Acyclic Thiol Prodrugs

Abstract

Disclosed herein are acyclic thiol prodrugs and pharmaceutical compositions thereof that can be used to treat or prevent medical disorders, such as cystinosis, cystinuria, cancer neurodegenerative diseases, Parkinson's disease, Huntington's disease, malaria, non-alcoholic fatty liver disease, radiation poisoning, arsenic poisoning, radiation protection, Wilson's disease, or rheumatoid arthritis.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 63 / 296,052, filed January 3, 2022, and U.S. Provisional Application No. 63 / 394,760, filed August 3, 2022, each of which is incorporated by reference in its entirety.

[0002] Disclosed herein are acyclic thiol prodrugs and pharmaceutical compositions thereof that can be used to treat or prevent medical disorders, such as cystinosis, cystinuria, cancer neurodegenerative diseases, Parkinson's disease, Huntington's disease, malaria, non-alcoholic fatty liver disease, radiation poisoning, arsenic poisoning, radiation protection, Wilson's disease, rheumatoid arthritis, and the like. [Background technology]

[0003] Most living organisms contain high concentrations of low molecular weight (LMW) thiols that act as redox buffers to protect cells against a variety of reactive species, such as reactive oxygen species (ROS), reactive nitrogen species, reactive electrophiles, metalloids, and some antibiotics. Glutathione (GSH) is the most ubiquitous of these LMW thiols, but certain cells contain high concentrations of other sulfur compounds, such as cysteine ​​(Cys), c-glutamylcysteine ​​(cGC), basilithiol (BSH), mycothiol (MSH), trypanothione (TSG), ovothiol, coenzyme A (CoA), and ergothionine (ESH). The concentrations and thiol / disulfide ratios of these various LMW thiols affect the redox potential of the intracellular reducing environment, which is essential for many metabolic processes.

[0004] The thiol (-SH) functional group is found in several drug compounds as well as human metabolites, and provides a unique combination of useful properties. Thiol-containing drugs are capable of reducing radicals and other toxic electrophiles, restoring cellular thiol pools, and forming stable complexes with heavy metals such as lead, arsenic, and copper. Thus, thiol drugs can treat a variety of pathologies by acting as radical scavengers, GSH prodrugs, or metal chelators. Many thiol drugs have been used for decades, and continued exploration of their properties has provided insights into the development and optimization of new treatments for clinical use. Thiols and their conjugate bases, thiolates, are also good nucleophiles and are therefore reactive towards electrophilic species, including ROS / RNS. Thus, thiol drugs are used as ROS / RNS scavengers to prevent their oxidation of nearby molecules, including proteins, lipids, and DNA.

[0005] A well-known thiol is N-acetylcysteine ​​(NAC) and its derivatives. In vitro and in vivo studies have shown that NAC acts as a cysteine ​​prodrug and a GSH precursor. NAC can also reduce disulfide bonds in proteins, scavenge free radicals, and bind to metals to form complexes. However, its main pharmacological use is to replace cysteine ​​and GSH lost due to acetaminophen toxicity. The best-known NAC preparation is Mucomyst. TM (or its generic version). It is usually administered orally for the treatment of acetaminophen overdose, but the formulation has a strong, unpleasant taste and is therefore usually mixed with fruit juice or a soft drink before ingestion. Furthermore, the treatment period required for effective use of the formulation results in longer hospital stays and higher overall health care costs versus oral NAC (Kondala et al., Current Opinion in Pharmacology 2007,7:355-359).

[0006] Another thiol used in clinical practice is the aminothiol cysteamine. Endogenously, cysteamine is derived from coenzyme A degradation, but its plasma concentration is low. Two formulations of cysteamine have been approved for the treatment of cystinosis, where cysteamine is formulated to reduce intralysosomal cystine accumulation. The odor of thiols, especially those with low molecular weight such as cysteamine, is often strong and unpleasant. (Besouw et al., Drug Discovery Today 18, (2013) 785).

[0007] Thiol drugs such as NAC and cysteamine exert their activity intracellularly. What is needed are novel strategies that allow intracellular delivery of LMW thiols. Such an approach would reduce the total dose as well as the frequency of administration. Intracellular administration of LMW thiols could lead to the treatment of cystinuria, cystinosis, cancer, neurodegenerative diseases, Parkinson's disease, Huntington's disease, malaria, nonalcoholic fatty liver disease, radiation poisoning, arsenic poisoning, Wilson's disease, or rheumatoid arthritis (https: / / doi.org / 10.1016 / j.nbd.2019.104530) and optimize many clinical applications of these compounds (Annalise R.et al.,Mini-Reviews in Medicinal Chemistry,(2019)1). Summary of the Invention [Means for solving the problem]

[0008] The present disclosure provides, in one aspect, a compound of structural formula (I): [ka] wherein R1 is a thiol residue of less than 1000 daltons molecular weight; Y is -NR2R3; X is -OR4 or -SR1; R2 and R3 are independently -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl; or R2 and R3 together with the atom to which they are attached form a cycloalkyl ring, a substituted cycloalkyl ring, a cycloalkenyl ring, a substituted cycloalkenyl ring, a substituted cycloalkenyl ring, R4 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, or substituted heteroarylalkyl, provided that R2 and R3 are not both -H, and one of R2 and R3 is -H, unless R2 and R3, together with the atom to which they are attached, form a cycloalkyl ring, substituted cycloalkyl ring, cycloalkenyl ring, substituted cycloalkenyl ring, heterocycloalkyl ring, substituted heterocycloalkyl ring, heterocycloalkenyl ring, or substituted heterocycloalkenyl ring. These and other needs are met by providing a compound of the formula: or a pharma- ceutically acceptable salt, hydrate, or solvate thereof.

[0009] Also provided are derivatives, including salts, esters, enol ethers, enol esters, solvates, hydrates, metabolites, and prodrugs of the compounds described herein. Additionally, provided are pharmaceutical compositions comprising a compound provided herein and a pharma- ceutically acceptable medium.

[0010] Also provided herein are methods for treating, preventing, or ameliorating symptoms of medical disorders, such as cystinuria, cystinosis, cancer neurodegenerative diseases, Parkinson's disease, Huntington's disease, malaria, non-alcoholic fatty liver disease, radiation poisoning, arsenic poisoning, Wilson's disease, rheumatoid arthritis, and the like. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0012] As used herein, unless otherwise indicated, the terms "about" and "approximately" when used in the context of a property with a numerical value or a range of values, suggest that the value or range of values ​​may deviate within a range that would be considered reasonable by one of ordinary skill in the art while still describing the particular property. Specifically, when used in this context, the terms "about" and "approximately" suggest that the numerical value or range of values ​​may vary by 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% of the recited value or range of values. Additionally, the singular forms "a" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to a "compound" includes a plurality of such compounds, and a reference to an "assay" includes a reference to one or more assays and equivalents thereof known to those of ordinary skill in the art.

[0013] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment of a substituent. For example, -C(O)NH2 is attached through the carbon atom. Dashes before or after a chemical group are for convenience, and a chemical group may be drawn with or without one or more dashes without losing its ordinary meaning. A wavy line drawn through a line in a structure indicates a point of attachment of the group. Unless chemically or structurally required, no directionality is suggested or implied by the order in which chemical groups are written or named.

[0014] Prefix “C” u~v " indicates that the group that follows has u to v carbon atoms. It should be understood that u to v carbons includes u+1 to v, u+2 to v, u+3+v, etc. carbons, u+1 to u+3 to v, u+1 to u+4 to v, u+2 to u+4 to v, etc., covering all possible permutations of u and v.

[0015] "Alkyl" by itself or as part of another substituent means a saturated or unsaturated branched, straight-chain, or cyclic monovalent hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, e.g., propan-1-yl, propan-2-yl, etc., butyl, e.g., butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, etc., among others. In some embodiments, an alkyl group contains 1 to 20 carbon atoms (C1 to C2). 20 In other embodiments, the alkyl group contains 1 to 10 carbon atoms (C1 to C 10 In yet other embodiments, the alkyl group contains 1 to 6 carbon atoms (C1-C6 alkyl).

[0016] "Alkenyl," by itself or as part of another substituent, means an unsaturated branched, straight chain, or cyclic alkyl group having at least one carbon-carbon double bond derived by the removal of a hydrogen atom from a single carbon atom of a parent alkene. The group may be in either the cis or trans conformation about the double bond. Exemplary alkenyl groups include, but are not limited to, ethenyl, propenyl, e.g., prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl, cycloprop-2-en-1-yl, butenyl, e.g., but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, and the like. In some embodiments, the alkenyl group contains 1 to 20 carbon atoms (C 20 In another embodiment, the alkenyl group contains 1 to 10 carbon atoms (C10 alkenyl). In yet other embodiments, the alkenyl group contains 1 to 6 carbon atoms (C1-C6 alkenyl).

[0017] "Alkynyl" by itself or as part of another substituent means an unsaturated branched, straight chain, or cyclic alkyl group having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, e.g., prop-1-yn-1-yl, prop-2-yn-1-yl, etc., butynyl, e.g., but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc., among others. In some embodiments, an alkynyl group contains 1 to 20 carbon atoms (C1-C 20 In another embodiment, the alkynyl group contains 1 to 10 carbon atoms (C 10 In yet other embodiments, the alkynyl group contains 1-6 carbon atoms (C1-C6 alkynyl).

[0018] "Aryl" by itself or as part of another substituent means a monovalent aromatic hydrocarbon radical derived by removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system, as defined herein. Exemplary aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like. In some embodiments, an aryl group contains 6 to 20 carbon atoms (C6-C8). 20 In another embodiment, the aryl group contains 6 to 15 carbon atoms (C15 In yet other embodiments, the aryl group contains 6 to 10 carbon atoms (C 10 aryl).

[0019] "Arylalkyl" by itself or as part of another substituent means an alkyl group consisting of a carbon atom, typically a terminal or sp 3 It refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced by an aryl group as defined herein. Exemplary arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethene-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl, and the like. In some embodiments, an arylalkyl group is any of the groups (C6-C 30 ) arylalkyl, for example, the alkyl portion of the arylalkyl group is (C1-C 10 ) alkyl and the aryl portion is (C6-C 20 In another embodiment, the arylalkyl group is (C6-C 20 ) arylalkyl, for example, the alkyl portion of the arylalkyl group is (C1-C8) alkyl and the aryl portion is (C6-C 12 In yet other embodiments, the arylalkyl group is (C6-C 15 ) arylalkyl, for example, the alkyl portion of the arylalkyl group is (C1-C5) alkyl and the aryl portion is (C6-C 10 ) aryl.

[0020] "Arylalkenyl," by itself or as part of another substituent, means an acyclic alkenyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced with an aryl group, as defined herein. In some embodiments, an arylalkenyl group is an alkyl group selected from the group consisting of (C6-C 30 ) arylalkenyl, for example, the alkenyl portion of the arylalkenyl group is (C1-C 10) alkenyl, and the aryl portion is (C6-C 20 In another embodiment, the arylalkenyl group is (C6-C 20 )arylalkenyl, for example, the alkenyl portion of the arylalkenyl group is (C1-C8)alkenyl and the aryl portion is (C6-C 12 In yet other embodiments, the arylalkenyl group is (C6-C 15 For example, the alkenyl portion of the arylalkenyl group is (C1-C5) alkenyl and the aryl portion is (C6-C 10 ) aryl.

[0021] "Arylalkynyl," by itself or as part of another substituent, means an acyclic alkynyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced with an aryl group, as defined herein. In some embodiments, an arylalkynyl group is an aryl group selected from the group consisting of (C6-C 30 ) arylalkynyl, for example, the alkynyl portion of the arylalkynyl group is (C1-C 10 ) alkynyl and the aryl portion is (C6-C 20 In another embodiment, the arylalkynyl group is (C6-C 20 )arylalkynyl, for example, the alkynyl portion of the arylalkenyl group is (C1-C8)alkynyl and the aryl portion is (C6-C 12 In yet other embodiments, the arylalkynyl group is (C6-C 15 )arylalkynyl, for example, the alkynyl portion of the arylalkynyl group is (C1-C5)alkynyl and the aryl portion is (C6-C 10 ) aryl.

