4
A(R
4 A) (R 4 A) (R 4 A. --NA) W N H HH N (R 4 A) v (R 4 A)\, (R 4 A)" (R~) 0 N j - - 00 N H R4A (R4A) 4A wherein each occurrence of R 4 A is independently hydrogen, alkyl, heteroalkyl, aiyl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -OR4B, -SR 4 B, N(R 4
B)
2 , -SO 2 N(R4B) 2 , -C(=O)N(R 4
B)
2 , halogen, -CN, -NO 2 , -C(=O)OR4B
N(R
4
B)C(=O)R
4 c, wherein each occcurrence of R 4 B and R 4c 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; [0134] lxxii) R 4 is hydrogen; [0135] lxxiii) R 4 is methyl, ethyl, propyl or one of: x 4A (w Ow X w -I X W ;-R 4 A I) OR4A x 40 WO 2005/005374 PCT/US2003/039276 wherein each occcurrence of R 4 A is independently hydrogen, lower alkyl or
C(=O)OR
4 B, wherein R 4 B 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; [0136] lxxiv) compounds of subset lxxiii) wherein w is 1; [0137] lxxv) compounds of subset lxxiii) wherein w is 0; [0138] lxxvi) compounds of subset lxxiii) wherein x is 1, 3 or 4; [0139] lxxvii) compounds of subset lxxiii) wherein X is chlorine or fluorine; [0140] lxxviii) compounds of subset lxxiii) wherein each occurrence of X is fluorine; [0141] lxxix) compounds of subset lxxiii) wherein R 4 A is methyl; [0142] lxxx) R 4 is methyl, ethyl, propyl, isopropyl or one of: '-/R4A 'R4AR4A wherein R 4 A is hydrogen, hydroxyl, lower alkyl, lower alkoxy, halogen,
C(=O)OR
4 B, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, wherein R 4 B is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteoraryl, -(alkyl)aryl, (alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl; [01431 lxxxi) R 4 is methyl, ethyl, propyl, isopropyl or one of: 41 WO 2005/005374 PCT/US2003/039276 I I I I I I
CO
2 H "OH "CO 2 Me [0144] lxxxii) R 4 is one of: F OH II [0145] lxxxiii) R 4 is methyl, ethyl, propyl, isopropyl or one of: F OH CO 2 H OMe Cl /- /.¢ / /
CO
2 Me [0146] lxxxiv) R 4 is methyl, ethyl, propyl or one of: F [0147] lxxxv) R', R 3 and R 3 ' are each hydrogen, X 1 is -C(=O)-, X 3 is C(=O)NH-, R 1 is as described in subset xxiii, R 2 is as described in subset xxxiv, X 2 is as described in subset li, and R 4 is as described in subset lxxxiii; [0148] lxxxvi) R', R 3 and R 3 ' are each hydrogen, X 1 is -C(=O)-, X 3 is C(=O)NH-, R' is as described in subset xxiv, R 2 is as described in subset xxxv, X 2 is as described in subset lii, and R 4 is as described in subset lxxxiv; and/or [0149] lxxxvii) R', R 3 and R 3 ' are each hydrogen, X 1 is -C(=O)-, X 3 is C(=O)NH-, R 1 is as described in subset xxiv, R 2 is as described in subset xxxvi, X 2 is as described in subset lii, and R 4 is as described in subset lxxxiv. 42 WO 2005/005374 PCT/US2003/039276 [0150] 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. [0151] The reader will also appreciate that all possible combinations of the variables described in i)- through lxxxvii) above (e.g., R', R 1 , X 1 , R 2 , R 3 , R 3 ', X 2 , X 3 and R 4 , 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', R', X 1 , R, R, R , X, X 3 and R 4 , and other variables/substituents (e.g., RXlA, R x A, Y, RX 3 A, R 4 A, etc.) as further defined for R',
R
1 , X 1 , R 2 , R 3 , R 3" , X 2 , X 3 and R 4 , described in i)- through lxxxvii) above. [0152] 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;
R
1 is alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl;
X
1 is -C(=O)-, -S(=O)-, -C(=NH)-, -C(=S)-, -NC(=O)-, -NC(=S)-, -N-C(=N C-N)-, -NS(O 2 )-, -CHRXl
A-
, -SO 2 -, -COO-, -C(=O)C(RXl1A) 2 -, or -SC(=O)- wherein each occurrence of RXIA is independently hydrogen, or an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety;
R
2 is alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl; R is hydrogen, halogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or (alkyl)heteroaryl;
R
3 is hydrogen, halogen, or lower alkyl;
R
4 is alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl;
X
2 is absent, -NR x A
(CHRX
2 A)j - ,
-NRX
2
AY
- , or -(CHRX 2 A)jY - wherein each occurrence of R x 2A is independently hydrogen or an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, each occurrence of Y is independently O RX 2 B N H t wherein, for each independent occurrence of t, RX2B is hydrogen, 43 WO 2005/005374 PCT/US2003/039276 or an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, and wherein each occurrence ofj and t is independently an integer from 1 to 4; and
X
3 is absent, -NHCO-, -NHSO 2 -, -NHCONH-, -NHCOO-, -CH 2 NH-, C(=O)-, -S(=O)-, -C(=NH)-, -C(=S)-, -NC(=S)N-, -N-C(=N-CEN)N-, -NS(0 2 )N-, SO2-, -CONR x 3A -, -COO-, -(CHRX 3 A)k-, -0-, or -NRX 3
A
- , wherein each occurrence of R x3 A is independently hydrogen, an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, and k is an integer from 1 to 3. [0153] Other exemplary combinations are illustrated by compounds of the following subgroups I and II: 10154] I. Compounds having the structure (and pharmaceutically acceptable derivatives thereof): HI NH2
R
1 N
X
2
XR
4 O R 2 RSR 3 wherein R', R 2 , R , R 3 ', X 2 , X 3 and R 4 are as defined generally and in classes and subclasses herein.
X
2
R
4 In certain embodiments, R 3
R
3 has one of the following structures:
RX
2 A
RX
2 A Y 3N Y R4 -) i]
:R
4
R
3 or R " RX2 wherein R 3 is hydrogen, halogen or an aliphatic, heteroaliphatic, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or (heteroalkyl)heteroaryl moiety;
R
4 is an aliphatic, heteroaliphatic, aryl, heteroaryl, -(alkyl)aryl, (alkyl)heteroaryl, -(heteroalkyl)aryl, or -(heteroalkyl)heteroaryl moiety, or R 4 , taken together with R x 2A' or a substituent present on Y or X 3 , may form a cycloaliphatic, cycloheteroaliphatic, aryl, or heteroaryl moiety;
R
X 2A 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, 44 WO 2005/005374 PCT/US2003/039276 or R X2A ' taken together with R 4 may form a cycloaliphatic, cycloheteroaliphatic, aryl or heteroaryl moiety; S0 RX2B Y is independently absent or is ( /t, wherein, for each independent occurrence of t, R x " is hydrogen, or an aliphatic, heteroaliphatic, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or (heteroalkyl)heteroaryl moiety, or one occurrence of R x 2 B taken together with R 4 may form a cycloaliphatic, cycloheteroaliphatic, aryl or heteroaryl moiety; t is an integer from 1 to 4; and
X
3 is absent, -NHCO-, -NHSO 2 -, -NHCONH-, -NHCOO-, -CH 2 NH-, C(=O)-, -S(=O)-, -C(=NH)
-
, -C(=S)-, -NC(=S)N-, -N-C(=N-C-N)N-, -NS(O 2 )N-, SO 2 -, -C(=O)NRx 3
A
-
, -C(=S)NRX 3
A
- , -COO-, (CHRX 3 A)k, -0-, -CH 2
NRX
3
A
-
, or NRX 3 A-, wherein each occurrence of RX 3 A is independently hydrogen, an aliphatic, heteroaliphatic, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or -(heteroalkyl)heteroaryl moiety, or RX 3 A taken together with R 4 may form a cycloaliphatic, cycloheteroaliphatic, aryl or heteroaryl moiety, and k is an integer from 1 to 3. X x3 2
R
4 [0155] In certain embodiments, R 3 R has one of the following structures:
RX
2 A RX2A ir" X3 ¢.TN .y R 4 YX3R4 R4
R
3 or R 3 RX2A' / x 2 x3 R 4 [0156] In certain embodiments, R 3
R
3 has one of the following structures: 45 WO 2005/005374 PCT/US2003/039276
RX
2A RX2A H 4 N'R4 NN R 'R' 3 X2TB
R
3 0 R o R R RX2A or H o RX2E / N N R4 X2A- H t wherein R 3 , R 4 , R X2A , RA, R
X
B and t are as defined above and in classes and subclasses herein.
SX
2
R
4 '-X3' [0157] In certain embodiments, R 3
R
3 has one of the following structures: O ; R 3 0 /' ; " N R or H 0 H N N , R4 - O; H wherein R and R 4 are as defined above and in classes and subclasses herein. [0158] II. Compounds having the structure (and pharmaceutically acceptable derivatives thereof): H NH 2 RX2A H
R
1 N N', R4 o 2 0 wherein R 1 , R2, RX2A and R 4 are as defined generally and in classes and subclasses herein. [0159] In certain embodiments for compounds as described in subgroups I II above, R' is a substituted or unsubstituted aryl, heteroaryl, -(alkyl)aryl, (alkyl)heteroaryl or heterocyclic moiety. In certain exemplary embodiments, R 1 has one of the following structures: 46 WO 2005/005374 PCT/US2003/039276 H N 0 H O O N ~N' 0 0 [0160] In certain embodiments, for compounds as described in subgroups I II above, R 2 has one of the following structures: I j Iv F F F F S S: [0161] In certain embodiments, for compounds as described in subgroup I above, R 3 is halogen. In certain exemplary embodiments, R 3 is F. In certain other embodiments, R 3 is hydrogen. [0162] In certain embodiments for compounds as described in subgroups I and II above, R 4 is substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl, phenyl or -(CH 2 )phenyl, wherein the phenyl group is optionally substituted with one or more occurrences of R 4 A, wherein R 4A is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -OR 4B , -SR 4B , -N(R B)2, SO 2 N(R4B) 2 , -C(=O)N(R 4
B)
2 , halogen, -CN, -NO 2 , -C(=O)OR 4B , -N(R4B)C(=O)R 4 C, wherein each occcurrence of R 4 B and R 4 C is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, (heteroalkyl)aryl, -(heteroalkyl)heteroaryl. In certain other exemplary embodiments,
R
4 is substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl, phenyl or -(CH 2 )phenyl, wherein the phenyl group is optionally substituted with one or more occurrences of R 4 A, wherein R 4 A is hydrogen, hydroxyl, alkyl, alkoxy or halogen. In certain exemplary embodiments, R 4 has one of the following structures: 47 WO 2005/005374 PCT/US2003/039276 F [0163] 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, RX 2 A is methyl, ethyl, propyl, isopropyl or phenethyl. [0164] 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. [0165] 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. [0166] Furthermore, certain compounds, as described herein may have one or more double bonds that can exist as either the Z or E isomer, unless otherwise indicated. The invention additionally encompasses the compounds as individual isomers substantially free of other isomers and alternatively, as mixtures of various isomers, e.g., racemic mixtures of stereoisomers. 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 48 WO 2005/005374 PCT/US2003/039276 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 pharmnaceutically acceptable compositions containing them. [01671 2) Synthetic Overview: [0168] 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', R', R 2 , R , R " and R 4 substituents and X 1 , X 2 and X 3 moieties. [0169] 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. [0170] Moreover, the practitioner is directed to the specific guidance and examples provided in this document relating to various exemplary compounds and intermediates thereof. [0171] As described above, the present invention provides novel compounds, specifically compounds having the following general structure: R' NH 2 REX4-N ' X3 R 4
R
2
R
3
R
3 (I) and pharmaceutically acceptable derivatives thereof; wherein R 1 , R 2,
R
3 , R 3 ', R, X 1 , X 2 , X 3 and R 4 are as defined generally above and in classes and subclasses herein. 49 WO 2005/005374 PCT/US2003/039276 [0172] 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 Fommla (IA): R' NH 2 XI X 2
R
4
R
3
R
3 (IA) [0173] 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
A
l : R' OH R' U
I
2 B RN X2, B RPN X .,B
R
2
R
3
R
3 '
R
2
R
3
R
3 R' U R- NH 2
R.X
1 N X.,B R 1 j 2
R
4 XT X2BX2 X
R
2
R
3
R
3 '
R
2
R
3
R
3 " (I) Scheme A R' OH R' U
XX
2 B Rp XPB -R R 3
X
3 k~2 R 3
R
3 ' 2
R
3
R
3 '
R
2
R
3
R
3 ' (lA) Scheme A 1 10174] Alternatively, substituent R 3 ' may be introduced at a later stage in the synthesis, as depicted for example in Schemes A 2 and A 3 : 50 WO 2005/005374 PCT/US2003/039276 R' OH R' U R' U 2 RBXN XRX 2 , RB X X 2 B Rp N X .. A/'B R,,- Rp1 " XA
R
2
R
3
R
2
R
3
R
2
R
3
R
3 R U R' NH 2 R NX2 B R.. 1N X2 R 4 X1,- XR
R
2
R
3
R
3 '
R
2
R
3
R
3 ' (I) Scheme A 2 R' OH R U R' U B I X XB RI R P I"N XA.B R " X R2 R 3 R2 R 3 2 R R' U R' NH 2
R..
1 .N B R 1 2
R
4 IXTA X, NX3 2
R
3
R
3
R
3
R
3 (1A) Scheme A 3 [0175] In certain embodiments, the inventive method comprises i) providing a compound having the structure: R' OH I X 2 B RPItN XA - B
R
2
R
3
R
3 ' wherein R', R2, R 3 , R 3 ' and X 2 are as defined generally above and in classes and subclasses herein,
R
P1 is a nitrogen protecting group; A is absent, -NHCO-, -NHSO 2 -, -NHCONH-, -NHCOO-, -CH 2 NH-, C(=O)-, -S(=O)-, -C(=NH)-, -C(=S)-, -NC(=S)N-, -N-C(=N-C-N)N-, -NS(O 2 )N-, SO 2 -, -C(=O)NR s -, -C(=S)NR s -, -COO-, -(CHR)r
-
, -0-, -CH 2
NR
s - or -NR 5 -, wherein each occurrence of R 5 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 -VR c , wherein V is -0-, -NRD - , 51 WO 2005/005374 PCT/US2003/039276 C(=O)-, -S(=O)- or -SO 2 -, 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: R' U X 2 B
R
2
R
3
R
3 wherein U is -NHR P2 or -N 3 , wherein R P2 is a nitrogen protecting group; iii) reacting the compound of step (ii) with suitable reagents to generate a compound having the structure: R' U R IXN j X 2 B
R
2
R
3
R
3 ; and iv) reacting the compound of step (iii) with suitable reagents to generate the free amine having the structure : R' NH 2 Ri' N
X
2
R
4
R
2
R
3
R
3 (I) wherein R', R', R 2 , R 3 , R y , R 4 , X', X 2 and X 3 are as defined generally above and in classes and subclasses herein. [0176] In certain embodiments, the present invention encompasses methods for the preparation of compounds having the general formula (IA), and classes and subclasses herein. R' NH 2
R
1 N X 2
R
4
R
2
R
3
R
3 ' (IA) [0177] In certain embodiments, the method comprises: i) providing a compound having the structure: 52 WO 2005/005374 PCT/US2003/039276 R' OH
X
2 B RpyN __ X ',B R2 R 3
R
3 wherein R', R 2 , R 3 , R 3 ' and X 2 are as defined above,
RP
1 is a nitrogen protecting group; A is absent, -NHCO-, -NHSO 2 -, -NHCONH-, -NHCOO-, -CH 2 NH-, C(=O)-, -S(=O)-, -C(=NH)-, -C(=S)-, -NC(=S)N-, -N-C(=N-CEN)N-, -NS(O 2 )N-, S02-, -C(=O)NR 5 -, -C(=S)NR'-, COO-, -(CHRs 5 )r
-
, -0-, -CH 2 NR- or -NR 5 -, wherein each occurrence of R 5 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 -0-, -NR
D-
, C(=O)-, -S(=O)- or -SO 2 -, 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: R' U RPr
X
2 B R2 R 3
R
3 wherein U is -NHRP 2 or -N 3 , wherein R P2 is a nitrogen protecting group; iii) reacting the compound of step (ii) with suitable reagents to generate a compound having the structure: R' U RItN'
X
2 B
R
2
R
3
R
3 ;and iv) reacting the compound of step (iii) with suitable reagents to generate the free amine having the structure (IA): R' NH 2 R ' X 2
R
4 2 R 3
R
3 53 WO 2005/005374 PCT/US2003/039276 (A) wherein R', R 1 , R 2 , R 3 , R ,
R
4 , X', X 2 and X 3 are as defined generally above and in classes and subclasses herein. [0178] In yet another aspect of the invention, methods for producing intermediates useful for the preparation of compounds of formulas (I') and (IA) are provided, embodiments of said methods being depicted generally in Schemes A 4 and
A
s : H OH H U R" X2AB X' R X 2 B
R
2
R
3
R
2 R Scheme A 4 R 2 B XA B RP-. R R RR3 H U H NH 2 R-. 1 N XAB R" N X 2
R
4 -X XT, x3' R2 R 3 IR2 R 3
(
- A) Scheme As [0179] In certain embodiments, the inventive method comprises i) providing a compound having the structure: H OH X2 2 RpRN X ,B R2 R R wherein R2, R 3 , and X 2 are as defined above, R" is a nitrogen protecting group; A is absent, -NHCO-, -NHSO 2 -, -NHCONH-, -NHCOO-, -CH 2 NH-, C(=O)-, -S(=O)-, -C(=NH)-, -C(=S)-, -NC(=S)N-, -N-C(=N-CEN)N-, -NS(O 2 )N-, 54 WO 2005/005374 PCT/US2003/039276
SO
2 -, -C(=O)NR 5 -, -C(=S)NR 5 -, -COO-, -(CHR')r
-
, -0-, -CI-1 2
NR
5 - or -NR - , wherein each occurrence of R 5 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 -0-, -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: H U I X2 RpyNX ,B R R3 wherein U is -NHR P2 or -N 3 , wherein RP 2 is a nitrogen protecting group; iii) reacting the compound of step (ii) with suitable reagents to generate a compound having the structure: H U X2 B R 'Xl.N X , R A 2 _ 3-AB R R ; and iv) reacting the compound of step (iii) with suitable reagents to generate the free amine having the structure : H NH 2
R
1 -. X X X 3R 4 R 2 R3 R R (F) wherein R', R 2 , R, R 4 , X 1 , X 2 and X 3 are as defined generally above and in classes and subclasses herein. [0180] In certain embodiments, the present invention encompasses methods for the preparation of compounds having the general formula (I'A), and classes and subclasses herein. H NH 2
R
1 XqN
X
2
R
4 2
R
3 55 WO 2005/005374 PCT/US2003/039276 (IA) [0181] In certain embodiments, the method comprises: i) providing a compound having the structure: H OH 2 RP yN X AB 2R3 R2 R wherein R 2 , R 3 , and X 2 are as defined above, R" is a nitrogen protecting group; A is absent, -NHCO-, -NHSO 2 -, -NHCONH-, -NHCOO-, -CH 2 NI-, C(=O)-, -S(=O)-, -C(=NH)-, -C(=S)-, -NC(=S)N-, -N-C(=N-C-N)N-, -NS(O 2 )N-, SO2-, -C(=O)NR 5 -, -C(=S)NR 5 -, -COO-, -(CHRs)r-, -0-, -CH 2
NR
5 - or -NR 5 -, wherein each occurrence of R 5 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 II is a protecting group, or an aliphatic, heteroaliphatic, aryl, heteroaryl, (alkyl)aryl or -(alkyl)heteroaryl moiety, or is -VR c , wherein V is -0-, -NR
D
-, C(=O)-, -S(=O)- or -SO 2 -, 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: H U RpyNX ,B R R 3 wherein U is -NHR P2 or -N 3 , wherein RP 2 is a nitrogen protecting group; iii) reacting the compound of step (ii) with suitable reagents to generate a compound having the structure: H U X X "iB R xlN x 2 B R2 R ; and 56 WO 2005/005374 PCT/US2003/039276 iv) reacting the compound of step (iii) with suitable reagents to generate the free amine having the structure (I'A): H NH 2 4 RE1XI'N X.
-
X R4X3 R 2
R
3 (rA) wherein R 1 , R 2 , R 3 , R 4 , X 1 , X 2 and X 3 are as defined generally above and in classes and subclasses herein. [0182] 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: 0 H 0 R X2A OH RX 2 A H 0 RX B -. B/]x A R N3 A RPR RP R 2 R2 fR 3 2 R 3 Y OH RX2A H ORP 3
RX
2 A N AB B B R1NRPT " B R2 R 3 R2 R 3
SN
3 RX2A H N 3 RX2A ZB Rtx - K 8 RP1 N . AB . R 2 R 3 R ~2 R 3 Hl N 3 RX2A R X2A R " XR 4 R X, 4 R1 -xM X3 .N X 3 I NH 2 RX2A 3 R2 R 3 R2 R (I"A) Scheme B wherein each of R
I
, X', RP 1 , R 2 , X 3 , and R 4 are as defined above and R P3 is an oxygen protecting group. [0183] 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 57 WO 2005/005374 PCT/US2003/039276 the Examples herein). Subsequent ring opening, protection, oxidation and stereoselective reduction yields the desired compound of provided in step i). Subsequent reduction to an azide in step ii) and reaction with a suitable reagent (to yield -X'-R l ) is also effected. Finally, reaction with a suitable reagent to generate X 3
-R
4 and deprotection yields the desired compound. It will be appreciated that a variety of methods can be utilized to effect these transformations, including those detailed in the specification herein, and additional general guidance as also described herein. [0184] Additionally, it will appreciated that compounds having the general structures depicted above, wherein X 3 is SO 2 can be effected using the methodology generally described herein and also methodology described in 5,585,397, the entire contents of which are hereby incorporated by reference. [0185] 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 -NH 2 . Examples of such prodrug moieties include the following: O For the synthesis of the prodrug groups, see Borchardt, R. T. et. al., O J. Org. Chem. 1997, 43, 3641-3652.
NH
2 1R
R
1 = all natural, unnatural amino acids O O II.\ J yNH For the synthesis ofthe prodrug groups, see SJR1O R 2 Zhou, X-X. et. al., PCTWO 99151613.
R
1 = C1-C4 alkyl, cycloalkyl, oxyalkyl, aminoalkyl, etc.
R
2 = all natural, unnatural amino acids 0 2 0RH 12 For the synthesis of the prodrug groups, see Ezra, A. et. al., N NH 2 J. Med. Chem. 2000, 43, 3641-3652. R 0
R
1 , R = all natural, unnatural amino acids 58 WO 2005/005374 PCT/US2003/039276 [0186] The present invention encompasses any prodrug form of the compounds described herein. Although certain other exemplary prodrug moieties generated from the inventive compounds amino group are detailed herein, it will be appreciated that the present invention is not intended to be limited to these prodrug moieties; rather, a variety of additional prodrug moieties can be readily identified by a person skilled in the relevant art. [0187] 3) Pharmaceutical Compositions [0188] As discussed above, certain of the compounds as described herein exhibit activity generally as inhibitors of aspartyl proteases and more specifically as inhibitors of P-secretase enzyme activity, and have the ability to halt or reduce the production of A P from APP and reduce or eliminate the formation of P-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 P3 amyloid peptide, such as P-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 Hemnorhage 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. [0189] 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 59 WO 2005/005374 PCT/US2003/039276 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 -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. [0190] 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 Pharmnaceutical 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, 60 WO 2005/005374 PCT/US2003/039276 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, fuimarate, 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, loweralkyl sulfonate and aryl sulfonate. [0191] 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. [0192] Furthermore, the term "pharmaceutically acceptable prodrugs" as used herein refers to those prodrugs of the compounds of the present invention 61 WO 2005/005374 PCT/US2003/039276 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. [0193] 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; pyrogenfree water; 62 WO 2005/005374 PCT/US2003/039276 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. [0194] 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. [0195] 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. [0196] 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. 63 WO 2005/005374 PCT/US2003/039276 [0197] 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. [0198] 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. [0199] 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 64 WO 2005/005374 PCT/US2003/039276 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. [0200] 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. [0201] 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. [0202] 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 65 WO 2005/005374 PCT/US2003/039276 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. [0203] 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 A p peptide or administration of anti-A 3 peptide antibodies; statins; and direct or indirect neurotropic agents such as Cerebrolysin®, 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 66 WO 2005/005374 PCT/US2003/039276 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. [0204] 4) Research Uses, Pharmaceutical Uses and Methods of Treatment [0205] Research Uses [0206] 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. [0207] In certain exemplary embodiments, compounds of this invention were assayed for their ability to inhibit aspartyl proteases, more specifically BACE. [0208] 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 (P3-secretase enzyme activity); o exhibit the ability to inhibit A P3 peptide production; * exhibit the ability to halt or reduce the production of A P from APP and reduces or eliminates the formation of 3-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 P3-amyloid peptide, such as 03 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). [0209] 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 BACEKapp < 10 jtM. In certain other embodiments, inventive compounds have BACEKi app < 7.5 PM. In certain other embodiments, inventive compounds have 67 WO 2005/005374 PCT/US2003/039276 BACEKiapp -< 5 pM. In certain other embodiments, inventive compounds have BACEKiaPP < 2.5 pM. In certain other embodiments, inventive compounds have BACEKapp < 1 rIM. 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 BACEK app < 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 5< 30 nM. In certain other embodiments, inventive compounds have BACEKiapp < 20 nM. In certain other embodiments, inventive compounds have BACEKiapp < 10 nM. [0210] In certain embodiments, catDKaPP for compounds of the invention is > 2 fold greater than BACEKiapp. In certain other embodiments, CatDK 1 app 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 BACEKaPP. In certain embodiments, CatDK aPP for compounds of the invention is > 7.5 fold greater than BACEKi pp. 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, catKiapp 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 BACEKaPP. In certain embodiments, CatDKiapp for compounds of the invention is > 150 fold greater than BACEKiaPP. In certain embodiments, CatDK;app for compounds of the invention is > 200 fold greater than BACEKiapp. In certain embodiments, CatDKjaPP for compounds of the invention is > 250 fold greater than BACEKjapP. In certain embodiments, catoKaPP for compounds of the invention is > 300 fold greater than BACEKiaPP. In certain embodiments, CatDK iapp for compounds of the invention is > 500 fold greater than BACEKiapp. In certain 68 WO 2005/005374 PCT/US2003/039276 embodiments, CatDKiapp for compounds of the invention is > 1000 fold greater than BACEK app [0211] In certain exemplary embodiments, inventive compounds have CellIC 50 values <10 pM. In certain other embodiments, inventive compounds have ceaIC 5 0 values < 7.5 tM. In certain other embodiments, inventive compounds have ce11ICso 0 values < 5 pM. In certain other embodiments, inventive compounds have cel1IC 50 values < 2.5 pM. In certain other embodiments, inventive compounds have cellIC 50 values < 1 pM. In certain other embodiments, inventive compounds have CellIC 50 values < 750 nM. In certain other embodiments, inventive compounds have cellIC 50 values < 500 nM. In certain other embodiments, inventive compounds have cellIC 50 values < 250 nM. In certain other embodiments, inventive compounds have cellIC 50 values < 100 nM. In certain other embodiments, inventive compounds have cellIC 50 values < 80 nM. In certain other embodiments, inventive compounds have cel1IC 50 values < 60 nM. In certain other embodiments, inventive compounds have cellC 50 values < 50 nM. In certain other embodiments, inventive compounds have cel1IC 5 0 values < 30 nM. In certain other embodiments, inventive compounds have cellIC 50 values < 20 nM. In certain other embodiments, inventive compounds have celIlICso values < 10 nM. [0212] Pharmaceutical Uses and Methods of Treatment [0213] 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 P-secretase enzyme activity. In certain embodiments compounds exhibit the ability to halt or reduce the production of A 3 from APP and reduce or eliminate the formation of P3 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 3 amyloid peptide, such as 3-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 69 WO 2005/005374 PCT/US2003/039276 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. [0214] 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. [0215] 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 P3-secretase enzyme activity and A P3 peptide production. Thus, in certain embodiments, the present invention provides compounds useful for the treatment of disorders mediated by a pathological form of P-amyloid peptide, such as 3 amyloid plaques, and for helping to prevent or delay the onset of such a condition. [0216] 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, 70 WO 2005/005374 PCT/US2003/039276 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. [0217] 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 P3-amyloid peptide, such as f3 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 P-amyloid peptide, such as P3 amyloid plaques. Thus, the expression "effective amount" as used herein, refers to a sufficient amount of agent to inhibit the production of A P3 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 71 WO 2005/005374 PCT/US2003/039276 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). [0218] Another aspect of the invention relates to a method for inhibiting (3 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. [0219] 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 [0220] 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 72 WO 2005/005374 PCT/US2003/039276 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 [0221] 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. [0222] 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 [0223] 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. 73 WO 2005/005374 PCT/US2003/039276 [0224] EXAMPLE 1 [0225] This example describes the enzyme assay for determining the apparent Ki of the compounds of the present invention. [0226] 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 6X His tag. [0227] 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: NH 2 -Arg-Glu(EDANS)-Glu-Val-Asn-Leu-1-Asp-Ala-Glu-Phe Lys(DABCYL)-Arg-COOH FS-2: MOCAc-Ser-Glu-Val-Asn-Leu-1-Asp-Ala-Glu-Phe-Lys(DNP)-Arg-Arg COOH where EDANS is 5-((2-aminoethyl)amino)napthalene-l1-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. [02281 FS-1 and FS-2 correspond to the Swedish APP 3-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 Xexcitation = 350 nm and Xemission = 490nm or Xexcitation = 328 nm and Xemission = 440nm (MOCAc). For determination of apparent inhibition constant (Ki app ) 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)): [E]o - [I]o - Ki app + V ([E]o-[Ij]o-KiaPP) 2 + 4[E]oKi app V = Vo 74 2[E]o WO 2005/005374 PCT/US2003/039276 where v is the initial rate measured in the presence of [I]o, the inhibitor concentration, using an enzyme concentration [E]o. vo is the initial rate measured in the absence of inhibitor. [0229] Inhibitors were resuspended in DMSO and serially diluted in DMSO at 20x final assay concentration. Compound dilutions (5 pL) were transferred to Black non-treated 96-well microtiter plates, and resuspended in 85 tL 35.3 ptM 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 10pL BACE-HT (100nM 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 KiaPPrs for preferred compounds is 0.1-500 nM. [0230] EXAMPLE 2 [0231] 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 AP3 peptide from cells expressing high levels of the human amyloid precursor protein ("APP"). [0232] 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 P695wt). 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 3695wt lines were obtained from Mayo Clinic (J. Neuroscience Methods 108(2): 171-9 (2001)). 75 WO 2005/005374 PCT/US2003/039276 [0233] The following media were used for the cell lines: DMEM + glucose, glutamine, sodium pyruvate, pyridoxine-HC1, antibiotics, and 10% FBS (A-204 cells); DMEM + glucose, glutamine, sodium pyruvate, pyridoxine-HC1, non essential amino acids, antibiotics, and 10% FBS (HEK 293 cells); Ham's F-12 + antibiotics, 10% FBS, and 400 pg/ml Zeocin (CHO2B7 cells); and Opti-MEM (Invitrogen)+ antibiotics, 10% FBS, and 500 pg/ml geneticin(H4 f695wt cells). [0234] Ifn the assay, cells were pre-treated with compounds for 1-2 hours to "wash out" any A3 in the secretory pathway prior to incubation with compounds for the conditioning period required to generate detectable concentrations of Ap. The production of secreted A3 in cultured cells was monitored by sandwich ELISA, using the anti-Ap3 monoclonal antibodies 6E10 and 4G8 (Signet Laboratories). The antibody 6E10 (specific to amino acids 1-17 of Aj3) was immobilized to the plate and used for capture, and a biotinylated version of the antibody 4G8 (specific to amino acids 17-24 of AP3) was used for detection, via subsequent treatment with Neutravidin-horseradish peroxidase conjugate and development with luminescent substrate. [0235] Cells were plated at 2.5x10 5 cells/well (HEK293 cells in 24 well poly-D-lysine coated plate), 1.3 x 105 cells/well (A-204 cells) (48 well plates) or 5 x 104 cells/well (CHO2B7 and H4APP cells) (96 well plates) in appropriate media (500 pL per well for 24 well plates, 300 pL per well for 48 well plates, 150 IL per well for 96 well plates) and grown at 370 C and 5% CO 2 for 16-20 h. Media was aspirated and replaced with appropriate media plus 0.1% DMSO and various concentrations of inhibitors, prepared by resuspension of the appropriate volume of a 1000X solution of inhibitor in DMSO with media on a separate plate. 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 pL of each sample applied to wells of Nunc Maxisorp white 96-well plates that had been previously coated with 10 gg/mL 6E 10 antibody in 50 mM Na 2