[0022] "Cycloalkyl" by itself or as part of another substituent means a saturated cyclic monovalent hydrocarbon radical derived by removal of one hydrogen atom from a single carbon atom of a parent cycloalkane. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, and the like. In some embodiments, cycloalkyl groups contain 3 to 20 carbon atoms (C1-C 15 In another embodiment, the cycloalkyl group contains 3 to 10 carbon atoms (C1 to C 10 In yet other embodiments, the cycloalkyl group contains 3 to 8 carbon atoms (C1-C8 cycloalkyl). The term "cyclic monovalent hydrocarbon group" also includes polycyclic hydrocarbon ring systems having a single radical and 3 to 12 carbon atoms. Exemplary polycyclic cycloalkyl rings include, for example, norbornyl, vinyl, and adamantyl.

[0023] "Cycloalkenyl" by itself or as part of another substituent means an unsaturated cyclic monovalent hydrocarbon radical derived by removal of one hydrogen atom from a single carbon atom of a parent cycloalkene. Exemplary cycloalkenyl groups include, but are not limited to, cyclopropene, cyclobutene, cyclopentene, and the like. In some embodiments, cycloalkenyl groups contain 3 to 20 carbon atoms (C1-C 20 In other embodiments, the cycloalkenyl group contains 3 to 10 carbon atoms (C 10 In yet other embodiments, the cycloalkenyl group contains 3 to 8 carbon atoms (C1-C8 cycloalkenyl). The term "cyclic monovalent hydrocarbon group" also includes polycyclic hydrocarbon ring systems having a single radical and 3 to 12 carbon atoms.

[0024] "Cycloheteroalkyl," by itself or as part of another substituent, means a cycloalkyl group, as defined herein, in which one or more of the carbon atoms (and optionally any associated hydrogen atoms) are each independently replaced with a heteroatom or heteroatom group that is the same or different as defined below for "heteroalkyl." In some embodiments, a cycloheteroalkyl group contains 3 to 20 carbon atoms and heteroatoms ( 1~20 In another embodiment, the cycloheteroalkyl group contains 3 to 10 carbon atoms and heteroatoms (cycloheteroalkyl). 1~10 In yet other embodiments, the cycloheteroalkyl group contains 3 to 8 carbon atoms and heteroatoms (cycloheteroalkyl). 1~8 The term "cyclic monovalent heteroalkyl group" also includes polycyclic heteroalkyl ring systems having a single radical and 3 to 12 carbon atoms and at least one heteroatom.

[0025] "Cycloheteroalkenyl," by itself or as part of another substituent, means a cycloalkenyl group, as defined herein, in which one or more of the carbon atoms (and optionally any associated hydrogen atoms) are each independently replaced with a heteroatom or heteroatom group that is the same or different as defined below under "heteroalkenyl." In some embodiments, a cycloheteroalkenyl group contains 3 to 20 carbon atoms and heteroatoms ( 1~20 In other embodiments, the cycloheteroalkenyl group contains 3 to 10 carbon atoms and heteroatoms ( 1~10) In yet other embodiments, the cycloheteroalkenyl group contains 3 to 8 carbon atoms and heteroatoms (e.g., cycloheteroalkenyl). 1~8 The term "cyclic monovalent heteroalkenyl group" also includes polycyclic heteroalkenyl ring systems having a single radical and 3 to 12 carbon atoms and at least one heteroatom.

[0026] "Compound" means a compound encompassed by the structural formulas disclosed herein, including any specific compound within the scope of the formulas whose structures are disclosed herein. A compound may be identified by either its chemical structure and / or chemical name. The chemical structure is determinative of the identity of a compound. Compounds described herein may contain one or more chiral centers and / or double bonds, and therefore may exist as stereoisomers, such as double bond isomers (i.e., geometric isomers), enantiomers, diastereomers, etc. Thus, chemical structures depicted herein encompass stereoisomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure forms) depicted in the structures. Chemical structures depicted herein also encompass enantiomeric and stereoisomeric derivatives of the depicted compounds. Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to those skilled in the art. Compounds may also exist in several tautomeric forms, including enol, keto, and mixtures thereof. Thus, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated compounds. The compounds described also include isotopically labeled compounds in which one or more atoms have an atomic mass different from the atomic mass conventionally found in nature. Examples of isotopes that may be incorporated into the compounds disclosed herein include, but are not limited to, 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 18 O. 17 O. Compounds can exist in unsolvated as well as solvated forms, including hydrated forms. In general, compounds can be hydrated or solvated. Certain compounds can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present disclosure. Furthermore, when a substructure of a compound is illustrated, it should be understood that the brackets indicate the point of attachment of the substructure to the remainder of the molecule.

[0027] "Halo" by itself or as part of another substituent means the groups -F, -Cl, -Br, or -I.

[0028] "Heteroalkyl" refers to an alkyl group in which one or more of the carbon atoms (and optionally any associated hydrogen atoms) are each independently replaced with the same or different heteroatoms or heteroatomic groups. Exemplary heteroatoms or heteroatomic groups that can replace a carbon atom include, but are not limited to, -O-, -S-, -N-, -Si-, -NH-, -S(O)-, -S(O)2-, -S(O)NH-, -S(O)2NH-, and the like, and combinations thereof. The heteroatoms or heteroatomic groups may be located at any of the interior positions of the alkyl, alkenyl, or alkynyl groups. Exemplary heteroatomic groups that may be included in these groups include, but are not limited to, -O-, -S-, -OO-, -SS-, -OS-, -NR 501 R 502 , =NN=, -N=N-, -N=N-NR 503 R 404 , -PR 505 -, -P(O)2-, -POR 506 -, -OP(O)2-, -SO-, -SO2-, -SnR 507 R 508 In this case, R 501 , R 502 , R 503 , R 504 , R 505 , R 506 , R 507 , and R 508 is independently hydrogen, alkyl, aryl, substituted aryl, heteroalkyl, heteroaryl, or substituted heteroaryl. In some embodiments, the heteroalkyl group contains 1 to 20 carbon atoms and heteroatoms ( 1~20 In other embodiments, the heteroalkyl group contains 1 to 10 carbon atoms and heteroatoms (heteroalkyl). 1~10 In yet other embodiments, the heteroalkyl group contains 1 to 6 carbon atoms and heteroatoms (heteroalkyl). 1~6Heteroalkyl).

[0029] "Heteroalkenyl" refers to an alkenyl group in which one or more of the carbon atoms (and optionally any associated hydrogen atoms) are each independently replaced with the same or different heteroatoms or heteroatomic groups. Exemplary heteroatoms or heteroatomic groups that can replace a carbon atom include, but are not limited to, -O-, -S-, -N-, -Si-, -NH-, -S(O)-, -S(O)2-, -S(O)NH-, -S(O)2NH-, and the like, and combinations thereof. The heteroatoms or heteroatomic groups may be located at any of the interior positions of the alkyl, alkenyl, or alkynyl groups. Exemplary heteroatomic groups that may be included in these groups include, but are not limited to, -O-, -S-, -OO-, -SS-, -OS-, -NR 501 R 502 , =NN=, -N=N-, -N=N-NR 503 R 404 , -PR 505 -, -P(O)2-, -POR 506 -, -OP(O)2-, -SO-, -SO2-, -SnR 507 R 508 In this case, R 501 , R 502 , R 503 , R 504 , R 505 , R 506 , R 507 , and R 508 is independently hydrogen, alkyl, aryl, substituted aryl, heteroalkyl, heteroaryl, or substituted heteroaryl. In some embodiments, heteroalkenyl groups contain 1 to 20 carbon atoms and heteroatoms (e.g., 1~20 In other embodiments, the heteroalkenyl group contains 1 to 10 carbon atoms and heteroatoms (e.g., 1~10 In yet other embodiments, the heteroalkenyl group contains 1 to 6 carbon atoms and heteroatoms (heteroalkenyl). 1~6 heteroalkenyl).

[0030] "Heteroaryl" by itself or as part of another substituent means a monovalent heteroaromatic group derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system, as defined herein. Exemplary heteroaryl groups include, but are not limited to, groups derived from acridine, β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like. In some embodiments, heteroaryl groups contain from 5 to 20 ring atoms (5-20 membered heteroaryl). In other embodiments, heteroaryl groups contain from 5 to 10 ring atoms (5-10 membered heteroaryl). Exemplary heteroaryl groups include those derived from furan, thiophene, pyrrole, benzothiophene, benzofuran, benzimidazole, indole, pyridine, pyrazole, quinoline, imidazole, oxazole, isoxazole, and pyrazine.

[0031] "Heteroarylalkyl" by itself or as part of another substituent means a heteroaryl group consisting of a carbon atom, typically a terminal or sp 3means an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced by a heteroaryl group. In some embodiments, the heteroarylalkyl group is a 6-21 membered heteroarylalkyl, e.g., the alkyl portion of the heteroarylalkyl is (C1-C6)alkyl and the heteroaryl portion is a 5-15 membered heteroaryl. In other embodiments, the heteroarylalkyl group is a 6-13 membered heteroarylalkyl, e.g., the alkyl portion is (C1-C3)alkyl and the heteroaryl portion is a 5-10 membered heteroaryl.

[0032] "Heteroarylalkenyl" by itself or as part of another substituent means an acyclic alkenyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced by a heteroaryl group. In some embodiments, a heteroarylalkenyl group is a 6-21 membered heteroarylalkyl, e.g., the alkenyl moiety of the heteroarylalkenyl is a (C1-C6)alkenyl and the heteroaryl moiety is a 5-15 membered heteroaryl. In other embodiments, a heteroarylalkenyl is a 6-13 membered heteroarylalkenyl, e.g., the alkenyl moiety is a (C1-C3)alkyl and the heteroaryl moiety is a 5-10 membered heteroaryl.

[0033] "Heteroarylalkynyl" by itself or as part of another substituent means an acyclic alkenyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced by a heteroaryl group. In some embodiments, a heteroarylalkynyl group is a 6-21 membered heteroarylalkyl, e.g., the alkynyl moiety of the heteroarylalkynyl is a (C1-C6)alkynyl and the heteroaryl moiety is a 5-15 membered heteroaryl. In other embodiments, a heteroarylalkynyl is a 6-13 membered heteroarylalkynyl, e.g., the alkynyl moiety is a (C1-C3)alkyl and the heteroaryl moiety is a 5-10 membered heteroaryl.

[0034] "Hydrate" refers to the incorporation of water into the crystal lattice of a compound described herein, resulting in the formation of an adduct in stoichiometric proportions. Methods for making hydrates include, but are not limited to, storage in an atmosphere containing water vapor, in a dosage form containing water, or routine pharmaceutical processing steps, such as crystallization (i.e., from water or mixed aqueous solvents), lyophilization, wet granulation, aqueous film coating, spray drying, and the like. Hydrates may also form from crystalline solvates upon exposure to water vapor or upon suspension of anhydrous materials in water under certain circumstances. Hydrates may also crystallize in more than one form, resulting in hydrate polymorphs. See, for example, (Guillory, K., Chapter 5, pp. 202-205 in Polymorphism in Pharmaceutical Solids, (Brittain, H. ed.), Marcel Dekker, Inc., New York, NY, 1999). The above methods for preparing hydrates are well within the scope of those skilled in the art, are completely conventional, and do not require any experimentation beyond the bounds of typical practice in the art. Hydrates may be characterized and / or analyzed by methods well known to those skilled in the art, such as single crystal X-ray diffraction, X-ray powder diffraction, polarized optical microscopy, thermal microscopy, thermogravimetry, differential thermal analysis, differential scanning calorimetry, IR spectroscopy, Raman spectroscopy, NMR spectroscopy, etc. (Brittain, H., Chapter 6, pp. 205-208 in Polymorphism in Pharmaceutical Solids, (Brittain, H. ed.), Marcel Dekker, Inc. New York, 1999). Additionally, many commercial companies routinely offer services that include the preparation and / or characterization of hydrates, such as, for example, HOLODIAG, Pharmaparc II, Voie de l'Innovation, 27100 Val de Reuil, France (http: / / www.holodiag.com).

[0035] "Parent Aromatic Ring System" means an unsaturated cyclic or polycyclic ring system having a conjugated p-electron system. Specifically included within the definition of "parent aromatic ring system" are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as fluorene, indane, indene, phenalene, etc. Exemplary parent aromatic ring systems include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like.