CO
3 , (pH 9.0) overnight at 4o C, blocked with Superblock in PBS (Pierce Chemicals; PBS=10 mM sodium phosphate + 150 mM NaC1, pH 7.4) for 1 hour at room temperature, and washed 3 times in wash buffer (PBS plus 0.05% Tween 20). 76 WO 2005/005374 PCT/US2003/039276 Binding was allowed to take place overnight at 4 oC, and plates were then washed 8 times and treated with 100 pL/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 pL/well of 1.5 ig/ Neutravidin horseradish peroxidase conjugate (Pierce Chemicals) for 40 minutes at room temperature, washed an additional 8 times, and developed with 100 tL/well Supersignal luminescent substrate (Pierce Chemicals) for 2 minutes. Luminescence was measured on a Gemini XS fluorescence/luminescence plate reader, and translated into AP3 concentrations using an internal standard curve of known AP3 concentrations (AP3 1-40 obtained from Oncogene). In general, ICs 5 o's of the compounds of the present invention range from about 5X to about 15X the observed KiaPP's against the BACE enzyme as determined using the method of Example 1. [0236] EXAMPLE 3 [0237] This example describes permeability experiments using MDCK cells. [0238] 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% CO 2 at 37 0 C. For transport studies, cells were plated at a density of 50 x 103 cells/cm 2 on 0.4 Vm pore size TranswellTM polyester membranes (Corning, Coming, NY). Culture medium was replaced every two days until a tight cell monolayer was formed as measured by preliminary R123 permeability measurements. Compounds, 10 pM, 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/AC 0 ) dQ/dt where A= surface area of the cell monolayers, Co is the initial concentration and dQ/dt represents the amount of drug flux in a specified time. 77 WO 2005/005374 PCT/US2003/039276 [0239] EXAMPLE 4 [0240] 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. [0241] 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 nmM NaC1, 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 (Tmx) were measured directly from concentration versus time profiles. Descriptive pharmacokinetic parameters were calculated using the WinNonlin software package (Pharsight Inc., Mountain View CA). Figure 1A and lB 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
IC
50 in cells of about 220 nIM. [0242] EXAMPLE 5 [0243] This example compares the biological properties of a hydroxy containing compound with an amino-containing compound. The two compounds are of the structure L'O H R H 0 AN N Nk 0 0 0 78 WO 2005/005374 PCT/US2003/039276 where R is either OH or NH 2 . In a surprising and unexpected finding, the amino containing compound possesses several superior biological properties over its hydroxy-containing counterpart. [0244] 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. Compound BACE Ki IC 5 0 so (H4 cells) Cat D Ki % recovery liver microsomes R=OH 150 nM 2000 nM 20 nM 0% at 60 minutes
R=NH
2 180 nM 740nM 610 nM 43% at 60 minutes [0245] 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. [0246] These trends appear to be a general phenomenon and have been observed in several scaffolds in addition to one exemplified above. [0247] The Ki for BACE and the IC 5 0 determinations were performed as described in Examples 1 and 2 respectively. [0248] 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. [0249] Plasma stability was determined by incubating the compounds in human plasma at a concentration of 1 pM at 37 'C for 0, 30 and 60 minutes. Reactions were stopped by addition of acetonitrile. Protein was precipitated by centrifugation (3000 rpm x 10 min) then supernatants were analyzed for remaining parent compound by LC/MS/MS. 79 WO 2005/005374 PCT/US2003/039276 [0250] Metabolic stability was determined by incubating the compounds with human liver microsomes (100 pg/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 VM. Reactions were stopped after 30 and 60 minutes by addition of acetonitrile. Protein was precipitated by centrifugation (3000 rpm x 10 min) then supernatants were analyzed for remaining parent compound by LC/MS/MS. [0251] General Description of Synthetic Strategy: [0252] 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. 10253] 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, WI), Bachem (Torrance, CA), Sigma (St. Louis, MO), or are prepared by methods well known to a person of ordinary skill in the art following procedures described in such references as Fieser and Fieser 1991, "Reagents for Organic Synthesis", vols 1-17, John Wiley and Sons, New York, NY, 1991; Rodd 1989 "Chemistry of Carbon Compounds", vols. 1-5 and supps, Elsevier Science Publishers, 1989; "Organic Reactions", vols 1-40, John Wiley and Sons, New York, NY, 1991; March 2001, "Advanced Organic Chemistry", 5th ed. John Wiley and Sons, New York, NY; 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. [0254] The starting materials, intermediates, and compounds of this invention may be isolated and purified using conventional techniques, including 80 WO 2005/005374 PCT/US2003/039276 filtration, distillation, crystallization, chromatography, and the like. They may be characterized using conventional methods, including physical constants and spectral data. [0255] General Reaction Procedures: [0256] 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. [02571 General Work Up Procedures: [0258] 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 0 C). 81 WO 2005/005374 PCT/US2003/039276 [0259] General Purification Procedures: [0260] 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 0 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. [0261] Synthesis of Exemplary Compounds: [0262] 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 R 1 , R 2 and R 3 substituents and X 1 , X 2 and X 3 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. Patent Nos: 5,585,397; 5,916,438 and 5,413,999; U.S. Application No. 10/462,127 filed June 16, 2003 and Published PCT application WO 02/02505, the entire contents of which are hereby incorporated by reference. A derivative of Fommla 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. [0263] Unless otherwise indicated, starting materials are either commercially available, as indicated or are obtained through laboratory synthesis by anyone reasonably familiar with the art. 82 WO 2005/005374 PCT/US2003/039276 [0264] EXAMPLE.6 [0265] This example describes the synthesis of amino acids and amino-acid like compounds of the formula O H 0 P * OH RA 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. [0266] Scheme 1 /" NH 1. LiN(TMS) 2 , H LiCI, THF OH 02 A 0 LiOt-Bu, THF: H 2 0 N NH 2
H
2 0 2. RAX -. OUNH 2 -HCI OH.- N/[ NH2'H20 1.1 H 1.2 1, NaOH, H 2 0, reflux 0 2. (Boc)20, TrCI or FmocCI P OH N NH 2 ____________N . OH N OH RA 1.4 1.3 [0267] 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, H20, refluxed) followed by protection of the amine gives compound 1.4. [0268] EXAMPLE 7 [0269] This example describes the synthesis of compounds of the formula H
N
3 pN OTBS RA [0270] where RA is as defined in Example 6. These compounds were prepared according to Scheme 2 and the procedure below. 83 WO 2005/005374 PCT/US2003/039276 [02711 Scheme 2 0 0 H OH H OH HN LAH PN OH TBSC IN OTBS RA RA RA 2.1 2.2 2.3 H 0 H OH H OMs DMPI pN . ) OTBS NaBH 4 p.,N OTBS MsCI pN OTBS RA RA RA 2.4 2.5 2.6 NaN 3 H N 3 N- N OTBS RA 1 [0272] 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 CH 2
C
2 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. [0273] EXAMPLE 8 [0274] An alternate procedure to prepare compound 1 is described in Scheme 3 and the procedure below. 84 WO 2005/005374 PCT/US2003/039276 [0275] Scheme 3 0 0 0 0 HOH H H tlo n-ui10Cr P OH HPN
OCH
3 CHsP(O)(OR) 2 OR n-BuL, -10 0 C-rt .- ,KH )'P " pkN--.3 PIN P'OR RA RA n-BuLi, -78 0 C RA Ethyl Pyruvate 1.4 3.1 3.2 00 0/ H pC 2 Et 1. NaBH4/MeOH, -780C 10 % Pd-C LAH A NN P, L RA 2.1N HCl RA RA 3.3 3.4 3.5 H OH | OH I H N 3 P H OH TBSCI HOTBS 1. MsCI pHNOTBS P__I_ N PN OTBS PNOB RA RA 2. NaN 3 RA 3.6 . [0276] 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 NaBH 4 to afford lactone 3.4. Hydrogenation of lactone 3.4 followed by reduction of LAH yields diol 3.6. The protection of primary alcohol gives TBS ether 3.7. The mesylation of 3.7 follow by the addition of sodium azide to the mesylate affords compound 1. [0277] EXAMPLE 9 [0278] Another alternate procedure to prepare compound 1 is described in Scheme 4 and the procedure below. [0279] Scheme 4 0 H Br OBn 1. H2 H--- Mg OBn 2. NaBH PN,. OH,- P' S4 RA RA ref RA 1.4 4.2 4.3 H TBSCI H OH1.MsCI H N O PIN OH TPIl p N OTBS ,sCOTBS RA 4 A 4 2. NaN 3 RA 444.5 1 [0280] 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 NaBH 4 , followed by hydrogenation gives 85 WO 2005/005374 PCT/US2003/039276 the corresponding diol 4.4. The protection of the primary alcohol by TBSC1 (1 eq), imidazole in CH 2 C1 2 affords compound 4.5. Mesylation of 4.5 followed by the addition of sodium azide to the mesylate 4.6 affords compound 1. [0281] EXAMPLE 10 [02821 This example describes the synthesis of H NH 2 H 0 0 o = o0 [0283] which was prepared according to Scheme 5 and the procedure below. [0284] Scheme 5 0 H 0 H 0 LAH H OH BocN OH Boc N Boc'N OH 51 5.2 OH H TBSCI H DMP N ,OTBS NaBH 4 Boc"N OTBS MPIBoc - -- Boc 5.3 5.4 H OH OMs N 3 H MsCI H N TB Boc. OTBS - Boc, N OTBS BocNOTBS 5.5 5.6 5.7 yo N NA~ OH a H N 4 N HCI H 2 N OH N 0 ,UN ' N OH 0 0 EDC, HOBt, DIEA 5.9 5.8 86 WO 2005/005374 PCT/US2003/039276 HATU, DIEA 0 H2NIJ Jones' reagent H N 3
H
2 N __N OH 0 0 0 5.10 N H2, 10 % Pd-C 5.11 L H NH 2 H 0 0 0 N -Y 0 5.12 a) Compound 5.1 ([3-Methyl-l-(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 LiAlH 4 (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 oC. A solution of 15% NaHSO 4 in water was added dropwise to the reaction mixture until no further precipitate was formed (6 ml of NaHSO 4 ). The reaction mixture was filtered, and concentrated, and the product 5.2 (5.4g, 93% yield) was used for next reaction without further purification. LCMS: 290(M+1). c) TBSCl(2.82g, 18.8mmol) was added to the solution of diol 5.2 (5.4g, 18.8mmol) and imidazole (2.6g, 38.2 mmol) in 30 ml of CH 2 C1 2 . After 30 minutes of stirring, the solvent was removed under reduced pressure. The reaction mixture was purified by colunm chromatography (40% ether / hexanes) to afford 6.5g (88% yield) of compound 5.3. LCMS: 404(M+1). 'H NMR( CDCl 3 )8: 4.7(1H, broad s), 3.72(1H, m), 3.6-3.4(3H, min), 3.2( 1H, broad s), 1.93 (1H, min), 1.7-1.55 (2H1, m), 1.45( 10H, min), 1.35-1.25 (2H, min), 0.95-0.85(18H, min), 0.04 (6H, s). 87 WO 2005/005374 PCT/US2003/039276 d) A solution of Dess-Martin periodatate (5.5g, 13 mmnol in 5.5 mniL CH 2 Cl 2 ) was added to a solution of compound 5.3 (3.5g, 8.68 mnol) in 30 mL of CH 2 C1 2 . After stirring for 15 minutes, the reaction mixture was purified by column (20% ether / hexanes) to afford compound 5.4 (3.2g, 91%). LCMS: 402(M+1). e) To a solution of ketone 5.4 (3.2g, 8.0 mmol) in 50 mL of MeOH, NaBH 4 (0.3g) was added at -78 'C. The reaction mixture was stirred for 10 minutes at 30 0 C, and was concentrated under reduced pressure. The reaction mixture was then extracted by ether (3 x 50 mL) water (50 mL) and washed with brine (50mL), and then concentrated to afford compound 5.5 (2.6g, 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, 9.7mmol) was added to the solution of alcohol 5.5 (2.6 g, 6.5mmol) and triethylamine (2 mL) in chloroform (20 mL) at O'C. The resulting mixture was stirred for 60 minutes, then purified by column chromatography (20% ether / hexanes) to afford mesylate 5.6 (2.5g, 80%). LCMS: 482 (M+1). g) Sodium azide (3.4g) was added to a solution of mesylate 5.6 (2.5g) in dimethylformamide ("DMF"; 20 mL). The reaction mixture was stirred for overnight at 75 0 C and extracted (ether 5x50mL/ Water 50 mL). The combined organic solution was dried, concentrated and purified by column chromatography (10%, ether/haxanes) to afford desired product 5.7 (1.05g, 55%), which used as common intermediate LCMS: 429( M+1) 1H NMR( CDC1 3 )6: 4.43(1H, broad), 3.77(1H, min), 3.63 ( 1H, min), 3.49( 2H, min), 1.85 (1H1, min), 1.7-1.6 (2H1, min), 1.45( 10H, min), 1.35-1.25 (2H1, min), 1.0-0.88(18H, min), 0.05(6H, s) and syn isomer (0.19g). h) A solution of 4N HC1 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. 88 WO 2005/005374 PCT/US2003/039276 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. IN HC1 (2 mL) was added, followed by addition of EtOAc (80 mL). After stirring for 10 minutes, the organic layer was separated, washed with brine and dried over MgSO 4 . After removal of solvents, the residue was purified by column chromatography to afford compound 5.9. Method 2: To a mixture of compound 5.8 and N,N-dipropyl-isophthalamic acid in CH 2 C1 2 , 2-(1H-azabenzotriazole-1l-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) 1 H NMR( CD 3 OD)8: 7.92(1H, d), 7.80(1H, s), 7.5-7.6(2H, min), 4.33(1H, in), 3.59(1H, m), 3.51( 2H, t), 3.22 (3H, t), 2.70 (1H11, in), 1.98( 1H, min), 1.80-1.35 (8H, min), 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 HC1 (2 mL) was added, followed by addition of EtOAc (80 mL). After stirring for 10 minutes, the organic layer was separated, washed with brine and dried over MgSO 4 . After removal of solvents, the residue was purified by column chromatography to afford compound 5.11. Method 2: To a mixture of compound 5.10 and 2-amino-N-benzyl-3-methyl-butyramide in
CH
2 C1 2 , HATU/DIEA was added. 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. 89 WO 2005/005374 PCT/US2003/039276 1) Method 1: Compound 5.11 is treated with 1M PhMe 3 in THF, and the resulting mixture is stirred for several hours until compound 5.11 is consumed. The reaction mixture is concentrated and 1N HCI is added. The resulting mixture is stirred overnight afterwhich 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. [0285] EXAMPLE 11 [0286] This example describes the synthesis of H NH 2 H 0 which was prepared according to Scheme 6 and the procedure below. [0303] Scheme 6 H 0 H 0 H 0 0 Boc-N OH - BocN-OCH 3 CHP()(OMe) Boc Men-BULi, -10 0 C-rt n-BuLi, -78 0 C 6 Ethyl Pyruvate ~- 61 ~- 6.2 0 0 H 0 C0 2 Et H 0 H " L BocN 2NaBH 4 /MeOH,-780C Boc 10 % Pd-C Boc LAH 6.3 6.4 6.5 H OH H OH 1.MsC H OMs BoGA - OH TBSCI Boc N OTBS 1. sCI Boc N OTBS 2. NaN 3 6.6 6.7 6.8 NOH H N 3
N
3 BOCN OTBS 4 N HCI H 2 N OH 0 0 6.9 6.10 EDC, HOBt, DIEA 6.9 6.190 90 WO 2005/005374 PCT/US2003/039276 HATU, DIEA 0 _ H N 3 H 0
H
2 N,, N NN . N __,_ N K H2H - H 0 0 -0 H 6.13 H NH 2 H 0
H
2 , 10 % Pd-C N NaIN 6.14 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 oC 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 NaHCO 3 and brine and then dried over MgSO 4 . Solvents were evaporated and the excess dimethyl methylphosphonate was removed by rotary evaporator under high vacuum in a 90 oC water bath. The resulted oily product 6.2 containing 5-10% dimethyl methylphosphonate (shown by 'H NMR) was used without purification. 1H NMR (400 MHz, CDC13) 8 ppm 1.29 (min, 6 H) 1.35 (s, 9 H) 2.92 (dd, J=14.24, 8.39 Hz, 1 H) 3.03 (dd, J=22.38, 13.73 Hz, 1 H) 3.22 (min, 2 H) 4.10 (min, 4 H) 4.55 (d, J=5.59 Hz, 1 H) 5.38 (d, J=7.88 Hz, 1 H) 7.20 (min, 5 H); 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 oC 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 oC for 30 minutes, and ethyl pyruvate (7.1 mL, 63.2 mmol) was added slowly. Stirring was continued at 0 oC for 1 hour and at room temperature overnight. The reaction was quenched with saturated aqueous NH 4 C1 (100 mL) and diluted with EtOAc (400 mL). The organic layer was separated, 91 WO 2005/005374 PCT/US2003/039276 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) 8 ppm 1.24 (t, J=7.12 Hz, 3 H) 1.33 (s, 9 H) 2.00 (d, J=1.27 Hz, 3 H) 2.86 (min, 1 H) 3.19 (dd, J=13.99, 5.09 Hz, 1 H) 4.18 (q, J=7.12 Hz, 2 H) 4.53 (m, 1 H) 6.13 (d, J=7.88 Hz, 1 H) 6.51 (d, J=1.27 Hz, 1 H) 7.22 (min, 5 H); MS: 384 (MNa+). c) To a solution of compound 6.3 (8.4 g, 23.2 mnol) in MeOH (200 mL) cooled to -78 'C was added soditun borohydride (1.7 g, 46.4 mmol). The mixture was stirred and warmed to -15 oC in 3 hours, and then kept at the same temperature overnight. 1N aqueous HCI (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 NaHCO 3 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. 'H NMR (400 MHz, CDCl 3 ) 8 ppm 1.36 (s, 9 H) 1.88 (s, 3 H) 2.80 (d, J=6.61 Hz, 2 H) 4.05 (min, 1 H) 4.68 (d, J=8.39 Hz, 1 H) 4.92 (s, 1 H) 6.91 (s, 1 H) 7.23 (min, 5 H); MS: 340 (Na+). d) Lactone 6.4 (3.5 g, 11.0 rmmol) was dissolved in THF (300 mL), and to this solution 10% Pd/C (350 mg) was added. The mixture was stirred under an atmosphere of H 2 (balloon) for 5 hours, followed by filtration and concentration in vacuo, to provide product 6.5 (3.5 g, 99%) as white solid. 1H NMR (400 MHz, CDCl 3 ) 8 ppm 1.26 (d, J=7.12 Hz, 3 H) 1.35 (s, 9 H) 1.71 (m, 1 H) 2.42 (m, 1 H) 2.64 (min, 1 H) 2.87 (min, 1 H) 3.01 (min, 1 H) 3.92 (m, 1 H) 4.25 (min, 1 H) 4.46 (m, 1 H) 7.24 (min, 5 H); 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 LiAlH 4 in DME (22.0 mL, 11.0 mmol). The mixture was stirred at 0 oC for 0.5 hours and warmed to room temperature. Stirring was continued until TLC indicated the reduction was completed. The mixture was 92 WO 2005/005374 PCT/US2003/039276 cooled to 0 'C and 1N NaHSO 4 (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 NaHCO 3 and brine and dried over MgSO 4 . 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, CDC1 3 ) 6 ppm 0.82 (d, J=6.61 Hz, 3 H) 1.19 (s, 9 H) 1.26 (min, 1 H) 1.41 (min, 1 H) 1.75 (min, J=15.13, 5.72 Hz, 1 H) 2.46 (dd, J=13.61, 10.05 Hz, 1 H) 2.93 (dd, J=13.73, 3.05 Hz, 1 H) 3.30 (min, 2 H) 3.50 (min, 2 H) 7.10 (min, 5 H); 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 TBSC1 (578 mg, 3.72 mmol) sequentially at 0 oC. After stirring at 0 oC for 1 hour, H 2 0 (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 H 2 0 and dried over MgSO 4 . 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. iH NMR (400 MHz, CDCl 3 ) 8 ppm 0.08 (s, 6 H) 0.87 (d, J=6.87 Hz, 3 H) 0.91 (s, 9 H) 1.32 (s, 9 H) 1.49 (min, J=6.36 Hz, 2 H) 1.80 (min, 1 H) 2.77 (m, 1 H) 2.89 (min, 1 H) 3.40 (m, 1 H) 3.58 (dd, J=10.05, 4.20 Hz, 1 H) 3.68 (s, 1 H) 3.81 (s, 1 H) 4.18 (inm, J=12.33, 4.96 Hz, 1 H) 4.78 (d, J=8.65 Hz, 1 H) 7.21 (min, 5 H); 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 oC. After stirring at 0 oC for 1 hour, 1 N HCI (5 mL) was added to quench the reaction. The organic layer was separated and the aqueous layer was extracted with CH 2 Cl 2 . The combined CH 2 Cl 2 solution was washed with H 2 0 and dried over MgSO 4 . 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. 'H NMR (400 MHz, CDCl 3 ) 6 ppm 0.04 (s, 6 H) 0.88 (min, 12 H) 1.32 (s, 9 H) 1.37 (min, 1 H) 1.79 (m, 1 H) 1.95 (m, 1 H) 2.66 93 WO 2005/005374 PCT/US2003/039276 (dd, J=13.22, 10.68 Hz, 1 H) 2.90 (dd, J=14.24, 4.83 Hz, 1 H) 3.03 (s, 3 H) 3.40 (inm, 1 H) 3.52 (min, 1 H) 4.16 (s, 1 H) 4.87 (d, J=8.65 Hz, 1 H) 4.96 (d, J=9.16 Hz, 1 H) 7.23 (min, 5 H); 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 NaN 3 (2.50g, 39.0 mmol). The mixture was heated to 60 oC with an oil bath and stirred at this temperature for 8 hours. The solvent was evaporated in vacuo and then H 2 0 (20 mL) was added to dissolve the solid. The solution was extracted with ether, and the combined extracts were dried over MgSO 4 . 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. 1 H NMR (400 MHz, CDC1 3 ) 6 ppm -0.05 (s, 3 H) -0.03 (s, 3 H) 0.74 (d, J=6.87 Hz, 3 H) 0.84 (s, 9 H) 1.39 (s, 9 H) 1.43 (min, 1 H) 1.63 (min, 1 H) 1.73 (min, 1 H) 2.75 (dd, J=13.61, 8.77 Hz, 1 H-) 2.92 (min, 1 H) 3.37 (m, 2 H) 3.53 (t, J=7.12 Hz, 1 H) 3.91 (q, J=8.22 Hz, 1 H) 4.65 (d, J=9.66 Hz, 1 H) 7.25 (min, 5 H); MS: 485 (MNa+). i) Azide 6.9 (109 mg, 0.24 miol) was treated with 4N HC1 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 HC1 (2 mL) was added, followed by addition of EtOAc (80 mL). After stirring for 10 minutes, the organic layer was separated, washed with brine and dried over MgSO 4 . After removal of solvents, the residue was purified by column chromatography (silica gel, DCM-MeOH 19:1) to afford pure product 6.11 (113 mg, 81% starting from 6.9) as colorless oil. 1 H NMR (400 MHz, CD 3 OD) 6 ppm 0.60 (t, J=7.12 Hz, 3 H) 0.81 (d, J=6.61 Hz, 3 H) 0.89 (t, J=7.25 Hz, 3 H) 1.32 (min, 1 H) 1.43 (min, 2 H) 1.64 (min, 3 H) 1.75 (min, 1 H) 2.84 (min, 1 H) 2.94 (m, 1 H) 3.06 (min, 2 H) 3.32 (min, 4 H) 3.61 (min, 1 H) 4.41 (min, 1 H) 7.06 (m, 1 94 WO 2005/005374 PCT/US2003/039276 H) 7.16 (q, J=7.46 Hz, 4 H) 7.40 (min, 2 H) 7.55 (s, 1 H) 7.67 (d, J=7.12 Hz, 1 H); 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. 'H NMR (400 MHz, METHANOL-D) 8 ppm 0.57 (t, J=7.25 Hz, 3 H) 0.76 (m, 6 H) 0.87 (t, J=7.25 Hz, 4 H) 0.98 (d, J=6.61 Hz, 3 H) 1.41 (min, 3 H) 1.59 (min, 2 H) 1.90 (min, 2 H) 2.66 (min, 1 H) 2.79 (dd, J=13.73, 9.66 Hz, 1 H) 2.94 (dd, J=13.99, 5.60 Hz, 1 H) 3.03 (inm, 2 H) 3.22 (s, 1 H) 3.36 (m, 3 H) 3.99 (d, J=7.63 Hz, 1 H) 4.25 (s, 2 H) 4.40 (s, 1 H) 7.10 (min, 10 H) 7.38 (q, J=7.97 Hz, 2 H) 7.53 (s, 1 H) 7.65 (d, J=6.87 Hz, 1 H); MS: 682 (MH+). 1) 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 H 2 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. IH NMR (400 MHz, METHANOL-D) 8 ppm 0.61 (t, J=7.25 Hz, 3 H) 0.76 (d, J=6.61 Hz, 6 H) 0.88 (m, 4 H) 0.98 (d, J=6.87 Hz, 3 H) 1.28 (min, 1 H) 1.42 (m, 2 H) 1.62 (min, 2 H) 1.79 (min, 1 H) 1.91 (min, 1 H) 2.65 (dd, J=14.62, 6.23 Hz, 1 H) 2.75 (min, 2 H) 2.91 (m, 1 H) 3.07 (min, 2 H) 3.37 (min, 2 H) 4.00 (d, J=7.38 Hz, 1 H) 4.27 (min, 2 H) 7.05 (t, J=7.12 Hz, 1 H) 7.16 (min, 9 H) 7.40 (min, 2 H) 7.58 (s, 1 H) 7.71 (d, J=7.38 Hz, 1 H); MS: 656 (MH+). 95 WO 2005/005374 PCT/US2003/039276 [0287] EXAMPLE 12 [0288] The example describes the synthesis of compounds of the formula NH ,o H NH 2 H 0 N. N oNKH 1111 OORA O; [0289] These compounds are prepared according the procedure of Example 10 or Example 11 except for using other amino acids and amino acid like compound H O H 0 BocN - OH N, Boc OH of the formula RA as a reagent instead of (Example 10) or o H0 Boc"~'OH (Example 11). Illustrative examples of amino acids and amino acid like compounds and their corresponding products are shown in Table 1. [0290] Table 1 Reagent Product
H
0 Boc OH H NH 2 H ~N 0 0 0 H F F H 0 N ' flOH H NH 2 H 0 -_, N 0 0 -' O H F BocN .. OH ,,, O H NH 2 H 0 uN .t N I 0 0 0 H F F 96 WO 2005/005374 PCT/US2003/039276 Reagent Product
H
0 Boc' OHH 0 - -,-,N N N N 0 0 0 H FX F H 0 Boc' OH H NH H -oo.-o N . N N.N O 0 0 H F F H 0 N 0 Boc~ 'OH jO H NI-I 2 H0 N ___ NNK * N F FL1 0 0 H F
H
0 Boc' OH j H NH9 H 0 O 0 0 H F F F H 0 N
-
- , , _ N , N N O 0 H 0 N N Bo " OH H NH 2 H - ~ -~~N *N~N N N -aOC~s0 0 ,IaH
OCH
3 97 WO 2005/005374 PCT/US2003/039276 Reagent Product H 0 Boc H NH H 0 B H H N H sH C1 H 0 BockN ' OH H NH H 0 1/ o o S 0 H H BOC' N,,v. . OH -,OH [0291] EXAMVPLE 13 [0292] This example describes the synthesis of Ny H O H NH 2 F - ~ -,N N N I N, 0 0 0 H 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. [0293] EXAMPLE 14 [0294] The example describes the synthesis of compounds of the formula H 0 Nj BOCH H NH 2 - - 'N v N N 'N [02911 EXAMPLE 13 [0292] This example describes the synthesis of j H_ INH 2 H _N
.
N N a 0 0 R A 0 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+l) 527. [0293] EXAMPLE 14 [0294] The example describes the synthesis of compounds of the formula a H N H 2 H N. N N N 0 0 RA 0 F 98 WO 2005/005374 PCT/US2003/039276 [0295] These compounds are prepared according to Example 13 except for H O Boc-N _- OH using amino acids and amino acid-like compounds of the formula RA H O Boc,"N OH instead of Exemplary amino acids and amino acid-like compounds are shown in Table 1. [0296] EXAMPLE 15 [0297] This example describes the synthesis of H NH 2 ,-_NN N n 0 0 0 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. [0298] EXAMPLE 16 [0299] The example describes the synthesis of compounds of the formula "A H NH 2 H N, 0 0 RA 0 [0300] These compounds are prepared according to Example 15 except for H O Bac'N ' OH using amino acids and amino acid-like compounds of the formula RA H O BacN OH instead of 99 WO 2005/005374 PCT/US2003/039276 [03011 EXAMPLE 17 [0302] This example describes the synthesis of 1'O,'H )'H2 H o 0 - 0 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. [0303] EXAMPLE 18 [0304] The example describes the synthesis of compounds of the formula H NH 2 H NN _ N n o 0 RA O [0305] These compounds are prepared according to Example 17 except for H O BocN " OH using amino acids and amino acid-like compounds of the formula RA H O BocN OH instead of [0306] EXAMPLE 19 [0307] This example describes the synthesis of H H 2 H O N N 0 0 Y 0 which was prepared according to Example 10 except for 2-methyl-butylamine instead of 2-amino-N-benzyl-3-methyl-butyramide in step k. 100 WO 2005/005374 PCT/US2003/039276 [0308] EXAMPLE 20 [0309] The example describes the synthesis of compounds of the formula H NH 2 H N N 0 0 R A O [0310] These compounds are prepared according to Example 19 except for H O Boc-N *'OH using amino acids and amino acid-like compounds of the formula RA H O Boc,'N OH instead of [0311] EXAMPLE 21 [0312] This example describes the synthesis of "O'H NH 2 f"OHH N N o o O F 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. [0313] EXAMPLE 22 [0314] This example describes the synthesis of compounds of the formula " O 'H NH 2 RB H [N N../,.[ 0 0 F 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 101 WO 2005/005374 PCT/US2003/039276 above) instead of 3-benzyloxy-2-oxo-propanic acid methyl ester. Exemplary esters and their corresponding products are shown in Table 2. [0315] Table 2 Ester Product 0 O o
NH
2 HO [0316] EXAMPLE 23 [0317] The example describes the synthesis of compounds of the formula RC N N 2NH 2 H N N o 0 F 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 NN-dipropyl-isophhalamic 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. 102 H H 2 H - N N N a [03 16] EXAMPLE 23 [0317] The example describes the synthesis of compounds of the formula H N 2 H RC N, N 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 NN-dipropyl-isophthalamic acid in step i and using 4-fluoroanaline instead of 2-arnino-N-benzyl-3-methyl-butyramide in step k. Illustrative examples of acids and their corresponding products are shown in Table 3. 102 WO 2005/005374 PCT/US2003/039276 [0318] Table 3 RcCOOH Product 0
N
0 - NH H H'r- 2 H N O H F, , N 000 0 0 S H H 12 H C' N N, N N N OH N 00 0 0 0 O F 0 HsNH 2 NH OHON,.NN 00 0 0 a 00 O O O oo H NH 2 H OH - o NNN 0 0 Y 0 T -O 0o o o N 0 -~H NH 2 H ,-NOH N N -: N N -C F 103 0 0 ON 0 H N2H 2 OH0 0I o 0 [0319] EXAMPLE 24 [0320] This example describes the synthesis of the compounds of the formula 103 WO 2005/005374 PCT/US2003/039276 O H NH NN N 0 0 RA 0 which are prepared according to Scheme 7 and the procedure below. [0321] Scheme 7 I!--0 h0 C" 0 NH ,-,,N-NN H,'j "n H" 0 0 RA 0. N 0 0 RA O 7.2 7.1 [0322] 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. [0323] EXAMPLE 25 [0324] This example describes the synthesis of compounds of the formula ORo REO OH 0 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. 104 WO 2005/005374 PCT/US2003/039276 [0325] Scheme 8 OH NaH OH NaH OR 2 R, X R 2 X HO OCH 3 DMF R 1 0 OCH 3 DMF R 1 0 OCH 3 S8.2 X = I or Br 0 8.3 X = I orBr 8.4 ORD LiOH
H
2 0/THF REO - OH O 8.1 [0326] 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, H20/THF) to give acid 8.1. Compounds 8.1, acids of the fonnrmula RcCOOH, are used to make additional compounds of the invention. Table 4 shows exemplary compounds 8.1's. [0327] Table 4 RDX REX RcCOOH O 0 -Ob OH OH 0 O NJ OH -oI 0 O o Br CH 3 l O& OH o 00 105 WO 2005/005374 PCT/US2003/039276 RDX REX RcCOOH D-Br I OH O -by O '10 Br IOO OH : -Br Br O aO-bI OH 0 ao 0 Br Br[OOH aOH 0 Br Br O ,OH OH 0 OH [0328] EXAMPLE 26 [0329] This example describes the synthesis of compounds of the formula o o RGS'N'R RFO OH R~O 0 106 WO 2005/005374 PCT/US2003/039276 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. [0330] Scheme 9
N.~O
2 RFOH; O 2
NH
2 PPh 3 , DEAD N.H 2 , Pd/C S. HO OCH3 THF RFO ! OC H3 MeOH RFO OCH 3 0 0 0 9.2 9.3 9.4 0 0 0 0 0 0 'S HRH RG" NNaH RG SN RH RG NRH RGS0 2 CI -. RHX LIOH Py/C RO O CH3 RO OCH3 H 2 0 RF OH O 9.5 O 9.6 MeOH O 9.1 THF [0331] 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, H20/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. [0332] Table 5 RFX RGSO2CI RHX RcCOOH o o 0 00 x MeSO 2 CI NT ..N- .oN OH O 107 WO 2005/005374 PCT/US20031039276 RFX RGS0 2 CI RHX RCCOOH ,~If MeSO 2 CI 6-rOH 0 o0 >IN
CH
3 1 MeSO 2 CI CH 3 1 "ob IOH 0 MeSO 2 CI CH 3 1 O-o::yH 0 >-r MeSO 2 CI CH 3 1 2 -0,6 OH 0 /Br >IN MeSO 2 CI CH 3 1 oj OH 0 r) 0 >N 1 D-r MeSO 2 CI CH 3 1Io b OH 0 o0 MeSO 2 CI CH 3 1ILO--t OH 0 108 WO 2005/005374 PCT/US20031039276 RFX RGS0 2 CI RHX RcCOOH 0 N Br MeSO 2 CI CH 3 1 -, 0,(% OH 0 00 PhIVI 1N PhSO 2 CI -i -tA--~ N OH 0 00 PhSO 2 CI bN/"' OH 0 Ph, "N
CH
3 1 PhSO 2 CI CH 3 1 llo~~OH 0 O Ph' "SN PhSO 2 CI CH 3 1I OH 0 0~ Ph ,N >-Br PhSO 2 CI CH 3 1 L2\ -C OH 0 0 PhSO 2 CI CH 3 1 N Cb OH 0 109 WO 2005/005374 PCT/US2003/039276 RFX RGSO 2 CI RHX RcCOOH 0 0 PhN B rPh S O 2 0p3 O O H PhSO 2 CI CH 3 1 OH O o0 Ph 'N S PhSO 2 CI CH 3 1 J O bOH 0, Ph~s N __/-Br PhSO 2 CI CH 3 1 -- 0Ob yOH 0 [03331 EXAMPLE 27 [0334] This example describes the synthesis of compounds of the formula OH RFO OH wherein RF is substituted or unsubstituted aliphatic or aromatic moiety. These compounds are prepared according to Scheme 10 and the procedure below. 110 WO 2005/005374 PCT/US2003/039276 [0335] Scheme 10