[0036] "Parent Heteroaromatic Ring System" means a parent aromatic ring system in which one or more carbon atoms (and optionally any associated hydrogen atoms) are each independently replaced with the same or different heteroatoms. Typical heteroatoms replacing carbon atoms include, but are not limited to, N, P, O, S, Si, etc. Specifically included within the definition of "parent heteroaromatic ring system" are fused ring systems in which one or more of the rings is aromatic and one or more of the rings is saturated or unsaturated, such as benzodioxanes, benzofurans, chromanes, chromenes, indoles, indolines, xanthenes, etc. Exemplary parent heteroaromatic ring systems include, but are not limited to, arsindole, carbazole, b-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like.

[0037] "Pharmaceutically acceptable salt" refers to a salt of a compound that possesses the desired pharmacological activity of the parent compound. Such salts include (1) salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with organic acids, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-hydroxy ... or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion, or when coordinated to an organic base, e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and the like.

[0038] "Preventing" or "prevention" refers to reducing the risk of suffering from a disease or disorder (i.e., preventing at least one clinical symptom of a disease from developing in a patient who may be exposed to or predisposed to the disease, but who has not yet experienced or developed symptoms of the disease). The application of a therapeutic agent to prevent or for the prevention of a disease or disorder is known as "prophylaxis." In some embodiments, the compounds provided herein provide superior prophylaxis due to fewer long-term side effects over the long term.

[0039] As used herein, "prodrug" refers to a derivative of a drug molecule that requires a transformation within the body to release the active drug. Prodrugs are often, though not necessarily, pharmacologically inactive until converted to the parent drug.

[0040] As used herein, "promoiety" refers to a form of protecting group that, when used to mask a functional group within a drug molecule, converts the drug into a prodrug. Typically, a promoiety will be attached to the drug via a bond that is cleaved in vivo by enzymatic or non-enzymatic means.

[0041] "Protecting group" means a group of atoms that, when attached to a reactive functional group in a molecule, masks, reduces, or prevents the reactivity of the functional group during chemical synthesis. Examples of protecting groups are described in Green et al., "Protective Groups in Organic Chemistry", (Wiley, 2003). nd ed. 1991) and Harrison et al., "Compendium of Synthetic Organic Methods", Vols. 1-8 (John Wiley and Sons, 1971-1996). Representative amino-protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("SES"), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC), nitro-veratryloxycarbonyl ("NVOC"), and the like. Representative hydroxy protecting groups include, but are not limited to, those in which the hydroxy group is either acylated or alkylated, such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers, and allyl ethers.

[0042] "Solvate" refers to the incorporation of a solvent into the crystal lattice of a compound described herein, resulting in the formation of an adduct in stoichiometric proportions. Methods for making solvates include, but are not limited to, storage in a solvent-containing atmosphere, in a dosage form containing the solvent, or by routine pharmaceutical processing steps, such as crystallization (i.e., from a solvent or mixture of solvents) vapor diffusion, and the like. Solvates may also form from other crystalline solvates or hydrates under certain circumstances upon exposure to a solvent or by suspending material in a solvent. Solvates may also crystallize in more than one form, resulting in solvate polymorphs. See, for example, (Guillory, K., Chapter 5, pp. 202-205 in Polymorphism in Pharmaceutical Solids, (Brittain, H. ed.), Marcel Dekker, Inc., New York, NY, 1999). The above methods for preparing solvates are well within the scope of the art, are completely conventional, and do not require any experimentation beyond the bounds of typical practice in the art. Solvates can be characterized and / or analyzed by methods well known to those skilled in the art, such as single crystal X-ray diffraction, X-ray powder diffraction, polarized optical microscopy, thermal microscopy, thermogravimetry, differential thermal analysis, differential scanning calorimetry, IR spectroscopy, Raman spectroscopy, NMR spectroscopy, and the like. (Brittain, H., Chapter 6, pp. 205-208 in Polymorphism in Pharmaceutical Solids, (Brittain, H. ed.), Marcel Dekker, Inc. New York, 1999). In addition, many commercial companies routinely offer services that include the preparation and / or characterization of solvates, such as, for example, HOLODIAG, Pharmaparc II, Voie de l'Innovation, 27100 Val de Reuil, France (http: / / www.holodiag.com).

[0043] "Substituted," when used to modify a specifically named group or radical, means that one or more of the hydrogen atoms of the specifically named group are each independently replaced with the same or different substituents. Substituents useful for replacing saturated carbon atoms of the specifically named group include R a , halo, -O-, =O, -OR b , -SR b , -S-, =S, -NR c R c , =NR b , =N-OR b , trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -N-OR b , -N-NR c R c , -NR b S(O)2R b , =N2, -N3, -S(O)2R, -S(O)2NR b R b , -S(O)2O-, -S(O)2OR b , -OS(O)2R b , -OS(O)2O-, -OS(O)2OR b , -OS(O)2NR c NR c , -P(O)(O-)2, -P(O)(OR b )(O-), -P(O)(OR b )(OR b ), -C(O)R b , -C(O)NR b -OR b -C(S)R b , -C(NR b )R b , -C(O)O-, -C(O)OR b , -C(S)OR b , -C(O)NR c R c , -C(NR b )NR c R c , -OC(O)R b , -OC(S)R b , -OC(O)O-, -OC(O)OR b , -OC(O)NR c R c, -OC(NCN)NR c R c -OC(S)OR b , -NR b C(O)R b , -NR b C(S)R b , -NR b C(O)O-, -NR b C(O)OR b , -NR b C(NCN)OR b , -NR b S(O)2NR c R c , -NR b C(S)OR b , -NR b C(O)NR c R c , -NR b C(S)NR c R c , -NR b C(S)NR b C(O)R a , -NR b S(O)2OR b , -NR b S(O)2R b , -NR b C(NCN)NR c R c , -NR b C(NR b )R b , and -NR b C(NR b )NR c R c (In the formula, each R a is independently aryl, substituted aryl, heteroalkyl, substituted heteroalkyl, heteroaryl, or substituted heteroaryl; each R b is independently hydrogen, alkyl, heteroalkyl, substituted heteroalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, or substituted heteroarylalkyl, and each R c are independently b or alternatively two R cmay be taken together with the nitrogen atom to which they are attached to form a 4-, 5-, 6-, or 7-membered cycloheteroalkyl, substituted cycloheteroalkyl, or aryl-fused cycloheteroalkyl, which may optionally contain 1 to 4 identical or different additional heteroatoms selected from the group consisting of O, N, and S. Specific examples include -NR c R c is intended to include -NH, -NH-alkyl, N-pyrrolidinyl, and N-morpholinyl. In other embodiments, substituents useful for substituting the saturated carbon atom of the specifically named groups include R a , Halo, -OR b , -NR c R c , trihalomethyl, -CN, -NR b S(O)2R b , -C(O)R b , -C(O)NR b -OR b , -C(O)OR b , -C(O)NR c R c , -OC(O)R b , -OC(O)OR b , -OS(O)2NR c NR c , -OC(O)NR c R c , and -NR b C(O)OR b (In the formula, each R a is independently alkyl, aryl, or heteroaryl; b are independently hydrogen, R a , heteroalkyl, arylalkyl, or heteroarylalkyl, and each R c are independently b or alternatively two R c together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered cycloheteroalkyl ring.

[0044] Substituents useful for replacing the unsaturated carbon atoms of the specifically depicted groups include -R a , halo, -O-, -OR b , -SRb 、-S-、-NR c R c 、トリハロメチル、-CF3、-CN、-OCN、-SCN、-NO、-NO2、-N3、-S(O)2O-、-S(O)2OR b 、-OS(O)2R b 、-OS(O)2OR b 、-OS(O)2O-、-P(O)(O-)2、-P(O)(OR b )(O-)、-P(O)(OR b )(OR b )、-C(O)R b 、-C(S)R b 、-C(NR b )R b 、-C(O)O-、-C(O)OR b 、-C(S)OR b 、-C(O)NR c R c 、-C(NR b )NR c R c 、-OC(O)R b 、-OC(S)R b 、-OC(O)O-、-OC(O)OR b 、-OC(S)OR b 、-OC(O)NR c R c 、-OS(O)2NR c NR c 、-NR b C(O)R b 、-NR b C(S)R b 、-NR b C(O)O-、-NR b C(O)OR b 、-NR b S(O)2OR a 、-NR b S(O)2R a 、-NR b C(S)OR b 、-NR b C(O)NR c R c 、-NR b C(NR b )R b -NR b C(NR b )NRc R c , and -C(NR b )NR b C(NR b )NR c R c (In the formula, R a , R b , and R c In other embodiments, substituents useful for replacing the unsaturated carbon atom of the specifically named groups include -R a , Halo, -OR b , -SR b , -NR c R c , trihalomethyl, -CN, -S(O)2OR b , -C(O)R b , -C(O)OR b , -C(O)NR c R c , -OC(O)R b , -OC(O)OR b , -OS(O)2NR c NR c , -NR b C(O)R b , and -NR b C(O)OR b (In the formula, R a , R b , and R c are as defined above).

[0045] Useful substituents for substituting nitrogen atoms on heteroalkyl and cycloheteroalkyl groups include, but are not limited to, -R a , -O-, -OR b , -SR b , -S-, -NR c R c , trihalomethyl, -CF3, -CN, -NO, -NO2, -S(O)2R, -S(O)2O-, -S(O)2OR b , -OS(O)2R b , -OS(O)2O-, -OS(O)2OR b , -P(O)(O-)2, -P(O)(OR b )(O-), -P(O)(OR b)(OR b ), -C(O)R b , -C(S)R b , -C(NR b )R b , -C(O)OR b , -C(S)OR b , -C(O)NR c R c , -C(NR b )NR c R c , -OC(O)R b , -OC(S)R b , -OC(O)OR b , -OC(S)OR b , -NR b C(O)R b , -NR b C(S)R b , -NR b C(O)OR b , -NR b C(S)OR b , -NR b C(O)NR c R c , -NR b C(NR b )R b -NR b C(NR b )NR c R c , and -C(NR b )NR b C(NR b )NR c R c (In the formula, R a , R b , and R c In some embodiments, useful substituents for substituting the nitrogen atom of heteroalkyl and cycloheteroalkyl groups include R a , Halo, -OR b , -NR c R c , trihalomethyl, -CN, -S(O)2OR b , -OS(O)2R b , -OS(O)2OR b , -C(O)R b , -C(NR b)R b , -C(O)OR b , -C(O)NR c R c , -OC(O)R b , -OC(O)OR b , -OS(O)2NR c NR c , -NR b C(O)R b and -NR b C(O)OR b (In the formula, R a , R b , and R c are as defined above).

[0046] Substituents from the above list that are useful for replacing other specifically named groups or atoms will be apparent to those of skill in the art.

[0047] The substituents used to substitute the specifically named groups can typically be further substituted with one or more of the same or different groups selected from the various groups specifically named above.

[0048] The terms "subject," "individual," or "patient" are used interchangeably herein to refer to a vertebrate, preferably a mammal, including, but not limited to, mice, rodents, simians, humans, farm animals, sport animals, and pets.

[0049] "Treating" or "treatment" of any disease or disorder, in some embodiments, means reversing the disease or disorder (i.e., arresting or reducing the onset of the disease or at least one of its clinical symptoms). Treatment may also be considered to include preemptive or prophylactic administration to reverse, arrest, or prevent the onset of the disease or at least one of its clinical symptoms. As an additional feature, the proposed treatments are less likely to have long-term side effects over the years. In other embodiments, "treating" or "treatment" means reversing at least one physical parameter that may not be discerned by the patient. In yet other embodiments, "treating" or "treatment" means inhibiting the disease or disorder either physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or both. In yet other embodiments, "treating" or "treatment" means delaying the onset of the disease or disorder.

[0050] "Therapeutically effective amount" means the amount of a compound that, when administered to a patient for treating a disease, is sufficient to treat the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, absorption, distribution, metabolism, excretion, etc., of the patient being treated.

[0051] "Vehicle" means a diluent, excipient, or carrier used in administration of a compound to a subject. In some embodiments, the vehicle is pharma- ceutically acceptable.