H
2 o
CIC
2
H
4
SO
2 CI 0 S NH NaH RFO OCH 3 PyFCH 2
CI
2
OCH
3 RDMF OCH 0 RFO 0 1O 9.4 0 10.2 0 10.3 LiOH
H
2 0 RFO- OH MeOH O 10.1 THF [0336] 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, H 2 0/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. [0337] Table 6 RF RcCOOH 00 o PS.N ,- OH 0 0 0 OH O - OH 0 WO 2005/005374 PCT/US2003/039276 RF RcCOOH 0 O P-N O . OH 0 0.. O<~ O
-
OH 0 0o-S--3N 0 o O N .OH 0 O N O OH 0 [03381 EXAMPLE 28 [0339] This example describes the preparation of compounds of the formula 0) G.R I Rj S, OH RK-N N 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. 112 WO 2005/005374 PCT/US2003/039276 [0340] Scheme 11 Ra SO(NH 2
)
2 RK' NaH XC0 2 R RK- 'N OCH 3 K"NH N 2 K"N' NH PyOCH 11.2 Py 11.3 0 11.4 LiOH RK OIN I O H RK'N' 'N OH H Lj MeOH 0 THF 11.1 [0341] 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, H 2 0/THF/MeOI-H) 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. [0342] Table 7
XCR
1 R COOC RKNHCH 2
CH
2 N RcCOOH H3 H 2 0 .. OH Br,.CO2Me NH2NO OOH Br..CO 2 Me NjNH2 N Oz -N OH 0 BrC~ NH2 ZN"- OH O N OH BrCO 2 Me N H 2 N 0 O 0 0 I OH Br_ CO 2 Me N NH 2 Y 0 0O/1 OH N j 2 N Br,_CO 2 Me 113 WO 2005/005374 PCT/US20031039276 XCRIRjCOOC RKNHCH 2
CH
2 N RCCOOH 113 H 2 0 o /I OH NH 2 N 0 Br.C 2 Me 0 o /I OH Br,,_CO 2 Me >-NH NH 2 0 oN OH N 2 N, Br,,,C 2 Me oz '9 OH Br,,_CO 2 Me NH 2 -N ,SNl 0-J 0~ OH
_,C
2 Me NH 2 -N, 0 Br,, Oz~N lyOH _rC 2 Me NH2 N 0 o 1N OH Br,,_C0 2 Me NHJ :N 0 o 11 OH _rNC0 2 Me NH 2 -N 0 114 WO 2005/005374 PCT/US2003/039276 XCRIRjCOOC RKNHCH 2
CH
2 N RcCOOH H3 H 2 O N OH Br ,CO 2 Me NH NH 2 N o OzN OH Br_ C 2 Me O -[>_NH NH 2 0 O0 N OH Br CO 0 2 Me NH NH 2 N- O 0 N OH Br CO 2 Me N NH 2 N O O 0 "--, J o0 N OH Br CO2Me N NH 2 N O O O-jSN yOH Br COMe N NH 2 N O O O N Br C2Me N2 oN,-N OH OH Br-CO 2 Me
NNH
2 NN O O O " OH NH 0 115 WO 2005/005374 PCT/US2003/039276 XCRIR3COOC RKNHCH 2
CH
2 N RcCOOH H3 H 2 O o O~N OH Br-CO 2 Me N O N NH2 Br CO 2 Me N NH 2 N O 0 O 1N OH Br CO 2 Me NH 2 N A NH 0 0 N OH BrXCO 2 Me NNH 2 -N O 10 OH Br COMe NHg HO 0 o OH O N OHr Br CO 2 Me NH NH 2 N' Oz OH Br CO 2 M6 N NH 2 N O 0 O N OH Br CO 2 Me NH NH 2 N O 116 WO 2005/005374 PCT/US2003/039276 [0343] EXAMPLE 29 [0344] This example describes the synthesis of compounds of the formula 0 R Rj N OH R(N 0 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. [0345] Scheme 12 amide coupling reagent reducing reagent H H PhCH H0 eucnHraen 2 BocN CO 2 H PhCH 2
NH
2 Boc N- N Ph - BocN .- N'Ph H H 12.2 12.3 12.4 0 o acid H2N R O_'PR HN NPh ON Ph Ph HN N Ph RN 12.5 12.6 12.7 Hydrogenation 0 NH XCRIRjCO 2 R O , OR sis O I ROH NH NHydrolysis N"1 1 O RNRN 0 RN O RL' N J RLN, 0 RL N_ 12.8 12.9 12.1 [0346] 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 Nail 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. [0347] 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. 117 WO 2005/005374 PCT/US2003/039276 [0348] Table 8 XCRIRCOO RLX RcCOOH Me 0 O O Br_,CO 2 Me BuBr ONA OH 0 0 O O BrCO 2 Me PrBr N O 0 N O BrCO 2 Me Br N O O BrI ,eN ) . N0O BrlCO 2 Me Br N OH N O0 Brr CO2MeOH 0 O O Br O N O H N 0 BrC0 2 Me 0 ON OH N 0 Br CO 2 Me Br 0 O N ,OH N 0 Br COMe >B Br.CO 2 Me BuBr o N O 10 \ OH 118 WO 2005/005374 PCT/US2003/039276 XCRIRjCOO RLX RcCOOH Me 0! Br_ CO 2 Me PrBr 0N O NO CO2 . .. OH O N OH Br- CO 2 Me Br . .N O 0 N Br ,,CO2Me / r0 lyO 0 O N OH Br._CO 2 Me Br N 0 O N OH Br N,'k o O Br-_CO 2 Me 0 O NX.OH rNO N 0 Br',_CO 2 Me Br O oO[ N OH 0 0 O Br CO2Me PrBr o o NO r,119CO2Me 119 WO 2005/005374 PCT/US2003/039276 XCRIR3COO RLX RcCOOH Me 0 = Br CO 2 Me N OH N O 0 0 -O O = Br CO2Me Br O N ,OH NO O Br CO 2 Me Br O N OH N 0 O Br CO 2 Me Br N NO O O OH Br CO 2 Me Br N O N O 0 BlBr N O N OH Br C0 2 Me 0 ,.N Br 0 O OH Br CO2Me BuBr N 0 0 O OH NO Br CO2Me Br O N OH 0 0 O OH Br CO 2 Me Br N N O0 120 WO 2005/005374 PCT/US2003/039276 XCRIR3COO RLX RcCOOH Me 0 O OH Br CBr 0 0N O°H 0 Br CO 2 Me Br N O 0 Br CMe O N OH BrC2MeBr N 0 0 Br C2eO' N OH yN 0 [0349] EXAMPLE 30 [0350] This example describes the synthesis of compounds of the formula ORM O_ rOH OH 0 wherein RM is substituted or unsubstituted aliphatic or aromatic moiety. These compounds are prepared according to Scheme 13 and the procedure below. 121 WO 2005/005374 PCT/US2003/039276 [0351] Scheme 13 OH - .OH OH NaH PPh 3 , DEAD RmX HO-OCH3 OCH 3 DMF HO 0DMF O O 13.2 X= I, BrorCl 13.3 X = I, Br, orCl ORM ORM LiOH - OCH 3
H
2 0 <OH O MeOH O O THF O 13.4 13.1 [0352] Mitsunobu reaction of 13.2 gives the corresponding aryl ether 13.3, which is followed by the alkylation with halide (Nal-, RMX, 1 eq) to afford aryl diether 13.4. Basic hydrolysis (LiOH, H 2 0/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. [0353] Table 9 RMX RcCOOH o O \ , 0 OH 0 OH 0 OH 0 O, I O1N OH 0 122 WO 2005/005374 PCT/US2003/039276 RMX RcCOOH 0_,, O OH - Br 0 0 " O- OH 0 BrO [0354] EXAMPLE 31 [0355] This example describes the synthesis of compounds of the formula
O
O RN , I -N' RO RQN OH O 0 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. [0356] Scheme 14 SRS ,RO RN 'NH NaH RN N' RNSO2CI RoX
H
3 CO OCH 3
H
3 CO OCH HCO OCH3DMF A 0M O O O 1 X = I, Br, or CI 14.4 14.2 14.3 14.4 0 0 HATU O 0 O 0 'S" I 0 Ip N'N RNS NI RR S NRO RN
H
2 0 HO OCH 3 N A OCH 3
H
2 0 RO N OcH MeOH R) MeOH O O THF O 0 0 0 THF 14.5 14.6 14.1 [0357] 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, 123 WO 2005/005374 PCT/US2003/039276
H
2 0/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. [0358] Table 10 RpNHRQ RNSO 2 CI RoX RcCOOH O ,S 'N / NH MeSO 2 CI -1 -N OH o 0 0 0 NH S MeS0 2 CI OH 0 0 0,P Ph 'N NH " P ' S N [ NH PhSO 2 CI - NOH 0 0 o0o FMeS02CI - N OH -,NH 0 0 0,0 ) 'N MeSO2CI N OH -0 0 c o F Ph 'N NH H NH PhSO2CI -1 N OH O O 124 WO 2005/005374 PCT/US2003/039276 RpNHRQ RNSO 2 CI RoX RcCOOH n,0 'N SMeSO 2 CI -I N OH 0 0 // SMeSO 2 CI N OH 0 0 0 00 /O Ph' 'N~ NHN o o PhSO 2 CI - N OH 00 O" OO 0 o NHN MeSO 2 CI N ,OH _,H N A OH 0 0 OO NH Ph 'N PhSO 2 CI - N OH 0 0 [0359] EXAMPLE 32 [0360] This example describes the synthesis of compounds of the formula RR s Ar OH Rs1 0 0 125 WO 2005/005374 PCT/US2003/039276 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. [0361] Scheme 15 HO OH rO LiOH(leq) HO O O O O O H 2 0 O O MeOH 15.2 15.3 THF 15.4 HATU FR RR LiOH RR NH A A r OH RsR H2 0 Rs IN 0 0 MeOH 0 THF 15.5 15.1 [0362] Esterfication of di-acid 15.2 with TMSCH 2
N
2 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, H20/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. [0363] Table 11 RRNHRs HO r OH RcCOOH o 0 0
/
11 S HO OH OH ONH 0 0 0 0 NH HO O HOA OH N OH 0 0 0 0 126 WO 2005/005374 PCT/US2003/039276 RRNHRs HO -r OH RcCOOH O O N.llO 0' NH 0 0 0 0 \ HO -, OH ONH 0 0 ON OH O 0 NH HO OH N OH 0 O 0 NH HO OH N OH O 0 0 0 oj oj O~ ,HO OH OH ON H N0 0. ONOH O O H~O~/OHNOH O 0 HO OH H ON H 0 0 N' OH O O 0 N7 0 0 127 WO 2005/005374 PCT/US2003/039276 RRNIHRS HO -lr OH RcCOOH O O HO H OOH O 0 O O HO OH OH O 0 '0 HO OH OH NH O O OH O 0 0 0 N O O OH O IH HO OH 0 0 NH o o O O j HOA-9 OH <N -"9 OH NH 0 0 0 0 ""0 N.H °o o ° o o ° HO OH N OH NH 0 0 0 0 HO OH OH A1o2 0 01 DNH0 0 128 WO 2005/005374 PCT/US2003/039276 RRNHRs HO -r OH RcCOOH O O O o HO ),OH I OH NH 0 0 0 0 oN, o © o O O SHO OH I N H N A OH O O O 0 O O O oHO A OH OHOH O 0 O 0 HO OH OH NH O O O 0 0 CNH0O 0 '-0 HO OH OH NH 0 0 Ho OH N OH 0 9 0 CNH 0 00 0 129 WO 2005/005374 PCT/US2003/039276 RRNHRs Ho ArOH RcCOOH O O HO ~ OH N OH O 0O NH HOOH OH HO OH NA OH NH 0 0 0 0 0O H\ HO OH OH HO OH OH Nj N ONH 0 0 0 0 O O O N ON HO OH OOH N H 0 0 0 HO 0 OH O NH HO OH OH 0 0 0 0 0 / N 0
/
1 N\ HOI HO OH .,\ N, NHH 0 0 N OH 0 0 NI ~ O 007*. O 0 0 ",\I HOjr nOH N ONH 0 0 N ' OH 0 0 0/ 1 0 ,,IHO OH / ,,I r ' ' 0 0 130 WO 2005/005374 PCT/US2003/039276 RRNHRs HO Ar OH RcCOOH O O ONH HO OH N 9 OH O O O O HO N OH N OH 0O O NH HO OH N OH N iN O 0 0 0 NN HO OH H N H 0 0 NU & OH O 0 HO OH N H 0 0 No OH O O HO OH NH 0 0 N OH O O O OJ SHO OH OH 0N H YN N '- O O O HO !OH O O O N1H 0 0 N 31OH 131 WO 2005/005374 PCT/US2003/039276 RRNHRS HO A OH RcCOOH O 0 o , HO OH " NH N O OH O O0 o 0 NH O O N OH HO OH0J HO OHOH O 0O O ,,1y o 0 HO OH O 0 N N OH OH O 0 HOr N 1 OH o o NH N N OH o 0 ci~2HO N OHF NHO 0 O N O o 0 HO 'AN. OH
(
NH 0 0N FOH o 0 132 WO 2005/005374 PCT/US2003/039276 RRNIIRs HO Y- OH RcCOOH 0 0 N HO OH H O O OH O O0 HO OH OOO H 0 HNO H OH 0 0 NH NO OH OH O O HOHOHN OH O OH N No o O O NH HO OH N OH O 0 0 0 NH HO OH N . OH HO OH ,I N I N N HO OH N NO H NH H A OH<N -9OH O O 133 0 0 GNH H~~ O N yNOH 0 00 0 0 00 0 j 133 WO 2005/005374 PCT/US2003/039276 RRNHRS HO ye , OH RcCOOH O 0 O O ON'H O O N OH O 0 0 0 NH HO OH N OH O O O O 0 0 0 0 HO OH N OH O 0 HJ HO N O H OHI NH HO N OH N OH N -N O 0 0 0 N 1N NH HO H oNOH O O 0 0 NH HO ~N OH N ) OH O 0 0 0 y NH HO N OH N OH 0 0 0 0 N ONHHO OH ON O NH HO N O N N' yOH 0 0 N 0 0 134 WO 2005/005374 PCT/US2003/039276 RRNHRS HO ys OH RcCOOH O O OO O 0 HO OH NOH O 0 0 ON OH O O -- o HOAN OH OH NH 0 N N OH O 0 N O O 0l N 0 J HO . O H OH <CNH N -T OH S0O 0 0 0 NH HO yOH NH O O O O 0 0 O 0 NH HO OH OH OO 0 0 0 O O O O 135 NH H N 1 , N N1 OH 0 0N 0 0 NH HO '.-. OH CN AN OH 0 00 0 CNH HO - AN OH N 'NI OH N- N 0 0 0 0 135 WO 2005/005374 PCT/US2003/039276 RRNHRs HO re OH RcCOOH O O 0 0 N HO OH O HO OH NOH 0 eHO OH 0CN OH 0 0 HO N 1 OH N H NH HOI~z, C N N. OH 0 0 0 0 O OH HO 0 0 OH OH NH NC 'N OH O 0 0 0 NH HO OH N N OH O 0 0 O O O H OH O O 0 HO OH N OH ND HY C N-, O 0 0 0 0 N I O O. OH O O 136 N HO N OH N -TO 0H C.~AN HO N. , OH N NfH 0 0 N N. OH 0 0 136 WO 2005/005374 PCT/US2003/039276 RRNHRs Ho Ar) OH RcCOOH O O NH HO N OH CN'N OH N N HO OHO O O 0 0 0 0"'0 S HO OH N N OH OO O OOO O 0 0 0 0 HH O OH ON O O OH OH S0O O 0 NH HO N OH N NI OH O N N HO O OH O O SHO N OH O NH 0 0 CNy N' OH O 0O NHO "NOH NO O O NH HO 0 N OH 0 0 HO OH O 0 137 H 0 N H _- N OH 0 00 0 N NN HO 'N OH yO ~NH x.N N4 O 0 0 137 WO 2005/005374 PCT/US2003/039276 RaNHRs HO Ar OH RcCOOH O 0 O O ONH O OH N OH O O HO OH N / NH O O OH O O J HO OH 0 N H O O OHY-,F S ' 0 0 H O OH NH N OH O 0 O Ho rOH 1\0 00 "\ 0 0 HO OH 0 NH O ON 3OH O 0 HO OH OO O NH 0 N OH 0 0 HO OH 0 0 N H N l1 OH 0 0 138 WO 2005/005374 PCT/US2003/039276 RRNHRs HO r OH RcCOOH O O HO OH 0 0 H OOH O O HO OH NH 0 0 N OH O 0 HO OH OH NH 0 N'j yOH O O HO OH OH~ O O0 [0364] EXAMPLE 33 [0365] This example describes the synthesis of compounds of the formula H NH 2 H RC N 0 RA 0 F. [0366] These compounds are prepared according to Example 23 except for using
H
0 No H O BocN OH BocN .OH [0367] RA as a reagent instead of [0368] EXAMPLE 34 [0369] This example describes the synthesis of compounds of the formula H
NH
2 H Rc N N RC IINN J O 0 139 WO 2005/005374 PCT/US2003/039276 which are prepared according to Example 13 except for using acids of the formula RcCOOH as a reagent instead of N,N-dipropyl-isophthalamnic acid. [0370] EXAMPLE 35 [03711 This example describes the synthesis of compounds of the formula H NH 2 H O RA O [0372] These compounds are prepared according to Example 34 except for using H O H 0 Boc'N OH BocN . OH RA as a reagent instead of [0373] EXAMPLE 36 [0374] This example describes the synthesis of N N NH', RT 0 0 0 O O ~-.S O 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 H 2 NRT instead of 2-amino-N-benzyl-3-methyl-butyramide in step k. [0375] EXAMPLE 37 [0376] This example describes the synthesis of compounds of the formula H INH H RC N N ' O O0 [0377] 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. 140 WO 2005/005374 PCT/US2003/039276 [0378] EXAMPLE 38 [0379] This example describes the synthesis of compounds of the formula H NH 2 ! H Rc N N O RA O [0380] These compounds are prepared according to Example 37 except for using
H
0 O H O Boc' OH BocN OH RA as a reagent instead of [0381] EXAMPLE 39 [0382] This example describes the synthesis of compounds of the formula H NH 2 Rc R 0 RA where Ru is substituted or unsubstituted alkyl. These compounds are made according to Scheme 16 and the procedure below. [03831 Scheme 16 H 0 o N H RuMgXH 0 P - OH PP N R N 0 -. RA RA RA 16.1 1.4 16.1 16.2 H OH 1, MsCI, H N 3
N
3 Reduction pN Ru 2. NaN 3 N Deprotection H 2 N Ru u P RU - U RA RA RA 16.3 16.4 16.5 RcCOOH N 3 Reduction NH 2 Rc HN Ru Rc HN R U O RA O RA 16. 16.7 6 [0384] 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 141 WO 2005/005374 PCT/US2003/039276 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. 142

Claims (35)

1. An isolated compound having the structure: R' NH 2 RXN X 2 3,R 4 R1x 1 -NX R 2 R 3 R 3 (I) or pharmaceutically acceptable derivative thereof; wherein R' is hydrogen or an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, or R', taken together with R 2 or a substituent present on R 1, may form a cycloheteroaliphatic moiety; R' is an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, or R 1, taken together with R', may form a cycloheteroaliphatic moiety; X 1 is -C(=O)-, -S(=O)-, -C(=NH)-, -C(=S)-, -NC(=O)-, -NC(=S)-, -N-C(=N C-N)-, -NS(0 2 )-, -CHRxlA-, -SO 2 -, -COO-, -C(=O)C(RXlA) 2 -, or -SC(=O)- wherein each occurrence of RXlA is independently hydrogen, or an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety; R is an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, or R 2 , taken together with R', may form a cycloheteroaliphatic moiety; R 3 is hydrogen, halogen, or an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety; RW is hydrogen, halogen, or lower alkyl; R 4 is hydrogen, an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, or R 4 , taken together with a substituent present on X 2 or X 3 , may form a cycloaliphatic, cycloheteroaliphatic, aromatic, or heteroaromatic moiety; X 2 is absent, -NR x2A-, -(CHRX2A)j, -NRX2AY-, -(CHRX2A)jY- or N(RX2A)CH(R2A')Y- wherein each occurrence of R X2 A is independently hydrogen or an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety; each occurrence O RX 2 B N H of Y is independently ) t wherein, for each independent occurrence of t, R x2 is hydrogen, or an aliphatic, heteroaliphatic, aromatic or heteroaromatic 143 WO 2005/005374 PCT/US2003/039276 moiety, or R X2A or one occurrence of R X2B taken together with R 4 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 X 3 is absent, -NHCO-, -NHSO 2 -, -NHCONH-, -NHCOO-, -CH 2 NH-, C(=O)-, -S(=O)-, -C(=NH)-, -C(=S)-, -NC(=S)N-, -N-C(=N-C-N)N-, -NS(O 2 )N-, SO 2 -, -C(=O)NRX 3 A - , -C(=S)N R X 3A -, -COO-, -(CHRX3A)k-, -0-, -CH 2 NR X 3A -, or NRx 3 A - , wherein each occurrence of RX 3 A is independently hydrogen, an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, or R X3 A taken together with R 4 may form a cycloaliphatic, cycloheteroaliphatic, aromatic or heteroaromatic moiety, and k is an integer from 1 to 3.
2. The compound of claim 1 wherein one or more of the following groups do not occur simultaneously as defined: (i) R', R and R 3 ' are each hydrogen; R 2 is alkyl, cycloalkylalkyl or aralkyl; X 2 -X 3 -R 4 together represents -CHReC(=0)NHCH(R)C(=0)NRxRY, wherein Re is hydrogen or alkyl, Rw is alkyl, and one of Rx or R y 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 SO 2 ; or Rx and R y together with the nitrogen atom to which they are attached represent a 1,2,3,4 tetrahydroisoquinoline ring; and -X'-R together represents an alkoxycarbonyl, aralkoxycarbonyl, alkanoyl, aralkanoyl, aroyl, cycloalkylcarbonyl, heterocyclylcarbonyl, heterocyclyl-alkanoyl, 6-(dibenzylcarbamoyl)-4-oxohexanoyl moiety or an acyl group of an a-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 144 WO 2005/005374 PCT/US2003/039276 "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', R 3 and R 3 ' are each hydrogen; X 1 is -C(=O)-, -SO 2 -, N(RX)SO 2 , N(RX)C(=O) or SC(=O0), wherein Rx is hydrogen, C1 5 alkyl or joined together with R 1 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-Cl 3 alkyl-piperazyl; R 1 is a substituted or unsubstituted C 1 6 alkyl, a 5-6 membered heterocycle or a 6-10 carbon atoms aryl moiety substituted with CI- 4 alkyl, C 1 . 3 alkoxy, hydroxy, halogen, N(Ra) 2 , C(=O)ORa, C(=O)N(Ra) 2 , -SO 2 N(Ra) 2 , CH 2 N(Ra) 2 , N(Ra)C(=O)Ra or N(Ra)SO 2 Ra; R is ORa, N(Ra) 2 , Cl- 4 alkenyl-Rc or -[CRbRCI]nRC; and -X2-X -R 4 together represent CH(Rd)C(=O)NHCH(Re)C(=O)-Y-[CRfRg]mR , wherein m is an integer from 0 to 5, Y is O or NH, Rd and Re are independently hydrogen, ORa, N(Ra) 2 , Ci- 4 alkenyl-Rc or -[CRbR]nR wherein n is an integer from 0 to 5, Ra is hydrogen or C 1 - 4 alkyl, Rb is hydrogen, hydroxy or C 1 - 4 alkyl and Ro is hydrogen, substituted or unsubstituted aryl,
5- or 6-membered heterocycle, C 1 6 alkyl or C._ 6 alkenyl, C 3 -7cycloalkyl, 5- to 7 membered carbocyclic or 7- to 10-membered bicyclic carbocyclic ring, benzofuryl, indolyl, azabicyclo C 7 -llcycloalkyl or benzopiperidinyl; R f is hydrogen, substituted or unsubstituted C 1 6 alkyl or (CH 2 CH 2 0)pCH 3 or (CH 2 CH 2 0)pH wherein p is an integer from 0 to 5, and R8 is hydrogen, or substituted or unsubstituted aryl, heterocycle, 5- to 7-membered carbocyclic or 7- to 10-membered bicyclic carbocyclic ring; (iii) R', R 3 and R13 are each hydrogen; X 1 is -C(=O)-, -SO2-, N(RX)SO 2 , N(Rx)C(=O) or SC(=0) , wherein Rx is hydrogen, C 1 -salkyl or joined together with R 1 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 145 WO 2005/005374 PCT/US2003/039276 morpholinyl, piperazyl, or N-Ci- 3 alkyl-piperazyl; R 1 is a substituted or unsubstituted Ci. 6 alkyl, a 5-6 membered heterocycle or a 6-10 carbon atoms aryl moiety substituted with C 14 alkyl, CI- 3 alkoxy, hydroxy, halogen, N(Ra) 2 , C(=O)ORa, C(=O)N(R) 2 , -SO 2 N(Ra) 2 , CH 2 N(Ra) 2 , N(Ra)C(=O)Ra or N(Ra)SO 2 R; R 2 is ORa, N(Ra) 2 , CI- 4 alkenyl-RC or -[CRbRc]nRc; and -X -X3-R together represent CH(Rd)C(=O)-Y-[CRR"]mR g, wherein m is an integer from 0 to 5, Y is O or NH, Rd is hydrogen, ORa, N(Ra) 2 , C1- 4 alkenyl-Re or -[CRbRc]nRo; wherein n is an integer from 0 to 5, R a is hydrogen or Ci 4 alkyl, Rb is hydrogen, hydroxy or Cl 4 alkyl and Re is hydrogen, substituted or unsubstituted aryl, 5- or 6-membered heterocycle, Cp. 6 alkyl or Ci 6 alkenyl, C 3 - 7 cycloalkyl, 5- to 7-membered carbocyclie or 7- to 10 membered bicyclic carbocyclic ring, benzofuryl, indolyl, azabicyclo C 7 .11cycloalkyl or benzopiperidinyl; R f is hydrogen, substituted or unsubstituted C1-6alkyl or (CH 2 CH 2 0)pCH 3 or (CH 2 CH 2 0)pH wherein p is an integer from 0 to 5, and R9 is hydrogen, or substituted or unsubstituted aryl, heterocycle, 5- to 7-membered carbocyclic or 7- to 10-membered bicyclic carbocyclic ring; (iv) R' and R 3 ' are each hydrogen; X' is -C(=O)-, -SO 2 -, N(RX)SO 2 , N(Rx)C(=0) or SC(=O), wherein Rx is hydrogen, Cl.salkyl or joined together with R' 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- 3 alkyl-piperazyl; R 1 is a substituted or unsubstituted C 1 6 alkyl, a 5-6 membered heterocycle or a 6-10 carbon atoms aryl moiety substituted with C 1 - 4 alkyl, CI- 3 alkoxy, hydroxy, halogen, N(Ra) 2 , C(=0)ORa, C(=O)N(Ra) 2 , -SO 2 N(Ra) 2 , CH 2 N(Ra) 2 , N(Ra)C(=O)Ra or N(Ra)SO 2 Ra; R 2 is ORa, N(Ra) 2 , C1- 4 alkenyl-R or -[CRbR]nRc; R is hydrogen, ORa, N(Ra) 2 , C1. 4 alkenyl-Re or -[CRbR]nRo; and -X 2 -X3-R 4 together represent -CH(RO)C(=O)NHCH(Re)C(=O) Y-[CR!Rg]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 , C1i- 4 alkenyl-Re or -[CRbRe]nRc wherein n is an integer from 0 to 5, Ra is hydrogen or C 14 alkyl, R b is hydrogen, hydroxy or C 1 . 4 alkyl and Re is hydrogen, substituted or unsubstituted aryl, 5- or 6-membered heterocycle, CI- 6 alkyl or Ci. 6 alkenyl, C 3 _ 7 cycloalkyl, 5- to 7-membered carbocyclic or 7- to 10-membered bicyclic carbocyclic ring, benzofuryl, indolyl, azabicyclo C7 146 WO 2005/005374 PCT/US2003/039276 11 cycloalkyl or benzopiperidinyl; R f is hydrogen, substituted or unsubstituted C 1 . 6 alkyl or (CH 2 CH 2 0)pCH 3 or (CH 2 CH 2 0)pH wherein p is an integer from 0 to 5, and R9 is hydrogen, or substituted or unsubstituted aryl, heterocycle, 5- to 7 membered carbocyclic or 7- to 10-membered bicyclic carbocyclic ring; (v) R' and R 3 are each hydrogen; X 1 is -C(=O)-, -SO 2 -, N(RX)SO 2 , N(RX)C(=O) or SC(=O), wherein Rx is hydrogen, C1 5 alkyl or joined together with R 1 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-C . 3 alkyl-piperazyl; R 1 is a substituted or unsubstituted CI 6 alkyl, a 5-6 membered heterocycle or a 6-10 carbon atoms aryl moiety substituted with C1 4 alkyl, C1- 3 alkoxy, hydroxy, halogen, N(Ra) 2 , C(=O)ORa, C(=O)N(Ra) 2 , -SO 2 N(Ra) 2 , CH 2 N(Ra) 2 , N(Ra)C(=O)Ra or N(Ra)SO 2 Ra; R 2 is ORa, N(Ra) 2 , C1 4 alkenyl-R' or -[CRbRo]nRe; R 3 is hydrogen, ORa, N(Ra) 2 , C1-4alkenyl-R c or -[CRbRcInRc; and -X 2 -X 3 -R 4 together represent -CH(Rd)C(=O)-Y-[CRfRg]mR g, wherein m is an integer from 0 to 5, Y is O or NH, R d is hydrogen, ORa, N(Ra) 2 , C 1 4 alkenyl-RC or -[CRbR]nRo; wherein n is an integer from 0 to 5, Ra is hydrogen or CI-4alkyl, Rb is hydrogen, hydroxy or C 1 - 4 alkyl and R e is hydrogen, substituted or unsubstituted aryl, 5- or 6-membered heterocycle, Ci- 6 alkyl or C1. 6 alkenyl, C 3 7 cycloalkyl, 5- to 7-membered carbocyclic or 7- to 10-membered bicyclic carbocyclic ring, benzofuryl, indolyl, azabicyclo C 7 . 1 Icycloalkyl or benzopiperidinyl; R is hydrogen, substituted or unsubstituted Ci- 6 alkyl or (CH 2 CH 2 0)pCH 3 or (CH 2 CH 2 0)pH wherein p is an integer from 0 to 5, and RO is hydrogen, or substituted or unsubstituted aryl, heterocycle, 5- to 7-membered carbocyclic or 7- to 10-membered bicyclic carbocyclic ring; and (vi) R', R 3 and R 3 ' are each hydrogen; R 2 is C 1 . 6 alkyl, C 2 - 6 alkenyl, C 3 7 cycloalkyl, aryl, heteroaryl, T-C 1 . 6 alkyl, T-C 2 - 6 alkenyl, wherein T is aryl, heteroaryl or C 3 . 7 cycloalkyl; R'-X 1 together represent W wherein W is Rx, RxCO, RxOCO, RXOCH(RY)CO, RxNHCH(RY)CO, RxSCH(RY)CO, RxSO 2 , RxSO or an amino acid with a blocked or unblocked amino terminus, wherein Rx and R y are each independently hydrogen, CI_ 6 alkyl, C 3 .- 7 cycloalkyl, aryl, heteroaryl, T-C 1 . 6 alkyl or T (CH 2 )nCH(T)(CH 2 )n wherein n is an integer from 1 to 4; and -X 2 -X 3 -R 4 together 147 WO 2005/005374 PCT/US2003/039276 represent -CH(Ra)C(=X)CHRbR e , wherein X is (OH,H) or O; R a is hydrogen, C 1 6 alkyl, C 2 -6alkenyl, C 3 -7cycloalkyl, aryl, heteroaryl, T-CI-6alkyl or T-C 2 -6alkenyl; Rb is hydrogen or OH; and R is Y, (CHRw)n-Y or =CRz(CHRw)n-Y, wherein Y is hydrogen, OH, -NRwR q, aryl, heteroaryl or CO-Z, n is an integer from 1 to 4, Z is OH, -NRWR q , ORw or an amino acid with a blocked or unblocked carboxy terminus, R q is H, CI 6 alkyl or arylCI-6alykl, and Rz and R' are each independently hydrogen, CI. 6 alkyl, C 3 - 7 cycloalkyl, aryl, heteroaryl, T-CI 6 alkyl or T-C 2 -6alkenyl. 3. The compound of claim 1 having the structure: H NH 2 R 1 N-X 2 XR 4 0 2 R 3 R 3 ' or pharmaceutically acceptable derivative thereof; wherein R 1 is an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety; R is an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, or R 2 , taken together with R', may form a cycloheteroaliphatic moiety; R 3 is hydrogen, halogen, or an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety; R 4 is hydrogen, an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, or R 4 , taken together with a substituent present on X 2 or X 3 , may form a cycloaliphatic, cycloheteroaliphatic, aromatic, or heteroaromatic moiety; X 2 is absent, -NR x2A -, -(CHREA)j-, -NRX2AY - , -(CHRMA)jY - or N(RXA)CH(RMA')Y - wherein each occurrence of R X 2 A is independently hydrogen or an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, each occurrence 0 RX 2 B N H of Y is independently )t wherein, for each independent occurrence of t, Rus is hydrogen, or an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, or RE A or one occurrence of Rx a B taken together with R 4 may form a cycloaliphatic, cycloheteroaliphatic, aromatic or heteroaromatic moiety, and wherein each occurrence ofj and t is independently an integer from 1 to 4; and 148 WO 2005/005374 PCT/US2003/039276 X 3 is absent, -NHCO-, -NHSO 2 -, -NHCONH-, -NHCOO-, -CH 2 NH-, C(=O)-, -S(=O)-, -C(=NH)-, -C(=S)-, -NC(=S)N-, -N-C(=N-CEN)N-, -NS(O 2 )N-, SO 2 -, -C(=O)NRX 3 A - , -C(=S)NR 3 A - , -COO-, -(CHRX 3 A)k-, -0-, -CH 2 NRX 3 A -, or NRX3A-, wherein each occurrence of R X3 A is independently hydrogen, an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, or RX 3 A taken together with R 4 may form a cycloaliphatic, cycloheteroaliphatic, aromatic or heteroaromatic moiety, and k is an integer from 1 to 3. 4. The compound of claim 3 wherein one or more of the following groups do not occur simultaneously as defined: (i) R 3 and R 3 ' are each hydrogen; R 2 is alkyl, cycloalkylalkyl or aralkyl; -X 2 X 3 -R 4 together represents -CIHReC(=O)NHCH(RW)C(=O)NRxRY, wherein Re is hydrogen or alkyl, Rw is alkyl, and one of Rx or R y 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 SO 2 ; or Rx and R Y together with the nitrogen atom to which they are attached represent a 1,2,3,4 tetrahydroisoquinoline ring; and -C(=O)-R 1 together represents an alkoxycarbonyl, aralkoxycarbonyl, alkanoyl, aralkanoyl, aroyl, cycloalkylcarbonyl, heterocyclylcarbonyl, heterocyclyl-alkanoyl, 6-(dibenzylcarbamoyl)-4-oxohexanoyl moiety or an acyl group of an a-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; 149 WO 2005/005374 PCT/US2003/039276 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 3 and R' are each hydrogen; R 1 is a substituted or unsubstituted C 1 . 6 alkyl, a 5-6 membered heterocycle or a 6-10 carbon atoms aryl moiety substituted with C 14 alkyl, C 1 . 3 alkoxy, hydroxy, halogen, N(Ra) 2 , C(=O)ORa, -C(=O)N(Ra) 2 , SO 2 N(Ra) 2 , CH 2 N(Ra) 2 , N(Ra)C(=O)Ra or N(Ra)SO 2 Ra; R 2 is ORa, N(Ra) 2 , C1 4 alkenyl-R or -[CRbR]nRo; and -X 2 -X 3 -R 4 together represent CH(Rd)C(=O)NHCH(Re)C(=O)-Y-[CR'R ]mR g, wherein m is an integer from 0 to 5, Y is O or NH, Rd and R are independently hydrogen, ORa, N(Ra) 2 , Cl-4alkenyl-R or -[CRbR]nRe wherein n is an integer from 0 to 5, Ra is hydrogen or C 1 - 4 alkyl, Rb is hydrogen, hydroxy or C 1 - 4 alkyl and Re is hydrogen, substituted or unsubstituted aryl, 5- or 6-membered heterocycle, C1- 6 alkyl or C_ 6 alkenyl, C 3 - 7 cycloalkyl, 5- to 7 membered carbocyclic or 7- to 10-membered bicyclic carbocyclic ring, benzofuryl, indolyl, azabicyclo C 7 _11cycloalkyl or benzopiperidinyl; R is hydrogen, substituted or unsubstituted C 1 6 alkyl or (CH 2 CH 2 0)pCH 3 or (CH 2 CH 2 0)pH wherein p is an integer from 0 to 5, and R is hydrogen, or substituted or unsubstituted aryl, heterocycle, 5- to 7-membered carbocyclic or 7- to 10-membered bicyclic carbocyclic ring; (iii) R 3 and R 3 W are each hydrogen; R 1 is a substituted or unsubstituted C 1 . 