[0052] compound As used herein, compounds of structural formula (I): [ka] wherein each R is independently a thiol residue of less than 1000 daltons molecular weight; Y is -NR2R3; X is -OR4 or -SR1; R2 and R3 are independently -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl; or R2 and R3 together with the atom to which they are attached form a cycloalkyl ring, a substituted cycloalkyl ring, a cycloalkenyl ring, a substituted cycloalkenyl ring, a substituted cycloalkenyl ring R4 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, or substituted heteroarylalkyl, provided that R2 and R3 are not both -H, and one of R2 and R3 is -H, unless R2 and R3, together with the atom to which they are attached, form a cycloalkyl ring, substituted cycloalkyl ring, cycloalkenyl ring, substituted cycloalkenyl ring, heterocycloalkyl ring, substituted heterocycloalkyl ring, heterocycloalkenyl ring, or substituted heterocycloalkenyl ring. or a pharma- ceutically acceptable salt, hydrate, or solvate thereof is provided.

[0053] In some embodiments, each R1 is independently a thiol residue of molecular weight less than 500 daltons. [ka] and R 101 ~R 103 , R 106 , R 109 , R 116 ~ 118 is independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, and R 104 , R 105 , R 107 , R 108 , R 110 ~R 115 , and R 119 ~R 129 is independently -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl. 101 ~R 103 , R 106 , R 109 , R 116 ~ 118 is independently alkyl or alkenyl. In yet other embodiments, R 104 , R 105 , R 107 , R 108 , R 110 ~R 115 , and R 119 ~R 129 is independently -H, alkyl, or alkenyl.

[0054] In some embodiments, R1 is substituted alkyl, substituted alkenyl, substituted alkynyl, substituted heteroalkyl, substituted heteroalkenyl, substituted heteroalkynyl, substituted aryl, or substituted heteroaryl. In other embodiments, R1 is alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, -NH2, or NHC(O)R 130 Substituted heteroaryl (wherein R 130 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl). 130 is alkyl or alkenyl.

[0055] In some embodiments, R2 and R3 are independently -H, substituted alkyl, substituted alkenyl, substituted aryl alkyl, substituted aryl alkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, substituted heteroaryl alkyl, or substituted heteroaryl alkenyl. In other embodiments, R2 and R3 are independently -H, substituted alkyl, substituted alkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, or substituted heteroalkenyl. In yet other embodiments, R2 and R3 are independently -H, substituted alkyl, substituted alkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, or substituted heteroalkenyl.

[0056] In some embodiments, R2 and R3 are independently -H or -CHR5CO2R6, where R5 is -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroaryl, or substituted heteroaryl, and R6 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, or substituted cycloheteroalkenyl. In other embodiments, R2 and R3 are independently -H or -CHR5CO2R6, where R5 is -H, alkyl, substituted alkyl, alkenyl, or substituted alkenyl, and R6 is alkyl, alkenyl, or arylalkenyl. In still other embodiments, R2 and R3 are independently -H or -CHR5CO2R6, where R5 is -H, alkyl, substituted alkyl, alkenyl, or substituted alkenyl, and R6 is alkyl, alkenyl, or arylalkenyl. [ka] In yet other embodiments, one of R2 and R3 is -H and the other of R2 and R3 is [ka] It is.

[0057] In some embodiments, R4 is alkyl, alkenyl, cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, or substituted heteroarylalkyl. In other embodiments, R4 is alkyl, alkenyl, aryl, or substituted aryl.

[0058] In some embodiments, the structural formula: [ka] and pharma-ceutically acceptable salts, hydrates, or solvates thereof. In another embodiment, the pharma-ceutically acceptable salt is a trifluoroacetate salt.

[0059] In some embodiments, the structural formula: [ka] and pharma-ceutically acceptable salts, hydrates, or solvates thereof. In another embodiment, the pharma-ceutically acceptable salt is a trifluoroacetate salt.

[0060] In some embodiments, the structural formula: [ka] and pharma- ceutically acceptable salts, hydrates, or solvates thereof. In other embodiments, the pharma- ceutically acceptable salt is a trifluoroacetate salt. In yet other embodiments, the pharma- ceutically acceptable salt is a fumarate salt.

[0061] In some embodiments, the structural formula: [ka] and pharma- ceutically acceptable salts, hydrates, or solvates thereof. In other embodiments, the pharma- ceutically acceptable salt is a trifluoroacetate salt. In yet other embodiments, the pharma- ceutically acceptable salt is a fumarate salt.

[0062] In some embodiments, the structural formula: [ka] and pharma- ceutically acceptable salts, hydrates, or solvates thereof. In other embodiments, the pharma- ceutically acceptable salt is a trifluoroacetate salt. In yet other embodiments, the pharma- ceutically acceptable salt is a fumarate salt.

[0063] Compounds of structural formula (I) are illustrated below in Table 1. It should be understood that when the compounds illustrated in Table 1 contain a free amine, the depicted structure can optionally include a trifluoroacetate salt of the amine in place of the amine. [Table 1] TIFF2025501308000012.tif224170TIFF2025501308000013.tif229170TIFF2025501308000014.tif194170TIFF2025501308000015.tif107170

[0064] In some embodiments, the compound of formula (I) is [ka] TIFF2025501308000017.tif229170TIFF2025501308000018.tif229170TIFF2025501308000019.tif224170.

[0065] Compositions and Methods of Administration The compositions provided herein contain a therapeutically effective amount of one or more compounds provided herein and a medium useful for preventing, treating, or ameliorating one or more symptoms of a disease or disorder described herein. Medium suitable for administering the compounds provided herein includes any such carrier known to those skilled in the art suitable for the particular mode of administration. In addition, the compounds may be formulated as the only active ingredient in the composition or may be combined with other active ingredients.

[0066] The composition contains one or more compounds provided herein. In some embodiments, the compound is formulated into suitable preparations such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations, elixirs, etc. for oral administration, or sterile solutions or suspensions for parenteral administration, as well as topical administration, transdermal administration, and oral inhalation via nebulizers, pressurized metered dose inhalers, and dry powder inhalers. In some embodiments, the compounds described above are formulated into compositions using techniques and procedures well known in the art (see, for example, Ansel, Introduction to Pharmaceutical Dosage Forms, Seventh Edition (1999)).

[0067] In the composition, an effective concentration of one or more compounds or derivatives thereof is mixed with a suitable medium. The compound may be derivatized as the corresponding salt, ester, enol ether or ester, acetal, ketal, orthoester, hemiacetal, hemiketal, acid, base, solvate, ion pair, hydrate, or prodrug prior to formulation as described above. The concentration of the compound in the composition is effective to deliver an amount that, upon administration, treats the disease or disorder described herein and prevents or reverses one or more of its symptoms. In some embodiments, the composition is formulated for single dose administration. To formulate the composition, a weight fraction of the compound is dissolved, suspended, dispersed, or otherwise mixed in a selected medium at an effective concentration to reduce, prevent, or reverse one or more of the symptoms of the treated condition.

[0068] The active compound is included in the medium in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects on the treated patient. The therapeutically effective concentration can be empirically predicted by testing the compound in in vitro and in vivo systems well known to those skilled in the art, and then extrapolated therefrom in terms of the dosage to be administered to humans. The human dosage is then typically fine-tuned in clinical trials, titrated up or down to effect.

[0069] The concentration of the active compound in the composition will depend on the absorption, inactivation, and excretion rates of the active compound, the physicochemical properties of the compound, the administration schedule, and the dosage, as well as other factors known to those of skill in the art, such as, for example, the amount delivered will be sufficient to ameliorate one or more of the symptoms of the diseases or disorders described herein.

[0070] In cases where a compound exhibits insufficient solubility, methods of solubilizing the compound may be used, such as the use of liposomes, prodrugs, complexation / chelation, nanoparticles, or emulsions or tertiary templating. Such methods are known to those skilled in the art and include, but are not limited to, the use of cosolvents such as dimethylsulfoxide (DMSO), surfactants or surface modifiers such as TWEEN®, complexing agents such as cyclodextrins, or dissolution by ionization enhancement (i.e., dissolution in aqueous sodium bicarbonate). Derivatives of the compound, such as prodrugs of the compound, may also be used to formulate the active composition.

[0071] Upon addition or mixing of a compound, the resulting mixture may be a solution, suspension, emulsion, etc. The form of the resulting mixture depends on several factors, including the intended mode of administration and the solubility of the compound in the selected medium. The effective concentration is sufficient for ameliorating the symptoms of the disease, disorder, or condition being treated and may be empirically determined.

[0072] The compositions are provided for administration to humans and animals in dosage forms appropriate for the indication, such as dry powder inhalers (DPIs), pressurized metered dose inhalers (pMDIs), nebulizers, tablets, capsules, pills, sublingual tapes / bioerodible strips, tablets or capsules, powders, granules, lozenges, lotions, salves, suppositories, fast melts, transdermal patches or other transdermal application devices / preparations, sterile parenteral solutions or suspensions, and oral solutions or suspensions, as well as oil-water emulsions, containing a suitable amount of the compound or its derivatives. The therapeutically active compounds and their derivatives are in some embodiments formulated and administered in unit dosage forms or multiple dosage forms. Unit dosage form, as used herein, refers to physically discrete units packaged individually suitable for human and animal subjects as known in the art. Each unit dose contains a predetermined amount of the therapeutically active compound sufficient to produce the desired therapeutic effect in combination with the required medium. Examples of unit dosage forms include ampoules and syringes, and individually packaged tablets or capsules. A unit dosage form can be administered in any fraction or multiple thereof. A multiple dosage form is a plurality of equivalent unit dosage forms packaged in a single container to be administered in separate unit dosage forms. Examples of multiple dosage forms include vials, bottles of tablets or capsules, or bottles of pints or gallons. Thus, a multiple dosage form is a plurality of unit doses that are not segregated during packaging.

[0073] Liquid compositions are prepared, for example, by dissolving, dispersing or otherwise mixing the active compound defined above and any adjuvants in a medium, such as water, saline, aqueous dextrose, glycerol, glycol, ethanol, etc., thereby forming a solution or suspension, colloidal dispersion, emulsion, or liposomal preparation. If desired, the composition to be administered may also contain minor amounts of non-toxic auxiliary substances, such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents, and the like, for example, acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and other such agents.

[0074] Actual methods for preparing such dosage forms are known or will be apparent to those skilled in the art, see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15th Edition, 1975, or subsequent editions.

[0075] Dosage forms or compositions may be prepared that contain the active ingredient in the range of 0.005% to 100%, with the remainder being made up of a medium or carrier. Methods for preparing such compositions are known to those skilled in the art. Contemplated compositions may contain the active ingredient in the range of 0.001% to 100%, in one embodiment 0.1 to 95%, and in another embodiment 0.4 to 10%.

[0076] In certain embodiments, the composition is a lactose-free composition that contains excipients known in the art, for example, those listed in the United States Pharmacopoeia (USP) 25-NF20 (2002). In general, lactose-free compositions contain active ingredients, binders / fillers, and lubricants in suitable amounts. A particular lactose-free dosage form contains active ingredients, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

[0077] In addition, anhydrous compositions and dosage forms containing active ingredients are provided, since water can accelerate the decomposition of some compounds. For example, the addition of water (e.g., 5%) is widely accepted as a means of simulating long-term storage to determine properties such as the shelf life and stability over time of formulations. See, for example, Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. In effect, water and heat accelerate the decomposition of some compounds. Thus, the effect of water on formulations can be quite significant, since moisture and / or humidity are commonly encountered during the manufacture, handling, packaging, storage, transportation, and use of formulations.

[0078] Anhydrous compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.

[0079] Anhydrous compositions should be prepared and stored such that their anhydrous nature is maintained.Thus, anhydrous compositions are generally packaged using materials known to prevent exposure to water so that they can be included in suitable formulary kits.Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

[0080] Oral dosage forms can be either solid, gel, or liquid. Solid dosage forms are tablets, capsules, granules, and bulk powders. Types of oral tablets include compressed chewable lozenges and tablets that can be enteric coated, sugar coated, or film coated. Capsules can be hard or soft gelatin capsules, and granules and powders can be provided in non-effervescent or effervescent forms with other ingredients known to those skilled in the art.

[0081] In certain embodiments, the formulation is a solid dosage form, such as a capsule or tablet. Tablets, pills, capsules, lozenges, etc. can contain one or more of the following ingredients: binders, lubricants, diluents, flow agents, disintegrants, colorants, sweeteners, flavorings, wetting agents, enteric coatings, film coatings, and modified release agents, or compounds of similar nature. Examples of binders include microcrystalline cellulose, methylparaben, polyalkylene oxides, tragacanth gum, glucose solution, acacia mucilage, gelatin solution, molasses, polyvinylpyrrolidine, povidone, crospovidone, sucrose, and starch and starch derivatives. Lubricants include talc, starch, magnesium / calcium stearate, lycopersicon gracilis, and stearic acid. Diluents include, for example, lactose, sucrose, trehalose, lysine, leucine, lecithin, starch, kaolin, salt, mannitol, and dicalcium phosphate. Flow agents include, but are not limited to, colloidal silicon dioxide. Disintegrants include, for example, croscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar, and carboxymethylcellulose. Coloring agents include, for example, approved certified water-soluble FD and C dyes, mixtures thereof, and water-insoluble FD and C dyes suspended on alumina hydrate, as well as any of the advanced coloring or anti-counterfeiting color / opalescent additives known to those skilled in the art. Sweetening agents include, for example, sucrose, lactose, mannitol, and artificial sweetening agents, such as saccharin and any number of spray-dried flavoring agents. Flavoring agents include natural flavors extracted from plants such as fruits and synthetic blends of compounds that produce a pleasant taste or mask unpleasant tastes, such as, but not limited to, peppermint and methyl salicylate.Humectants include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether.Enteric coating agents include fatty acids, fats, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Film coating agents include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Modified release agents include polymers such as the Eudragit® series and cellulose esters.

[0082] The compound or its derivatives can be provided in a composition that protects it from the acidic environment of the stomach. For example, the composition can be formulated with an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition can also be formulated in combination with an antacid or other such ingredient.

[0083] When the dosage unit form is a capsule, it can contain, in addition to the above types of materials, a liquid carrier such as fatty oil. In addition, the dosage unit form can contain various other materials that modify the physical dosage unit form, such as sugar coatings and other enteric agents. The compound can also be administered as a component of an elixir, suspension, syrup, wafer, sprinkle, chewing gum, or the like. The syrup can contain, in addition to the active compound, sucrose as a sweetener, as well as certain preservatives, dyes and colorings, and flavorings.

[0084] The active materials can also be mixed with other active materials which do not impair the desired action, or with materials which supplement the desired action, such as antacids, H2 blockers, and diuretics. The active ingredient is a compound described herein or a derivative thereof. Higher concentrations, up to about 98% by weight of the active ingredient, can be included.

[0085] In all embodiments, the tablet and capsule formulations may be coated as known to those skilled in the art to modify or sustain dissolution of the active ingredient, for example, they may be coated with conventional enteric digestible coatings such as phenyl salicylate, waxes, cellulose acetate phthalate, and the like.

[0086] Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules. Aqueous solutions include, for example, elixirs and syrups. Emulsions are either oil-in-water or water-in-oil.

[0087] Elixirs are clear sweetened hydroalcoholic preparations. The vehicle used in elixirs includes a solvent. Syrups are concentrated aqueous solutions of a sugar, such as sucrose, and may contain a preservative. Emulsions are two-phase systems in which one liquid is dispersed in the form of small globules throughout another liquid. The carriers used in emulsions are non-aqueous liquids, emulsifying agents, and preservatives. In suspensions, suspending agents and preservatives are used. Acceptable substances used in non-effervescent granules to be reconstituted into a liquid oral dosage form include diluents, sweeteners, and wetting agents. Acceptable substances used in effervescent granules to be reconstituted into a liquid oral dosage form include organic acids and a carbon dioxide source. Coloring and flavoring agents are used in all of the above dosage forms.

[0088] Solvents include glycerin, sorbitol, ethyl alcohol, and syrup. Examples of preservatives include glycerin, methyl and propyl parabens, benzoic acid, sodium benzoate, and alcohol. Examples of non-aqueous liquids utilized in emulsions include mineral oil and Mentha oil. Examples of emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate. Suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum, and acacia. Sweetening agents include sucrose, syrup, glycerin, and artificial sweetening agents such as saccharin. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Organic acids include citric acid and tartaric acid. Carbon dioxide sources include sodium bicarbonate and sodium carbonate. Coloring agents include any of the approved certified water soluble FD and C dyes, and mixtures thereof. Flavoring agents include natural flavors extracted from plants, such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation.

[0089] For solid dosage forms, solutions or suspensions, for example in propylene carbonate, vegetable oils, or triglycerides, are in some embodiments encapsulated in a gelatin capsule. Such solutions and their preparation and encapsulation are disclosed in U.S. Patent Nos. 4,328,245, 4,409,239, and 4,410,545. For liquid dosage forms, the solutions, for example in polyethylene glycol, may be diluted with a liquid medium, for example, a sufficient quantity of water, to be easily measured for administration.

[0090] Alternatively, liquid or semi-solid oral formulations can be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g., propylene carbonate), and other such carriers and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells. Other useful formulations include those shown in U.S. Reissue Patent No. 28,819 and U.S. Patent No. 4,358,603. Briefly, such formulations include, but are not limited to, those containing a compound provided herein, a dialkylated mono- or polyalkylene glycol (including, but not limited to, 1,2-dimethoxyethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, where 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol), and one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates.

[0091] Other formulations include, but are not limited to, aqueous alcoholic solutions containing acetals. The alcohols used in this formulation are any water-miscible solvents having one or more hydroxyl groups, including, but not limited to, propylene glycol and ethanol. Acetals include, but are not limited to, di(lower alkyl) acetals of lower alkyl aldehydes, such as acetaldehyde diethyl acetal.

[0092] In some embodiments, parenteral administration, characterized by injection either subcutaneously, intramuscularly, or intravenously, is also contemplated herein. Injectables can be prepared in conventional manner, either as liquid solutions or suspensions in solid form suitable for dissolving or suspending in liquid prior to injection, or as emulsions. Injectable solutions and emulsions also contain one or more excipients. Suitable excipients are, for example, water, saline, dextrose, glycerol, or ethanol. In addition, if desired, the administered composition may also contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffers, stabilizers, solubility enhancers, and other such agents, such as sodium acetate, sorbitan monolaurate, triethanolamine oleate, cyclodextrins, and the like.

[0093] Implantation of a slow release or sustained release system (see, e.g., U.S. Pat. No. 3,710,795), such that a constant level of dosage is maintained, is also contemplated herein. Briefly, the compounds provided herein are administered through a membrane that is insoluble in body fluids and is coated with an outer polymeric membrane, such as polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl acetate, vinylidene chloride, vinyl chloride copolymers with ethylene and propylene, ionomeric polyethylene terephthalate, butyl rubber, or the like. The solid inner matrix is ​​dispersed in a matrix of epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol copolymer, such as polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, hydrophilic polymers such as hydrogels of acrylic and methacrylic acid esters, collagen, crosslinked polyvinyl alcohol, and crosslinked partially hydrolyzed polyvinyl acetate. The compound diffuses through the outer polymeric membrane in a release rate controlling step. The percentage of active compound contained in such parenteral compositions is highly dependent on the specific nature of the composition as well as the activity of the compound and the needs of the subject.

[0094] Parenteral administration of the composition includes intravenous, subcutaneous, and intramuscular administration. Preparations for parenteral administration include sterile ready-to-inject solutions, sterile dry solubles, such as lyophilized powders (including tablets for subcutaneous injection) that can be combined with a solvent immediately before use, sterile ready-to-inject suspensions, sterile dry insolubles that can be combined with a medium immediately before use, and sterile emulsions. Solutions can be either aqueous or non-aqueous.

[0095] For intravenous administration, suitable carriers include saline or phosphate buffered saline (PBS), as well as solutions containing thickening or solubilizing agents, such as glucose, polyethylene glycol, polypropylene glycol, or mixtures thereof.

[0096] Vehicles used in parenteral preparations include aqueous vehicles, non-aqueous vehicles, antimicrobial agents, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents, and other substances.

[0097] Examples of aqueous media include sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringer's injection. Non-aqueous parenteral media include fixed oils of vegetable origin, Mentha oil, corn oil, sesame oil, and peanut oil. Parenteral preparations packaged in multi-dose containers must be supplemented with bacteriostatic or fungistatic concentrations of antimicrobial agents, including phenol or cresol, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride, and benzethonium chloride. Isotonicity agents include sodium chloride and dextrose. Buffers include phosphates and citrates. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Emulsifying agents include polysorbate 80 (Tween® 80). Sequestering or chelating agents for metal ions include EDTA. Carriers also include ethyl alcohol, polyethylene glycol, and propylene glycol for water-miscible vehicles, and sodium hydroxide, hydrochloric acid, citric acid, or lactic acid for pH adjustment.

[0098] The concentration of the compound is adjusted so that the injection provides an effective amount to produce the desired pharmacological effect. The exact dose depends on the age, weight, body surface area, and condition of the patient or animal, as is known in the art.

[0099] Unit dose parenteral preparations are packaged in an ampule, vial, or a syringe with a needle. All preparations for parenteral administration must be sterile, as is known and practiced in the art.

[0100] Illustratively, intravenous or intraarterial infusion of a sterile aqueous solution containing an active compound is an effective mode of administration. Another embodiment is a sterile aqueous or oily solution or suspension containing an active material injected as necessary to produce the desired pharmacological effect.

[0101] Injectables are designed for local and systemic administration. In some embodiments, a therapeutically effective dose is formulated to contain a concentration of at least about 0.01% w / w to about 90% w / w or more of the active compound relative to the treated tissue, and in certain embodiments, greater than 0.1% w / w.

[0102] The compound may be suspended in micronized or other suitable form, or may be derivatized to produce a more soluble active or to produce a prodrug. The form of the resulting mixture depends on several factors, including the intended mode of administration and the solubility of the compound in the selected carrier or medium. The effective concentration is sufficient to ameliorate the symptoms of the pathology and may be empirically determined.

[0103] The active ingredients provided herein can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, U.S. Pat. Nos. 3,845,770, 3,916,899, 3,536,809, 3,598,123, 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, 5,639,480, 5,733,566, 5,739,108, 5,891,474, 5, Examples of suitable fluoropolymers include those described in US Pat. Nos. 922,356, 5,972,891, 5,980,945, 5,993,855, 6,045,830, 6,087,324, 6,113,943, 6,197,350, 6,248,363, 6,264,970, 6,267,981, 6,376,461, 6,419,961, 6,589,548, 6,613,358, 6,699,500, and 6,740,634. Such dosage forms can be used to provide slow or controlled release of one or more active ingredients using, for example, hydroxypropylmethylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof to provide the desired release profile at various rates. Suitable controlled release formulations known to those of skill in the art can be readily selected for use with the active ingredients provided herein, including those described herein.

[0104] All controlled release products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled release preparation in a medical treatment is characterized by utilizing a minimum amount of drug substance to cure or control a pathology in a minimum amount of time. Advantages of controlled release formulations include extended drug activity, reduced dosing frequency, and increased patient compliance. Additionally, controlled release formulations can be used to affect the time of onset of action or other characteristics, such as blood drug levels, and thus the occurrence of side effects (e.g., adverse effects).

[0105] Most controlled release formulations are designed to initially release an amount of drug (active ingredient) that rapidly produces the desired therapeutic effect, and then slowly and intermittently release other amounts of drug to maintain this level of therapeutic or prophylactic effect over time. To maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled release of the active ingredient can be stimulated by various conditions, including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions, or compounds.

[0106] In certain embodiments, the agent may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration. In some embodiments, a pump may be used (see Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)). In other embodiments, polymeric materials may be used. In other embodiments, the controlled release system may be placed in close proximity to the therapeutic target, i.e., thus requiring only a fraction of the systemic dose (see, e.g., Goodson, Medical Applications of Controlled Release, vol. 2, pp. 115-138 (1984)). In some embodiments, the controlled release device is introduced into the subject in close proximity to a site of inappropriate immune activation or tumor. Other controlled release systems are discussed in the review by Langer (Science 249:1527-1533 (1990)).The active ingredient is coated with an outer polymeric membrane that is insoluble in body fluids, such as polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl acetate, vinylidene chloride, vinyl chloride copolymers with ethylene and propylene, ionomeric polyethylene terephthalate, butyl rubber. The solid inner matrix may be dispersed in, for example, polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, hydrophilic polymers such as hydrogels of acrylic and methacrylic acid esters, collagen, crosslinked polyvinyl alcohol, and crosslinked partially hydrolyzed polyvinyl acetate, surrounded by epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol copolymer. The active ingredient then diffuses through the outer polymeric membrane in a release rate controlling step. The percentage of active ingredient contained in such parenteral compositions is highly dependent on its specific nature and the needs of the subject.