6 alkyl, a 5-6 membered heterocycle or a 6-10 carbon atoms aryl moiety substituted with Cl 4 alkyl, C1- 3 alkoxy, hydroxy, halogen, N(Ra) 2 , C(=0)ORa, -C(=0)N(Ra) 2 , SO 2 N(Ra) 2 , CH 2 N(Ra) 2 , N(Ra)C(=O0)Ra or N(Ra)SO 2 Ra; R is ORa, N(Ra) 2 , C1 4 alkenyl-Rc or -[CRbR]nRo; and -X 2 -X 3 -R 4 together represent -CH(Rd)C(=O)-Y [CRg]mR g , wherein m is an integer from 0 to 5, Y is O or NH, Rd is hydrogen, ORa, N(Ra) 2 , Cl- 4 alkenyl-R or -[CRbR ]nRe; wherein n is an integer from 0 to 5, R a is hydrogen or C 1 .- 4 alkyl, Rb is hydrogen, hydroxy or C 1 4 alkyl and R e is hydrogen, substituted or unsubstituted aryl, 5- or 6-membered heterocycle, C 1 - 6 alkyl or C 1 6 alkenyl, C 3 . 7 cycloalkyl, 5- to 7-membered carbocyclic or 7- to 10-membered bicyclic carbocyclic ring, benzofuryl, indolyl, azabicyclo C 7 . 11 cycloalkyl or benzopiperidinyl; R is hydrogen, substituted or unsubstituted C 1 . 6 alkyl or 150 WO 2005/005374 PCT/US2003/039276 (CH 2 CH 2 0)pCH 3 or (CH 2 CH 2 0)pH wherein p is an integer from 0 to 5, and R is hydrogen, or substituted or unsubstituted aryl, heterocycle, 5- to 7-membered carbocyclic or 7- to 10-membered bicyclic carbocyclic ring; (iv) R 3 ' is hydrogen; R 1 is a substituted or unsubstituted C 1 - 6 alkyl, a 5-6 membered heterocycle or a 6-10 carbon atoms aryl moiety substituted with C 1 4 alkyl, C 1 _ 3 alkoxy, hydroxy, halogen, N(Ra) 2 , C(=O)ORa, -C(=O)N(Ra) 2 , SO 2 N(Ra) 2 , CH 2 N(Ra) 2 , N(Ra)C(=O)Ra or N(Ra)SO 2 Ra; R is ORa, N(Ra) 2 , Cl. 4 alkenyl-R or -[CRbRo]nR; R 3 is hydrogen, ORa, N(Ra) 2 , C 1 .- 4 alkenyl-R or [CRbR]nRC; and -X 2 -X 3 -R 4 together represent -CH(Rd)C(=O)NHCH(Re)C(=O)-Y [CRfRg]mR9, wherein m is an integer from 0 to 5, Y is O or NH, Rd and Re are independently hydrogen, OR a , N(Ra) 2 , CI- 4 alkenyl-R or -[CRbRo]nR wherein n is an integer from 0 to 5, Ra is hydrogen or C 1 - 4 alkyl, R b is hydrogen, hydroxy or C 1 4 alkyl and R is hydrogen, substituted or unsubstituted aryl, 5- or 6-membered heterocycle, CI- 6 alkyl or C 1 - 6 alkenyl, C 3 . 7 cycloalkyl, 5- to 7-membered carbocyclic or 7- to 10-membered bicyclic carbocyclic ring, benzofuryl, indolyl, azabicyclo C7 icycloalkyl or benzopiperidinyl; R' is hydrogen, substituted or unsubstituted C 1 6 alkyl or (CH 2 CH 2 0)pCH 3 or (CH 2 CH 2 0)pH wherein p is an integer from 0 to 5, and R9 is hydrogen, or substituted or unsubstituted aryl, heterocycle, 5- to 7 membered carbocyclic or 7- to 1 0-membered bicyclic carbocyclic ring; (v) R 3 is hydrogen; R 1 is a substituted or unsubstituted C1. 6 alkyl, a 5-6 membered heterocycle or a 6-10 carbon atoms aryl moiety substituted with C 1 . 4 alkyl, C 1 - 3 alkoxy, hydroxy, halogen, N(Ra) 2 , C(=0)ORa, -C(=0)N(R) 2 , SO 2 N(Ra) 2 , CH 2 N(Ra) 2 , N(Ra)C(=0)Ra or N(Ra)SO 2 R; R 2 is ORa, N(Ra) 2 , C1 4 alkenyl-R or -[CRbR]nRR; R is hydrogen, ORa, N(Ra) 2 , Cl-4alkenyl-Ro or [CRbRI]nR; and -X-X 3 -R 4 together represent -CH(R)C(=O)-Y-[CR'Rg]mR g, wherein m is an integer from 0 to 5, Y is O or NH, Rd is hydrogen, ORa, N(Ra) 2 , C 1 4 alkenyl-R or -[CRbRc]nRc; wherein n is an integer from 0 to 5, Ra is hydrogen or C 1 - 4 alkyl, Rb is hydrogen, hydroxy or Cl 4 alkyl and Re is hydrogen, substituted or unsubstituted aryl, 5- or 6-membered heterocycle, C 1 - 6 alkyl or C 1 - 6 alkenyl, C 3 7 cycloalkyl, 5- to 7-membered carbocyclic or 7- to 10-membered bicyclic carbocyclic ring, benzofuryl, indolyl, azabicyclo C 7 . 1 cycloalkyl or benzopiperidinyl; R f is hydrogen, substituted or unsubstituted C 1 . 6 alkyl or 151 WO 2005/005374 PCT/US2003/039276 (CH 2 CH 2 0)pCH 3 or (CH 2 CH 2 0)pH wherein p is an integer from 0 to 5, and R' is hydrogen, or substituted or unsubstituted aryl, heterocycle, 5- to 7-membered carbocyclic or 7- to 10-membered bicyclic carbocyclic ring; and (vi) R 3 and R y are each hydrogen; R 2 is C 1 . 6 alkyl, C 2 - 6 alkenyl, C 3 7cycloalkyl, aryl, heteroaryl, T-C 1 - 6 alkyl, T-C 2 - 6 alkenyl, wherein T is aryl, heteroaryl or C 3 - 7 cycloalkyl; R 1 -C(=O)- together represent W wherein W is Rx, RxCO, RxOCO, RXOCH(RY)CO, RXNHCH(RY)CO, RXSCH(RY)CO, RxSO 2 , RxSO or an amino acid with a blocked or unblocked amino terminus, wherein Rx and RI are each independently hydrogen, Ci.- 6 alkyl, C 3 - 7 cycloalkyl, aryl, heteroaryl, T-CI. 6 alkyl or T (CH 2 )nCH(T)(CH 2 )n wherein n is an integer from 1 to 4; and -X 2 -X 3 -R 4 together represent -CH(Ra)C(=X)CHRbR, wherein X is (OH,H) or O; Ra is hydrogen, CI 6 alkyl, C 2 - 6 alkenyl, C 3 7 cycloalkyl, aryl, heteroaryl, T-C 1 . 6 alkyl or T-C 2 - 6 alkenyl; Rb is hydrogen or OH; and R is Y, (CHRW),-Y or =CRz(CHRW),-Y, wherein Y is hydrogen, OH, -NRWR q, aryl, heteroaryl or CO-Z, n is an integer from 1 to 4, Z is OH, -NR7R q, ORW or an amino acid with a blocked or unblocked carboxy terminus, R q is H, C 1 - 6 alkyl or arylCl16alykl, and Rz and R' are each independently hydrogen, C1- 6 alkyl, C 3 . 7 cycloalkyl, aryl, heteroaryl, T-Ci. 6 alkyl or T-C 2 _ 6 alkenyl. S X 2 R 4 5. The compound of claim 3, wherein R 3 R 3 has one of the following structures: RX 2 A RX 2 A I SXR4 R or R 3 RX2A wherein R 3 is hydrogen, halogen or an aliphatic, heteroaliphatic, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or (heteroalkyl)heteroaryl moiety; R 4 is an aliphatic, heteroaliphatic, aryl, heteroaryl, -(alkyl)aryl, (alkyl)heteroaryl, -(heteroalkyl)aryl, or -(heteroalkyl)heteroaryl moiety, or R 4 , taken together with R x 2A ' or a substituent present on Y or X 3 , may form a cycloaliphatic, cycloheteroaliphatic, aryl, or heteroaryl moiety; 152 WO 2005/005374 PCT/US2003/039276 R X2A is hydrogen or an aliphatic, heteroaliphatic, aryl, heteroaryl, (alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or -(heteroalkyl)heteroaryl moiety; REA' is hydrogen, or an aliphatic, heteroaliphatic, aryl, heteroaryl, (alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or -(heteroalkyl)heteroaryl moiety, or R 2 A' taken together with R 4 may form a cycloaliphatic, cycloheteroaliphatic, aryl or heteroaryl moiety; 0 RX2B Y is independently absent or is t, 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 R x2B taken together with R 4 may form a cycloaliphatic, cycloheteroaliphatic, aryl or heteroaryl moiety; t is an integer from 1 to 4; and X 3 is absent, -NHCO-, -NHSO 2 -, -NHCONH-, -NHCOO-, -CH 2 NH-, C(=O)-, -S(=O)-, -C(=NH)-, -C(=S)-, -NC(=S)N-, -N-C(=N-C-N)N-, -NS(O 2 )N-, SO 2 -, -C(=O)NRX 3 A-, -C(=S)NRX 3 A-, -COO-, (CHRX 3 A)k, -- , -CH 2 NR x A- , or NREA - , wherein each occurrence of RX 3 A is independently hydrogen, an aliphatic, heteroaliphatic, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or -(heteroalkyl)heteroaryl moiety, or R x 3 A taken together with R 4 may form a cycloaliphatic, cycloheteroaliphatic, aryl or heteroaryl moiety, and k is an integer from 1 to 3. / X 2 R 4 " X3
6. The compound of claim 5, wherein R 3 R 3 has one of the following structures: 153 WO 2005/005374 PCT/US2003/039276 RX 2 A H RX2A H NN R 4 H 0 RX 2 E NR N N R4 OX2A H t wherein R , R R x2A R X2A , R x2B and t are as defined in claim 2. / X 2 R 4 'X 3
7. The compound of claim 5, wherein R 3 R 3 has one of the following structures: H H 0 N " R 4 A N 'R 4 N R 4 YO R E3 H H 4 R O R 3 O ^ * ' "<N / or H 0H N R 4 - H O wherein R? and R 4 are as defined in claim 2.
8. The compound of claim 3 having the structure: H NH 2 RX 2 A H RI N N' R4 0 k2 0 wherein R x2A is hydrogen or an aliphatic, heteroaliphatic, aryl, heteroaryl, (alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or -(heteroalkyl)heteroaryl moiety.
9. The compound of claim 8, wherein R x2 A is a substituted or unsubstituted, linear or branched lower alkyl moiety.
10. The compound of claim 5, wherein R X2 A is methyl, ethyl, propyl, isopropyl or phenethyl. 154 WO 2005/005374 PCT/US2003/039276
11. The compound of claim 3 or 8, wherein R 1 has one of the following structures: (R1A (RA) (RA- (R1 1A n 1A) (1A)n(1 n i (R1) (R n (R1A) (RIA) (RA)n (R A) n (R 1 )n o P 0 0 p 0 P o.-../, "R A ',,.A)IA .N . (RA (R N (lAN HN N P P H H N(R1A)IA (R1AORA (RA (RA)nv (RA /N ' (R1A)nP HH H N N"P Hl~ 0 ID~ 19' 0\"0 N'_'j N-S=0 wherein R 1 A is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, (alkyl)heteroaryl, -OR B, -SR B, -N(R B) 2 , -SO 2 N(RB)2, -C(=O)N(RB) 2 , halogen, CN, -NO 2 , -C(=O)OR 1 B, N(R1B)C(=O)Rlc or -N(R'B)SO 2 RlC; wherein each occurrence of R IB and Ri c is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl; or RIB and Ri c , taken together with the atoms to which they are attached, form a substituted or unsubstituted heterocyclic moiety; RID 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. 155 WO 2005/005374 PCT/US2003/039276
12. The compound of claim 11, wherein R 1 has one of the following structures: ( RA )R A-.RSO R R1D 00 0 0 00 R0 0 (R1A)n (R1A)n R 1ID S/ R D NK
13. The compound of claim 11, wherein R 1 has one of the following structures: ROIB 1An 1RA n 1RA)n -( 1A)n I R1 R R1F S R0O 0IF 0R 0 /10 o (RA) N( RIE N1F )n,, IP (1~ _ .[[ . A p RNi =O R N O R R R- RIF (RA). 0 0 R 2 () ID 0 RID "RID 0 wherein R 1 D is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, (alkyl)aryl; -(alkyl)heteroaryl or acyl; RIE and R 1F are each independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, C(=O)R i c or -SO 2 Ri c , where Ric is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl; or RIE and R 1 F taken together form a 5 8 membered heterocyclic ring; or R1E and one occurrence of RlA, taken together, form a substituted or unsubstituted, saturated or unsaturated heterocyclic ring.
14. The compound of claim 11, wherein R' has one of the following structures: 156 WO 2005/005374 PCT/US2003/039276 OMeN I NK, ,NI o 0 0 o OMe 0 0 0 0 e-ON 'N - e--N 0N o 0 H 0 o 00 0 0P
15. The compound of claim 11, wherein R' has one of the following structures: 157 WO 2005/005374 PCT/US2003/039276 OMe S N0N 0 0 0 0 OMe OMe I O FN N N N 0 0 0 0 OMe OMe OMe S 1 o 7 oN 0 0 0 0' 0 Oe .NS -N-S. -- N-S F =Ho' N
16. The compound of claim 11, wherein R 1 has one of the following structures: FO _ N 0 H /-N N N H- 16. The compound of claim 11r , wherein R has oneofter ollown -CrucR 2 turs: (CH2)phenyl, wherein the phenyl group is optionally substituted with one or more occurrences of R 2c, wherein R 2c is hydrogen, alkyl, alkoxy or halogen; and wherein R 2A and R 2B are each independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alky1)heteroaryl; whereby each of the foregoing alkyl and heteroalkyl moieties may be linear or branched, substituted or unsubstituted, 158 'NN 0 0 \ NN 0 0
17. The compound of claim 3 or 8, wherein R 2 is lower alkyl, -CH1 2 NR R or (CLI 2 )phenyl, wherein the phenyl group is optionally substituted with one or more occurrences of R 2 c, wherein R~c is hydrogen, alkyl, alkoxy or halogen; and wherein RA and R 2 B 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, 158 WO 2005/005374 PCT/US2003/039276 cyclic or acylic, and each of the foregoing aryl, heteroaryl, -(alkyl)aryl and (alkyl)heteroaryl moieties may be substituted or unsusbtituted.
18. The compound of claim 17, wherein R 2 has one of the following structures: N (R 2 A)q (R2A)q (R (R2A) (R2A), O H 2A O, (R 2 A (R N A (R )q wherein R 2 A iS hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or (alkyl)heteroaryl, -OR 2 B , -SR 2B , -(R2B)2, -SO2R )2, -C(=)N(R 2B)2, halogen, HN N N SH H HH CN, -NO2, -C(=)OR 2 B , -N(R2B)C(=)R 2 c , wherein each occurrence of R 2 B and R 2c is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, (alkyl)ary(alkyl)alkyl)heteroaryl, wherein q a nd s are eac h i n dependently in t egers BRA~ 2A)2 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.
19. The compound of claim 17, wherein R 2 has one of the following structures: 159 WO 2005/005374 PCT/US2003/039276 (9 N N Sj S S q<N_ X X R 2 A I-OR 2 A x -'o 0 N DI N wherein each occcurrence of R 2 A 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.