[0107] Also of interest herein are lyophilized powders that can be reconstituted for administration as solutions, emulsions, and other mixtures. They may also be formulated and reconstituted as solids or gels.

[0108] Sterile lyophilized powders are prepared by dissolving a compound provided herein or a derivative thereof in a suitable solvent. The solvent may contain excipients that improve stability or other pharmacological components of the powder or reconstituted solution prepared from the powder. Excipients that may be used may include, but are not limited to, antioxidants, buffers, and bulking agents. In some embodiments, the excipients are selected from dextrose, sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose, and other suitable agents. The solvent may contain a buffer, such as citrate, sodium or potassium phosphate, or other such buffers known to those of skill in the art, at about neutral pH. Subsequent sterile filtration of the solution followed by lyophilization under standard conditions known to those of skill in the art provides the desired formulation. In some embodiments, the resulting solution will be apportioned into vials for lyophilization. Each vial will contain a single dose or multiple doses of the compound. The lyophilized powders can be stored under appropriate conditions, for example, at about 4° C. to room temperature.

[0109] Reconstitution of this lyophilized powder with water for injection provides a formulation for use in parenteral administration. For reconstitution, the lyophilized powder is added to sterile water or other suitable carrier. The precise amount depends on the compound selected. Such amounts can be determined empirically.

[0110] Topical mixtures are prepared as described for local and systemic administration. The resulting mixtures can be solutions, suspensions, emulsions, etc., and are formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, irrigations, sprays, suppositories, bandages, dermal patches, or any other formulation suitable for topical administration.

[0111] The compound or its derivatives may be formulated as an aerosol for topical application, such as by inhalation (see, for example, U.S. Pat. Nos. 4,044,126, 4,414,209, and 4,364,923, which describe aerosols for the delivery of steroids useful in the treatment of inflammatory diseases, particularly asthma). Such formulations for administration to the respiratory tract may be in the form of an aerosol or solution for nebulizers or microfine powders for insufflation, alone or in combination with an inert carrier such as lactose. In such cases, the particles of the formulation have a mass median geometric diameter of less than 5 microns in some embodiments, and less than 10 microns in other embodiments.

[0112] Oral inhalation formulations of the compound or its derivatives suitable for inhalation include metered dose inhalers, dry powder inhalers, and liquid preparations for administration from a nebulizer or metered dose liquid dispensing system. For both metered dose inhalers and dry powder inhalers, the crystalline form of the compound or its derivatives is the preferred physical form of the drug, which confers longer product stability.

[0113] In addition to particle size reduction methods known to those skilled in the art, crystalline particles of the compound or its derivatives can be generated using supercritical fluid processing, which offers significant advantages in the production of respirable particles of a desired size in a single step, for the production of such particles for inhalation delivery. (See, e.g., WO 2005 / 025506). To ensure that a significant fraction of the compound or its derivatives is deposited in the lungs, a controlled particle size of microcrystals can be selected. In some embodiments, such particles have a mass median aerodynamic diameter of about 0.1 to about 10 microns, in other embodiments about 1 to about 5 microns, and in other embodiments about 1.2 to about 3 microns.

[0114] The inert and non-flammable HFA propellants are selected from HFA134a (1,1,1,2-tetrafluoroethane) and HFA227e (1,1,1,2,3,3,3-heptafluoropropane), either alone or in a ratio that matches the density of the crystalline particles of the compound or its derivatives. The ratio is also selected to ensure that deleterious settling or creaming of the article suspension (which may cause irreversible agglomeration) is avoided, instead promoting a loosely flocculated system that disperses easily when shaken. A loosely agitated system is well regarded as providing optimal stability for the pMDI canister. As a result of the nature of the formulation, it contained no ethanol or surfactants / stabilizers.

[0115] The compounds can be formulated for local or topical application, for example, for topical application to the skin and mucous membranes (e.g., in the eye), in the form of gels, creams, and lotions, as well as for application to the eye, or for intracisternal or intrathecal application. Topical administration is contemplated for transdermal delivery, as well as for administration to the eye or mucous membranes, or for inhalation therapy. Nasal solutions of the active compounds can also be administered alone or in combination with other excipients.

[0116] For nasal administration, the preparation may contain the esterified phosphonate compound dissolved or suspended in a liquid carrier, particularly an aqueous carrier, for aerosol application. The carrier may contain solubilizing or suspending agents such as propylene glycol, surfactants, absorption enhancers such as lecithin or cyclodextrin, or preservatives.

[0117] Solutions, particularly those intended for ophthalmic use, may be formulated as 0.01% to 10% isotonic solutions (pH about 5 to 7.4) containing appropriate salts.

[0118] Other routes of administration, such as transdermal patches, are also contemplated herein, including iontophoretic and electrophoretic devices and rectal administration.

[0119] Transdermal patches are well known to those skilled in the art, including iontophoretic and electrophoretic devices.For example, such patches are disclosed in U.S. Patent Nos. 6,267,983, 6,261,595, 6,256,533, 6,167,301, 6,024,975, 6,010715, 5,985,317, 5,983,134, 5,948,433 and 5,860,957.

[0120] For example, dosage forms for rectal administration are rectal suppositories, and for systemic effect are capsules and tablets. Rectal suppositories, as used herein, refer to solid bodies for insertion into the rectum that melt or soften at body temperature to release one or more pharmacologically or therapeutically active ingredients. The materials utilized in rectal suppositories are bases or vehicles and melting point elevating agents. Examples of bases include cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol), and appropriate mixtures of mono-, di-, and triglycerides of fatty acids. Combinations of various bases may be used. Melting point elevating agents for suppositories include gelatin and wax. Rectal suppositories may be prepared by either compressed or molding methods. The weight of a rectal suppository is about 2 to 3 grams in one embodiment. Tablets and capsules for rectal administration are manufactured using the same materials and by the same methods as formulations for oral administration.

[0121] The compounds provided herein or derivatives thereof can also be formulated to target specific tissues, receptors, or other areas of the body of the subject being treated. Many such targeting methods are well known to those skilled in the art. All such targeting methods are contemplated herein for use in the present compositions. Non-limiting examples of targeting methods are described, for example, in U.S. Pat. Nos. 6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060, See US Pat. Nos. 5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542, and 5,709,874.

[0122] In some embodiments, liposomal suspensions may also be suitable as carriers, including tissue-targeted liposomes, such as tumor-targeted liposomes. These may be prepared according to methods known to those skilled in the art. For example, liposomal formulations may be prepared as described in U.S. Pat. No. 4,522,811. Briefly, liposomes, such as multilamellar vesicles (MLVs), may be formed by drying down phosphatidylcholine and phosphatidylserine (7:3 molar ratio) in a flask. A solution of a compound provided herein in phosphate buffered saline (PBS) lacking divalent cations is added, and the flask is shaken until the lipid film is dispersed. The resulting vesicles are washed to remove unencapsulated compound, pelleted by centrifugation, and then resuspended in PBS.

[0123] The compound or derivative thereof may be packaged as an article of manufacture containing packaging material, a compound provided herein or a derivative thereof effective for treating, preventing, or ameliorating one or more of the symptoms of the aforementioned diseases or disorders within the packaging material, and a label indicating that the compound or composition or derivative thereof is used for treating, preventing, or ameliorating one or more of the symptoms of the aforementioned diseases or disorders.

[0124] The products provided herein contain packaging materials. Packaging materials used in packaging items are well known to those skilled in the art. For example, see U.S. Patent Nos. 5,323,907, 5,052,558, and 5,033,252. Examples of packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for the formulation selected and intended mode of administration and treatment. A broad range of formulations of the compounds and compositions provided herein are contemplated for various treatments of any disease or disorder described herein.

[0125] Dosage For use in treating or preventing infectious diseases, the compounds described herein or pharmaceutical compositions thereof are administered or applied in a therapeutically effective amount. For human treatment, the physician will determine the most appropriate dosing regimen according to preventive or curative treatment and according to age, weight, disease stage, and other factors specific to the subject being treated. The amount of active ingredient in the formulations provided herein that is effective for preventing or treating infectious diseases will vary according to the nature and severity of the disease or condition and the route of administration of the active ingredient. The frequency and dosage will also vary according to factors specific to each subject, which depend on the specific therapeutic agent (e.g., therapeutic or prophylactic agent) administered, the severity of the infection, the route of administration, as well as the age, physical condition, weight, response, and medical history of the subject.

[0126] Exemplary dosage forms contain milligram or microgram amounts of active compound per kilogram of subject (e.g., from about 1 microgram / kilogram to about 50 milligrams / kilogram, from about 10 micrograms / kilogram to about 30 milligrams / kilogram, from about 100 micrograms / kilogram to about 10 milligrams / kilogram, or from about 100 micrograms / kilogram to about 5 milligrams / kilogram).

[0127] In some embodiments, a therapeutically effective dosage should produce a serum concentration of the active ingredient of about 0.001 ng / ml to about 50-200 μg / ml. The composition should provide a dosage of about 0.0001 mg to about 70 mg of compound per kilogram of body weight per day in other embodiments. Dosage unit forms are prepared to provide about 0.01 mg, 0.1 mg, or 1 mg to about 500 mg, 1000 mg, or 5000 mg, in some embodiments about 10 mg to about 500 mg of the active ingredient or essential ingredient combination per dosage unit form.

[0128] The active ingredient can be administered at once or divided into several smaller doses and administered at time intervals. It is understood that the precise dosage and duration of treatment are a function of the disease being treated and can be determined empirically using known testing protocols or by inference from in vivo or in vitro test data or subsequent clinical testing. It should be noted that concentrations and dosage values ​​can also vary with the severity of the condition being alleviated. It should be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the composition, and that the concentration ranges set forth herein are merely exemplary and are not intended to limit the scope or practical application of the claimed compositions.

[0129] As will be apparent to those skilled in the art, in some cases it may be necessary to use dosages of the active ingredients outside the ranges disclosed herein.Furthermore, it should be noted that the clinician or treating physician will know how and when to interrupt, adjust, or stop therapy in relation to subject response.

[0130] For systemic administration, the therapeutically effective dose can be estimated initially from in vitro assays. For example, the dose can be determined based on the IC 50 (i.e., the concentration of a test compound at which 50% of the cell cultures are lethal) or IC determined in cell culture 100 The compound can be formulated in animal models to achieve a circulating concentration range that includes the compound (i.e., the concentration of the compound that is lethal in 100% of the cell cultures). Such information can be used to more accurately determine useful doses in humans.

[0131] Initial dosages can also be estimated from in vivo data (e.g., animal models) using techniques well known in the art. Those skilled in the art can readily optimize human dosages based on animal data.

[0132] Alternatively, the initial dose may be administered at or above the IC 50 , MIC, and / or I 100 The initial dosage can be determined from the dosage of the known agent by comparing the initial dosage to that of the known agent and adjusting the initial dosage accordingly. Optimal dosages can be obtained from these initial values ​​by routine optimization.

[0133] In cases of local administration or selective uptake, the effective local concentration of compound used may not be related to plasma concentration. Those skilled in the art will be able to optimize therapeutically effective local doses without undue experimentation.

[0134] Ideally, a therapeutically effective dose of the compounds described herein will provide therapeutic benefit without causing substantial toxicity. Toxicity of the compounds can be assessed using standard pharmaceutical procedures in cell cultures or experimental animals, e.g., LD 50(the dose at which 50% of the population is lethal) or LD 100 The dose ratio between toxic and therapeutic effects is the therapeutic index. Compounds that exhibit high therapeutic indices are preferred. Data obtained from such cell culture assays and animal studies can be used to formulate a non-toxic dosage range for use in subjects. The dosage of the compounds described herein is preferably within a range of circulating concentrations that include the effective dose with little or no toxicity. Dosages can vary within this range depending on the dosage form employed and the route of administration utilized. The exact formulation, route of administration, and dosage can be selected by the individual physician in view of the patient's condition (see, for example, Fingl et al., 1975, In: The Pharmacological Basis of Therapeutics, Ch.1, p.1).

[0135] The therapy may be repeated intermittently. In certain embodiments, administration of the same formulation provided herein may be repeated, and administration may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.