20. The compound of claim 17, wherein each occurrence of X is independenly chlorine or fluorine and R 2A is methyl.
21. The compound of claim 17, wherein R 2 has one of the following structures: NN CI F F-F -Me I-OMe F 0 >-016 160 WO 2005/005374 PCT/US2003/039276
22. The compound of claim 17, wherein R 2 has one of the following structures: F F F F SS
23. The compound of claim 3, wherein R 3 is hydrogen or halogen.
24. The compound of claim 3 or 8, wherein R 4 is substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl, phenyl or -(CH 2 )phenyl, wherein the phenyl group is optionally substituted with one or more occurrences of R 4 A, wherein R4A is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or (alkyl)heteroaryl, -OR 4B , -SR 4B , -N(R 4 B) 2 , -SO 2 N(R4B)2, -C(=O)N(R 4 B) 2 , halogen, CN, -NO 2 , -C(=O)OR 4B, -N(R 4 B)C(=O)R 4 c, wherein each occurrence of R 4B and R 4 c is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, (alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, -(heteroalkyl)heteroaryl.
25. The compound of claim 24, wherein R 4 is substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl, phenyl or -(CH 2 )phenyl, wherein the phenyl group is optionally substituted with one or more occurrences of R 4 A, wherein R 4 A is hydrogen, hydroxyl, alkyl, alkoxy or halogen.
26. The compound of claim 24, wherein R 4 has one of the following structures: 161 WO 2005/005374 PCT/US2003/039276 N. (4A ( R4A "94A 4ARvT /....y (R4A )v(4A)v 9j N4A)V (R4AV v (R4A)v (R4A) (4A N (4A)v.. (R 4 A) O-O 0 0 W 0 (R )v (R 4 A)V (R4A (R 4 A) 4AV NNI HN N WY1- 0 v C N w N W HN"- H H N R >AV , (R 4 VA) ., (R 4 A) " I H (R4 4A) 0r A 1- z C).(R '-...N - ( x"' wherein each occurrence of R 4 A is independently hydrogen, alkyl, heteroalkyl, aiyl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -OR 4 B, -SR 4 B N(R 4 B) 2 , -SO 2 N(R 4 B) 2 , -C(=O)N(R 4 B) 2 , halogen, -CN, -NO 2 , -C(=O)OR 4 B, N(R 4 B)C(=0)R 4 C, wherein each occcurrence of R 4 B and R 4 C 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.
27. The compound of claim 24, wherein R 4 is methyl, ethyl, propyl or one of: I IC wN WJ WN W "NR R4A wKX -X -- R 4 A ~ OR 4 A X x 162 WO 2005/005374 PCT/US2003/039276 wherein each occcurrence of R 4 A is independently hydrogen, lower alkyl or C(=O)OR 4 B, wherein R 4 B 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.
28. The compound of claim 27, wherein each occurrence of X is independenly chlorine or fluorine and R 4 A is methyl.
29. The compound of claim 24, wherein R 4 is methyl, ethyl, propyl or one of: I I i I I II /O " 'R4A R4A wherein R 4 A is hydrogen, hydroxyl, lower alkyl, lower alkoxy, halogen, C(=O)OR 4 B, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, wherein R 4 B is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteoraryl, -(alkyl)aryl, (alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl.
30. The compound of claim 24, wherein R 4 is methyl, ethyl, propyl, isopropyl or one of: F OH CO2H OMe C CO 2 Me 163 WO 2005/005374 PCT/US2003/039276
31. The compound of claim 24, wherein R 4 has one of the following structures: F
32. A pharmaceutical composition comprising a compound of claim 3 or 8, and a pharmaceutically acceptable carrier or diluent, optionally further comprising an additional therapeutic agent.
33. The pharmaceutical composition of claim 32, wherein the compound is present in an amount effective to inhibit P-secretase activity.
34. The pharmaceutical composition of claim 32, wherein the additional therapeutic agent is an agent for the treatment of Alzheimer's Disease.
35. A method for inhibiting -secretase activity in a patient or a biological sample, comprising administering to said patient, or contacting said biological sample with an effective inhibitory amount of a compound of claim 3 or 8.
36. A method for treating or preventing a disease characterized by 3-amyloid deposits in the brain comprising administering to a patient a therapeutically effective amount of a compound of claim 3 or 8.
37. The method of claim 36, 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. 164 WO 2005 /005374 ived by the International Bureau on 18 June 2004 (18.06.0PCT/US2003/039276 original claims 3, 5, 6, 7, 10 and 20 replaced by new claims 3, 5, 6, 7, 10 and 20; and 1-2, and 4 cancelled; remaining claims unchanged (8 pages)] + STATEMENT 3. An isolated compound having the structure: H NH 2 R' N X X " R O R2 R3 R 4 or pharmaceutically acceptable derivative thereof; wherein R and R 2 are independently an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety; or R 2 , taken together with R', may form a cycloheteroaliphatic moiety; R is hydrogen, halogen, or an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety; R " is hydrogen, halogen, or lower alkyl; R 4 is hydrogen, an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, or R 4 , taken together with a substituent present on X 2 or X 3 , may form a cycloaliphatic, cycloheteroaliphatic, aromatic, or heteroaromatic moiety; X is absent, -NR 2A -, -(CHRX2A)j-, -NRX2AY-, -(CHRX2A)jY - or N(R2A)CH(R2A')Y- wherein each occurrence of R X2 A is independently hydrogen or an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, each occurrence 0 RX 2 B H / VN) of Y is independently /) t wherein, for each independent occurrence of t, R X2 B is hydrogen, or an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, or R x A or one occurrence of R x 2B taken together with R 4 may form a cycloaliphatic, cycloheteroaliphatic, aromatic or heteroaromatic moiety, and wherein each occurrence ofj and t is independently an integer from 1 to 4; and X 3 is absent, -NHCO-, -NIISO 2 -, -NHCONH-, -NHCOO-, -CH 2 NH-, C(=O) - , -S(=O) - , -C(=NH) - , -C(=S) -, -N(ReA)C(=S)N(ReA) , -N(RX3A)c(=N C-N)N(R3A)-, -N(ReA)S(O 2 )N(ReA) - , -SO2-,-C(=O)NR 3A- , -C(=S)NR3A_, COO-, -(CHR3A)k-, -0-, -CH 2 NReA-, or -NR X3A- , wherein each occurrence of ReA is independently hydrogen, an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, or R X3 A taken together with R 4 may form a cycloaliphatic, cycloheteroaliphatic, aromatic or heteroaromatic moiety, and k is an integer from 1 to 3; AMENDED SHEET (ARTICLE 19) 165 WO 2005/005374 PCT/US2003/039276 with the proviso that (i) the compound does not have one of the structures: NH 2 H Boc-Phe-His N le-His-NH2 0 NH 2 H Boc-Phe-His N Ile-NH-CH2CH 2 Ph 0 oo ; or NH 2 H M B N Ile-NH-CHzCH 2 -(2-pyridyl) Boc-Phe-ePhe (ii) when-C(R 3 )(R 3 ')-X 2 -X 3 -R 4 has the structure: 0 RX3A R4A N R4B H-1 RA O0 wherein R 2 A is hydrogen or Ci.salkyl; R x A is CiSalkyl; one of R 4 A or R 4 B represents hydrogen and the other represents hydrogen, Csalkyl, Ar, -CIsalkyl-Ar, 1-C1.sialkoxycarbonyl-2 phenylethyl, 1 -C8.salkoxycarbonyl-2-(imidazol-4-yl)ethyl, 2 (imidazol-1-yl)ethyl, indanyl, heterocyclyl-C 1 .salkyl-, carboxyC. 8 alkyl, -C.salkylC(=O)OC 1 .s 8 alkyl, -Ci-salkylC(=O)OAr, -C _ salkylC(=O)OCI.salkylAr or a group of the formula -A-N(Ra)(Rb) in which A represents Ci.salkylene and Ra and Rb each represents C 1 salkyl or Ra and Rb together represent a pentamethylene group in which one methylene group can be replaced by NH, N-CI-salkyl, N Ci.salkanoyl, N-aralkoxycarbonyl, O, S, SO, or S02; or R 4 A and R 4 B AMENDED SHEET (ARTICLE 19) 166 WO 2005/005374 PCT/US2003/039276 together with the nitrogen atom to which they are attached represent a 1,2,3,4-tetrahydroisoquinoline ring; then R 1 is not -OC1.alkyl, -OCz.salkylAr, -C1.salkyl, -Ci.salkylAr, -OAr, C3.scycloalkyl, Het, -Cl.8alkyl-Het, (PhCH 2 ) 2 NC(=O)CH 2 CH 2 C(=O)CH 2 CH 2 - or the aminoalkyl radical of an a-amino acid residue in which the amino group is substituted by -C(=O)OC 1 .salkyl, -C(=O)OC 1 .salkylAr, -C(=O)N(C1.salkylAr) 2 , C(=O)Ci.-salkyl(C1.salkylAr) 2 or -C(=O)C1.salkylAr; wherein Ar is phenyl or naphthyl optionally substituted with one or more substituents selected from halogen, -OH, -Cisalkoxy and CI.salkyl; and Het is a saturated, partially unsaturated or aromatic monocyclic, bicyclic or tricyclic heterocycle which is attached via a carbon atom, contains one or more heteroatoms selected from N, O and S, and is optionally substituted on one or more carbon atoms by Ci-salkyl, C 1 -salkoxy and/or halogen; and (iii) when -C(R 3 )(R 3 ')-X 2 -X 3 -R 4 has the structure: w RX2 o ; wherein each occurrence of n is independently 0 or 1; RDB is hydrogen, CI. 6 alkyl; -CH 2 Ar, cyclohexyl or adamantyl; W is -ORWl; -N(RWl) 2 ; -NRW2-(CH 2 )m-QI; an optionally amide- or ester-protected serine, lysine or arginine residue, or optionally ester or ether-protected amino alcohol derivative thereof; or an N containing heterocyclic ring attached via the N atom containing 1-3 heteroatoms selected from N, O and S, optionally substituted with one or more substituents selected from Rwl and -CH 2 RWl; wherein m is 2-6; Q1 is NH 2 or -NH-C(=NH)NH 2 wherein any of the hydrogen atoms attached to the nitrogen atoms may be substituted with C 1 . 6 alkyl, cycloalkyl or Rw 2 ; Rw l , for each occurrence, is independently hydrogen, C 1 - 6 alkyl, C 3 . 7 cycloalkyl, C 7 1 2 bi or tricycloalkyl, Ar or -C 1 - 6 alkyl-Ar; and RW 2 is hydrogen, -(CH 2 )p R w 3 , -C(=O)-R W3 , -COORw 3, -C(=O)-(CH2)pR3 C(=O)O(CH 2 )pRW 3 , -C(=O)-(CH 2 )pORW 3 , -SO 2 -Rw 3 or AMENDED SHEET (ARTICLE 19) 167 WO 2005/005374 PCT/US2003/039276 C(=O)N(RWJ) 2 , wherein p is 0-5; and Rw 3 for each occurrence takes the definition ofRwl above; then R is not hydrogen, -RIA, -OR 1 A, -(CH 2 )pRIA, -O(CH 2 )pRIA, (CH 2 )pOR 1 A or - N(RIA) 2 , wherein p is 0-5; and R 1 A for each occurrence takes the definition of Rw l above; wherein Ar is phenyl or naphthyl optionally substituted with one or more substituents selected from halogen, -OH, C1. 6 alkyl and -CF 3 . AMENDED SHEET (ARTICLE 19) 168 WO 2005/005374 PCT/US2003/039276 / X 2 R 4 %X3 5. The compound of claim 3, wherein R 3 R 3 has one of the following structures: RX2A RX2A RX2A / XR4 "R4 R 3 or R RXA' wherein R 3 is hydrogen, halogen or an aliphatic, heteroaliphatic, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or (heteroalkyl)heteroaryl moiety; R 4 is an aliphatic, heteroaliphatic, aryl, heteroaryl, -(alkyl)aryl, (alkyl)heteroaryl, -(heteroalkyl)aryl, or -(heteroalkyl)heteroaryl moiety, or R 4 , taken together with R x A ' or a substituent present on Y or X 3 , may form a cycloaliphatic, cycloheteroaliphatic, aryl, or heteroaryl moiety; R 2A is hydrogen or an aliphatic, heteroaliphatic, aryl, heteroaryl, (alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or -(heteroalkyl)heteroaryl moiety; R2A' is hydrogen, or an aliphatic, heteroaliphatic, aryl, heteroaryl, (alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or -(heteroalkyl)heteroaryl moiety, or REA' taken together with R 4 may form a cycloaliphatic, cycloheteroaliphatic, aryl or heteroaryl moiety; 0 RX2B Y is independently absent or is t, wherein, for each independent occurrence of t, R x 2B is hydrogen, or an aliphatic, heteroaliphatic, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or (heteroalkyl)heteroaryl moiety, or one occurrence of R x a B taken together with R 4 AMENDED SHEET (ARTICLE 19) 169 WO 2005/005374 PCT/US2003/039276 may form a cycloaliphatic, cycloheteroaliphatic, aryl or heteroaryl moiety; t is an integer from 1 to 4; and X 3 is absent, -NHCO-, -NHSO 2 -, -NHCONH-, -NHCOO-, -CH 2 NH-, C(=O)-, -S(=O) -, -C(=NH) -, -C(=S)-, -N(RX3A)C(=S)N(ReA) - , -N(REA)-C(-N C-N)N(ReA) -, -N(ReA)S(O2)N(ReA) -, -SO2-, -C(=O)NRe A-, -C(=S)NR x 3 A-, COO-, (CHR3A)k, -0-, -CH 2 NReA-, or -NR 3A-, wherein each occurrence of R 3 A is independently hydrogen, an aliphatic, heteroaliphatic, aryl, heteroaryl, (alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or -(heteroalkyl)heteroaryl moiety, or RE 3 A taken together with R 4 may form a cycloaliphatic, cycloheteroaliphatic, aryl or heteroaryl moiety, and k is an integer from 1 to 3. / X 2 R 4 X 6. The compound of claim 5, wherein R 3 R 3 has one of the following structures: RX2A RX2A H 4 H N N 4 N '[4 "B R R 0 t ; R 3 RX2A or H 0 RX 2 E t wherein R, R 4, Re A, R X2A' , R x and t are as defined in claim 5. / X 2 R 4 11X3, 7. The compound of claim 5, wherein R 3 R 3 has one of the following structures: AMENDED SHEET (ARTICLE 19) 170 WO 2005/005374 PCT/US2003/039276 H H 0 4 N N R4 R 3 O ; ; fNV ' or H 0 H N N N R4 H 0 wherein R 3 and R 4 are as defined in claim 5. 8. The compound of claim 3 having the structure: H NH 2 RX2A H R 1 N N, R4 O j 2 O ; wherein RE A is hydrogen or an aliphatic, heteroaliphatic, aryl, heteroaryl, (alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or -(heteroalkyl)heteroaryl moiety. 9. The compound of claim 8, wherein R 2 A is a substituted or unsubstituted, linear or branched lower alkyl moiety. 10. The compound of claim 8, wherein R 2 A is methyl, ethyl, propyl, isopropyl or phenethyl. AMENDED SHEET (ARTICLE 19) 171 WO 2005/005374 PCT/US2003/039276 vuv d W :r S SN N N I u x ~~~ NO>s > wherein each occurrence of R 2 A 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. 20. The compound of claim 19, wherein each occurrence of X is independenly chlorine or fluorine and R 2 A is methyl. 21. The compound of claim 17, wherein R 2 has one of the following structures: N .N : - N N' N N I I -CI I-F I F I-Me I-OMe F AMENDED SHEET (ARTICLE 19) 172 WO 2005/005374 PCT/US2003/039276 STATEMENT UNDER ARTICLE 19(1) Applicant respectfully submits that no new matter is presented with the amendments set forth in the "Letter for PCT Article 19 Amendment of Claims" filed concurrently herewith. Specifically, the claims have been amended in order to more clearly set forth what is intended as Applicants' invention, to expedite prosecution or to correct typographical or clerical errors. For example, claims 3 has been amended (i) to present the claim in independent form, (ii) to add a definition for variable R 3 W ', which had been inadvertently omitted at the time of filing; and (iii) to correct some of the functional groups that are recited for variable X 3 (i.e., " NC(=S)N-, -N-C(=N-C-N)N-, -NS(O 2 )N-" was replaced with "-N(RA)C(=S)N(R3A)-, N(RX3A)-C(=N-CN)N(RA)-, -N(RX3A)S(O 2 )N(RX 3 A)-"). Support for the definition of R 3 , can be found, for example, in original claim 1. With respect to the recitation of functional groups "-NC(=S)N- , -N-C(=N-C-N)N-, -NS(0 2 )N-", amendment is necessary to correct the error in valency on some of the nitrogen atoms. Specifically, the valency in the highlighted nitrogen atoms in -NC(=S)N-, -N-C(=N-C-N)N- and -NS(O 2 )N- is defective. The correct valency is "-N(ReA)C(=S)N(RX3A) -, -N(RX3A)-C(=N-CN)N(R 3 A), N(RX 3 A)S(O 2 )N(ReA)-." Claim 3 has been amended to reflect this. A similar amendment was made in claim 5. In addition, claim 3, as amended, include provisos (i) - (iii), which specifically exclude compounds disclosed in EP 0 386 611 and EP 0 316 965 (i.e., references cited under category "X" in the International Search Report mailed 20 April 2004). Proviso (ii) finds support in original claim 4 (See proviso (i) in (now canceled) claim 4), and specifically 173 WO 2005/005374 PCT/US2003/039276 excludes compounds generically disclosed in EP 0 386 611. Similarly, proviso (i) in amended claim 3 excludes compounds 18-20 disclosed on page 23 of EP 0 316 965; and proviso (iii) excludes compounds generically disclosed in claim 1 of EP 0 316 965. Claims 6, 7, 10 and 20 were amended to correct claim dependency. No new matter is introduced by the claim amendments submitted herein. Therefore, Applicant respectfully requests entry of these amendments, and consideration of these amendments in processing the application. 174
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