[0136] Methods of Use of the Compounds and Compositions Described herein are methods of treating, preventing, or ameliorating symptoms of medical disorders with the compounds and pharmaceutical compositions disclosed herein, for example, cystinosis, cystinuria, cancer neurodegenerative diseases, Parkinson's disease, Huntington's disease, malaria, non-alcoholic fatty liver disease, radiation poisoning, arsenic poisoning, radioprotection, Wilson's disease, rheumatoid arthritis, etc. In practicing the methods, the compounds or compositions listed herein are administered in therapeutically effective amounts to a patient suffering from a disorder or condition.

[0137] Combination Therapy The compounds and compositions disclosed herein may also be used in combination with one or more other active ingredients.In certain embodiments, the compounds may be administered in combination with or sequentially with another therapeutic agent.Such other therapeutic agents include those known for treating, preventing, or ameliorating one or more symptoms associated with cystinuria, cystinosis, cancer, neurodegenerative diseases, Parkinson's disease, Huntington's disease, malaria, non-alcoholic fatty liver disease, radiation poisoning, arsenic poisoning, Wilson's disease, or rheumatoid arthritis.

[0138] It should be understood that any suitable combination of the compounds and compositions provided herein with one or more of the above therapeutic agents and, optionally, one or more additional pharmacologically active substances is considered to be within the scope of the present disclosure. In some embodiments, the compounds and compositions provided herein are administered prior to or subsequent to one or more additional active ingredients.

[0139] Finally, it should be noted that there are alternative implementations of the present invention. Thus, the present embodiments should be considered as illustrative rather than restrictive and should not be limited to the details given herein, but may be modified within the scope and equivalents of the appended claims. All publications and patents cited herein are incorporated by reference in their entirety.

[0140] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the present invention. EXAMPLES

[0141] Scheme 1 illustrates the preparation of compound 7. [ka]

[0142] Isopropyl(chloro(phenoxy)phosphoryl)-L-alaninate (103) [ka]

[0143] To a solution of L-alanine isopropyl ester HCl (102) (6.0 g, 35.79 mmol) and phenyl dichlorophosphate (101) (7.55 gm, 35.785 mmol) in DCM (120.0 ml) at −78° C. was added a solution of triethylamine (10.5 ml, 72.5 mmol) in DCM (20.0 ml) over 50 min. The reaction mixture was stirred for an additional 1.5 h, filtered through a sintered glass funnel and concentrated under reduced pressure to give compound (103) (12.0 gm) as a gummy solid, which was used in the next step without any further purification.

[0144] Isopropyl(((2-((tert-butoxycarbonylamino)ethyl)thio)(phenoxy)phosphoryl)-L-alaninate (104) [ka]

[0145] To a solution of isopropyl(chloro(phenoxy)phosphoryl)-L-alaninate (103) (12.0 gm, crude) in DCM (120.0 ml) was added 2-(Boc-amino)ethanethiol) (6.97 gm, 35.799 mmol) at 25°C and the reaction mixture was stirred for 30 minutes. The reaction mixture was then cooled to -78°C and triethylamine (11.05 ml, 77.6 mmol) was added dropwise over 20 minutes. The temperature was then gradually increased to 25-30°C and stirred for 24 hours, water was added and the organic layer was separated. The aqueous layer was extracted with DCM (100 ml) and the combined organic layers were dried over anhydrous Na2SO4 and concentrated to give crude compound 104 as a colourless gummy liquid. The crude product was purified by silica gel chromatography (100-200 mesh, 10-30% ethyl acetate in petroleum ether). The pure fractions were concentrated to provide compound 104 (3.5 g, 21%, diastereomeric mixture) as a colorless liquid. 1H-NMR (400MHz, CDCl3): δ:1.23-1.28(m,6H),1.40-1.43(m,12H),2.91-3.00(m, 2H),3.33-3.41(m,2H),3.97-4.14(m,2H),5.00-5.07(m,2H),7.17-7.36(m,5H). LC-MS:447.21[(M+H)] + , a mixture of two isomers.

[0146] Example 1: Isopropyl (((2-aminoethyl)thio)(phenoxy)phosphoryl)-L-alaninate (7) [ka]

[0147] To a solution of isopropyl(((2-((tert-butoxycarbonylamino)ethyl)thio)(phenoxy)phosphoryl)-L-alaninate (104) (1.0 g, 2.2 mmol) in DCM (20 ml) was added trifluoroacetic acid (0.87 ml, 11 mmol) dropwise at 0° C. The reaction mixture was warmed to 25° C. and stirred for 16 h. After the reaction was complete, the solvent was removed to give the crude compound as a thick gummy liquid, which was purified by using reversed-phase prep-HPLC and lyophilized to give compound (7) (0.2, 28%, diastereomeric mixture) as a gummy liquid. 1 H-NMR (400MHz, CDCl3): δ:1.20-1.24(m,6H),1.35-1.39(m,3H),3.01-3.26(m,4H),3. 92-4.08(m,1H),4.96-5.05(m,1H),5.19-5.35(m,1H),7.17-7.35(m,5H),8.35(m,3H). LC-MS:347.14[(M-CF3COOH)+H] + .

[0148] Example 2: Isopropyl (((2-acetamidoethyl)thio)(phenoxy)phosphoryl)-L-alaninate (1) [ka]

[0149] To a solution of compound isopropyl(chloro(phenoxy)phosphoryl)-L-alaninate (103) (6 g, crude) in DCM (120 ml) was added N-acetylcysteamine (2.13 g, 17.8 mmol) at 25° C. and the reaction mixture was stirred for 30 min. The reaction mixture was then cooled to −78° C. and triethylamine (4.9 ml, 35.6 mmol) was added dropwise over 20 min. The reaction mixture was warmed to 25° C., stirred for 24 h and water was added. The reaction mixture was extracted with DCM (100 ml, 2×) and the combined organic extracts were dried over anhydrous Na2SO4 and concentrated under vacuum to give the crude compound as a pale yellow liquid. The crude compound was purified by using reverse phase prepHPLC and lyophilized to provide compound (1) (0.25 mg, diastereomeric mixture) as a gummy liquid. 1 HNMR(400MHz,DMSO-d6):δ:1.16-1.21(m,6H),1.25-1.27(d,3H,J=8MHz),1.78(s,3H),2.79-2.89(m,2H),3.23-3.28(m ,2H),3.83-3.90(m,1H),4.85-4.92(m,1H),6.50-6.56(m,1H),7.16-7.23(m,3H),7.36-7.40(m,2H),8.03-8.06(m,1H). LC-MS:389.18[M+H] + .

[0150] Example 3: Isopropyl(bis((2-acetamidoethyl)thio)phosphoryl)-L-alaninate (4) [ka]

[0151] To a stirred solution of L-alanine isopropyl ester hydrochloride (102) (2.0 g, 9.1 mmol) in DCM (60 ml) was added POCl3 (1.82 g, 9.1 mmol) at 25° C. and the reaction mixture was stirred for 30 min. The reaction mixture was then cooled to −78° C. and triethylamine was added dropwise over 20 min. The reaction mixture was stirred at −78° C. for a further 1 h and N-acetylcysteamine (2.84 g, 18.2 mmol) was added followed by triethylamine (2.41 g, 18.2 mmol). The reaction mixture was warmed to 25° C. and stirred for 24 h. Water was added and the reaction mixture was extracted with DCM (100 ml, 2×). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under vacuum to give the crude compound as a pale yellow liquid. The crude material was purified by using reverse-phase prepHPLC and lyophilized to provide compound (4) (0.38 g, 7.7%) as a gummy liquid. 1 H-NMR(400MHz,CDCl3)δ=1.25-1.29(t,6H,J=16MHz),1.44-1.46(d,3H,J=8MHz),2.0(s,3H),3.03-3.10(m,4H),3 .49-3.69(m,4H),4.01-4.08(m,1H),4.23-4.29(t,1H,J=12MHz),5.02-5.08(m,1H),6.66-6.72(d,2H,J=24MHz). LC-MS:414.13[M+H] + .

[0152] Example 4: Ethyl N-acetyl-S-((((S)-1-isopropoxy-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)-L-cysteinate (2) [ka]

[0153] To a solution of compound 103 (1.0 gm, 3.27 mmol, crude) in DCM (30 ml) was added ethyl acetyl-L-cysteinate (0.57 gm, 2.973 mmol) at 25° C. and the reaction mixture was stirred for 30 min. The reaction mixture was then cooled to −78° C. and triethylamine (0.9 ml, 5.95 mmol) was added dropwise over 20 min. The reaction mixture was warmed to 25° C. and stirred for 24 h. Water was added and the reaction mixture was extracted with DCM (100 ml, 2×). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under vacuum to give the crude compound as a pale yellow liquid. The crude material was purified by reverse phase prepHPLC and lyophilized to provide compound 2 (0.105 g, 8% diastereomeric mixture) as a gummy liquid. 1 H-NMR(400MHz,DMSO-d6):δ:1.15-1.20(m,9H),1.26-1.28(d,3H,J=8MHz)3.0-3.21(m,2H),3.82-3.90(m,1H),4.05-4.13(m,2H) ),4.44-4.50(m,1H),4.85-4.93(m,1H),6.56-6.66(m,1H),7.19-7.23(m,31H),7.367-7.41(m,2H),8.41-8.43(d,13H,J=8MHz). LC-MS:461.21[M+H] + .

[0154] Example 5: Isopropyl ((((R)-2-acetamido-3-amino-3-oxopropyl)thio)(phenoxy)phosphoryl)-L-alaninate (3) [ka]

[0155] To a solution of compound 103 (1.0 gm, 3.2722 mmol, crude) in DCM was added (R)-2-acetamido-3-mercaptopropanamide (0.483 gm, 2.977 mmol) at 25° C. and stirred for 30 min. The reaction mixture was then cooled to −78° C. and triethylamine (0.9 ml, 5.95 mmol) was added dropwise over 20 min. The reaction mixture was warmed to 25° C. and stirred for 24 h. Water was added and the reaction mixture was extracted with DCM (100 ml, 2×). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under vacuum to give the crude compound as a pale yellow liquid. The crude material was purified by reverse phase prepHPLC and lyophilized to provide compound 3 (0.075 g, 6%, diastereomeric mixture) as a white solid. 1 H-NMR(400MHz,DMSO-d6):δ:1.16-1.28(m,9H),1.84(S,3H),2.93-3.01(m,1H),3.08-3.16(m,1H),3.63-3.91(m,1H),4. 39-4.45(m,1H),4.83-4.88(m,1H),6.49-6.58(m,1H),7.07-7.23(m,4H),7.36-7.40(m,3H),8.11-8.13(d,1H,J=8MHz). LC-MS:432.13[M+H] + .

[0156] Example 6: (S,S) and (R,S) isopropyl(((2-acetamidoethyl)thio)(phenoxy)phosphoryl)-L-alaninate (10) and (11) [ka]

[0157] Isopropyl(((2-acetamidoethyl)thio)(phenoxy)phosphoryl)-L-alaninate 11 (0.1 g, 0.25 mmol) was purified by using reversed phase Prep-HPLC (Sun fire C18 150*19*5, 0.1% formic acid in water and acetonitrile T / B: 0 / 33, 14 / 33, 14.1 / 98, flow rate 15 ml / min solubility: water:ACN) to give 25.0 mg of 10 and 22.0 mg of 11.

[0158] 10: Colorless garnet-like liquid. Chemical formula:C 16 H 25 N2O5PS. 1 H-NMR (400MHz, DMSO-d6): δ:8.06(t,J=5.2Hz,2H),7.39(t,J=8.4Hz,2H),7.23-7.18(m,3H),6.51(dd,J=10.0Hz,10.0Hz,1H),4.92-4.86(m, 1H),3.90-3.83(m,1H),3.28-3.23(m,2H),2.86-2.79(m,2H),1.78(s, 3H), 1.26 (d, J=6.8Hz, 3H), 1.20-1.16 (m, 6H), HPLC: Rt=2.09 points (97.3%).

[0159] 11:Colorless liquid. Chemical formula:C 16 H 25 N2O5PS. 1 H-NMR (400MHz, DMSO-d6): δ: 8.04(t,J=5.2Hz,2H),7.38(t,J=8.0Hz,2H),7.22-7.18(m,3H),6.53(dd,J=10.0Hz,10.0Hz,1H),4.91-4.85(m, 1H),3.90-3.83(m,1H),3.27-3.22(m,2H),2.89-2.82(m,2H),1.78(s, 3H), 1.26 (d, J=6.8Hz, 3H), 1.19-1.16 (m, 6H), HPLC: Rt=2.09 points (97.3%).

[0160] Example 7: (S,S) and (R,S)イソプロピル (((2-アミノエチル)チオ)(フェノキシ)ホスホリル)-L-アラニネート(12) and び(13)

change

[0161] Isopropyl(((2-aminoethyl)thio)(phenoxy)phosphoryl)-L-alaninate (TFA salt) 7 (0.1 g, 0.22 mmol) was purified by using reverse phase Prep-HPLC {Phenyl Hexyl(29*50Mm)U 0.1% TFA:ACN, 0 / 22, 1 / 22, 12 / 33) to provide 25.0 mg of 12 and 20.0 mg of 12.

[0162] 12: TFA salt (colorless gummy liquid). Chemical formula: C 14 H 23 N2O4PS. 1 H-NMR(400MHz,DMSO-d6)δ:7.85(bs,3H),7.40(t,J=8.0Hz,2H),7.24-7.20(m,3H),6.66(dd,J=10.0Hz,10.0Hz,1H),4.9 2-4.86(m,1H),3.94-3.87(m,1H),3.10-2.97(m,4H),1.27(d,J=7.2Hz,3H),1.19-1.17(m,6H),HPLC:Rt=2.51min(97.5%).

[0163] 13: TFA salt (colorless gummy liquid). Chemical formula: C 14 H 23 N2O4PS. 1 H-NMR(400MHz,DMSO-d6)δppm:7.81(bs,3H),7.40(t,J=8.4Hz,2H),7.25-7.21(m,3H),6.65(dd,J=10.0Hz,10.0Hz,1H), 4.93-4.87(m,1H),3.94-3.87(m,1H),3.09-2.93(m,4H),1.25(d,J=8.4Hz,3H),1.20-1.15(m,6H),HPLC:Rt=2.57min(99%).

[0164] Scheme 2 illustrates the preparation of compounds 14, 15, and 16. [ka]

[0165] Isopropyl (((2-((tert-butoxycarbonyl)amino)ethyl)thio)(ethoxy)phosphoryl)-L-alaninate [ka]

[0166] To a stirred solution of L-alanine isopropyl ester hydrochloride (102) (2.2 g, 13.12 mmol) in anhydrous CHCl (50 mL) was added ethyl phosphorodichloridate (105) (2.13 g, 13.12 mmol) at room temperature and the mixture was stirred at room temperature for 20 min. The reaction mixture was then cooled to -78°C and trimethylamine (3.68 mL, 26.18 mmol) was added dropwise over 20 min. After the addition, the reaction mixture was maintained at the same temperature for another 1 h. After 1 h, tert-butyl (2-mercaptoethyl)carbamate (2.32 g, 13.12 mmol) and trimethylamine (3.68 mL, 26.18 mmol) were added and the reaction was warmed to room temperature and stirred for 16 h. After completion of the reaction, water was added to the reaction mixture and the desired product was extracted into DCM (100 mL x 2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum below 45 °C to give the crude compound as a pale yellow liquid. The crude compound was purified on silica gel (100-200 mesh) using 40% ethyl acetate in n-hexane as the eluent to give the pure compound as a pale yellow liquid 106 (1.0 g, 19.12%). Chemical formula: C 15 H 31 N2O6PS. 1 H-NMR(400MHz,CDCl3)δ:5.37-5.25(bs,1H),5.07-5.01(m,1H),4.19-4.11(m,2H),4.03-3.72(m,1H),3.44-3.41(m,1H) ),2.96-2.89(m,2H),1.55-1.36(s,12H),1.34-1.30(m,3H),1.28-1.21(m,6H),LC-MS:Rt=2.25min(99%),m / z399.27[M+H] + .

[0167] Example 8: Isopropyl(ethoxy((2-((2,2,2-trifluoroacetyl)-14-azaneyl)ethyl)thio)phosphoryl)-L-alaninate (14) [ka]

[0168] To a stirred solution of isopropyl(((2-((tert-butoxycarbonyl)amino)ethyl)thio)(ethyl)phosphoryl)-L-alaninate (106, 1.0 g, 2.51 mmol) in anhydrous CHCl (20 mL) at 0° C. was added trifluoroacetic acid (0.86 mL, 11.22 mmol) dropwise over 10 min. After the addition was complete, the reaction mixture was gradually warmed to room temperature and maintained at room temperature for 24 h. The progress of the reaction was monitored by LCMS. After completion of the reaction, the solvent was removed by distillation under reduced pressure at 45° C. to give compound 14 as a pale yellow liquid (0.95 g, 95%).

[0169] Example 9: (S,S) and (R,S) isopropyl(ethoxy((2-((2,2,2 trifluoroacetyl)-14-azanayl)ethyl)thio)phosphoryl)-L-alaninate (15) and (16) [ka]

[0170] Isopropyl(ethoxy((2-((2,2,2 trifluoroacetyl)-14 azaneyl)ethyl)thio)phosphoryl)-L-alaninate TFA salt (14) ((1.4 g, 4.69 mmol) was purified by using mass-based Prep-HPLC (Mobile Phase A: - 0.1% TFA in HO Mobile Phase B: - ACN, Column: - X-SELECT PHENYL HEXYL (250*21.2) mm, 5u, Flow Rate: - 20 ml / min, Method: - (T / %B): 0 / 5, 2 / 5, 12 / 30, 12.1 / 99, 17 / 99, 17.1 / 5, 20 / 5 Solubility: ACN+HO Temperature: - Ambient) to provide 50.0 mg of 15 and 70.0 mg of 16.

[0171] 15: Colorless gummy liquid. Chemical formula: C 10 H 23 N2O4PS. 1 H-NMR(400MHz,DMSO-d6)δ:7.80(S,3H),6.20(dd,J=10.4Hz,J=10.0Hz,1H),4.93-4.87(m,1H),4.06-3.99(m ,2H),3.81-3.74(m,1H),3.10-3.06(m,2H),2.96-2.89(m,2H),1.29-1.19(m,12H),HPLC:Rt=4.72min(97.03%).

[0172] 16: Colorless gummy liquid. Chemical formula: C 10 H 23 N2O4PS. 1 H-NMR(400MHz,DMSO-d6)δ:7.77(S,3H),6.14(dd,J=10.0Hz,J=10.0Hz,1H),4.93-4.86(m,1H),4.09-4.02(m,2H),3.80 -3.73(m,1H),3.08(t,J=7.2Hz,2H),2.94-2.88(m,2H),1.29-1.24(m,6H),1.21-1.18(m,6H),HPLC:Rt=4.89min(95.06%).

[0173] Scheme 3 illustrates the preparation of compounds 13 and 17. [ka]

[0174] Isopropyl ((R)-((2-((tert-butoxycarbonyl)amino)ethyl)thio)(phenoxy)phosphoryl)-L-alaninate (108) [ka]

[0175] To a stirred solution of tert-butyl (2-mercaptoethyl)carbamate (15.62 g, 88.30 mmol) in THF (250 mL) was added sodium hydride (3.17 g, 132.45 mmol) in portions over 30 min at 0° C. The reaction mixture was gradually warmed to room temperature and maintained at room temperature for 30 min. The reaction mixture was cooled to 0° C. and a solution of isopropyl((S)-(perfluorophenoxy)(phenoxy)phosphoryl)-L-alaninate (107) (40 g, 88.30 mmol) in THF (250 mL) was added dropwise over 30 min at 0° C. After completion of the addition, the reaction mixture was gradually warmed to room temperature and maintained at room temperature for 16 h. The reaction mixture was cooled to 0° C., quenched with ice-cold water (500.0 mL) and extracted with ethyl acetate (2×500 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure at 45 °C to give a pale yellow gummy liquid. The crude compound was purified on silica gel (100-200 mesh) using 0-40% ethyl acetate in n-hexane as eluent to give the pure compound as a gummy liquid (108) (14 g, 35%). Chemical formula: C 19 H 31 N2O6PS. 1 H-NMR(400MHz,CDCl3)δppm:7.34(d,J=7.6Hz,2H),7.25-7.16(m,3H),5.20(bs,1H),5.07-5.03(m,1H),4.13-3.98(m,2H),3.39 -3.35(m,2H),2.99-2.92(m,2H),1.43(s,9H),1.41(d,J=6.8Hz,3H),1.28-1.24(m,6H),HPLC:Rt=7.0min(84.9%),m / z447.19[M+H] + .

[0176] Example 10: Isopropyl ((R)-((2-aminoethyl)thio)(phenoxy)phosphoryl)-L-alaninate (TFA salt) (13) [ka]

[0177] To a stirred solution of isopropyl ((R)-((2-((tert-butoxycarbonyl)amino)ethyl)thio)(phenoxy)phosphoryl)-L-alaninate (108) (14 g, 156.95 mmol) in CHCl (150 mL) was added trifluoroacetic acid (12 mL, 63.34 mmol, 2 eq) dropwise over 10 min at 0° C. After addition, the reaction mixture was allowed to warm to room temperature and stirring was continued at room temperature for 24 h. The progress of the reaction was monitored by LC-MS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure at 45° C. and co-distilled with toluene to provide crude compound (13) (14 g, 98% as TFA salt) as a thick gummy liquid. Chemical formula: C 14 H 23 N2O4PS. 1 H-NMR(500MHz,DMSO-d6)δppm:7.89(bs,3H),7.40(t,J=7.6Hz,1H),7.25-7.21(m,3H),6.65(dd,J=10.0Hz,10.0Hz,1H),4.93-4.87 (m,1H),3.94-3.87(m,1H),3.09-3.05(m,2H),3.02-2.93(m,2H),1.25(d,J=8.4Hz,3H),1.20-1.15(m,6H),HPLC:Rt=2.40min(86.6%)

[0178] Example 11: Isopropyl ((R)-((2-aminoethyl)thio)(phenoxy)phosphoryl)-L-alaninate fumarate (17) [ka]

[0179] Isopropyl ((R)-((2-aminoethyl)thio)(phenoxy)phosphoryl)-L-alaninate TFA salt (17) (2.5 g, 5.62 mmol) was dissolved in water (10 mL) and cooled to 0-5 °C. Aqueous NaHCO3 solution was then added until the pH was 7.5-8.0. After stirring at 0-5 °C for 15 min, diethyl ether (25 mL) was added to the reaction mixture and the organic layer was separated. The aqueous layer was re-extracted with diethyl ether (25 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was cooled to 0 °C and fumaric acid (0.522 g, 4.49 mmol) was added to the above reaction mixture. After addition, the reaction mixture was stirred at rt for 16 h. After 16 hours, the solids were isolated by filtration and dried under vacuum to give isopropyl((R)-((2-aminoethyl)thio)(phenoxy)phosphoryl)-L-alaninate fumarate salt (17) as an off-white solid (250 mg, 19.22%). Chemical formula: C 14 H 23 N2O4PS. 1 H-NMR(500MHz,DMSO-d6)δ:8.80(bs,3H),7.40(t,J=8.0Hz,1H),7.24-7.19(m,3H),6.46(s,2H),4.92-4.86(m, 1H), 3.91-3.87 (m, 1H), 2.96-2.94 (m, 4H), 1.27 (d, J = 7.2Hz, 3H), 1.19-1.17 (m, 6H), HPLC: Rt = 8.66 minutes (97.49%).

[0180] Scheme 4 illustrates the preparation of compounds 19 and 20. [ka]

[0181] tert-Butyl (2-((diethoxyphosphoryl)thio)ethyl)carbamate (110)

[0182] To a stirred solution of O,O-diethyl-s-hydrogen phosphorothioate potassium salt (109) (3.0 g, 14.33 mmol) in DMF (10 mL) in a microwave vial at room temperature, tert-butyl (2-bromoethyl)carbamate (3.21 g, 14.33 mmol) was added. After addition, the vial was kept in the microwave and heated to 80 °C for 10 min. The progress of the reaction was monitored by TLC. After completion of the reaction, ice water was added to the reaction mixture and extracted into ethyl acetate (2 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum at 45 °C to give the crude compound as a yellow liquid (5.1 g). The crude compound was purified on silica gel (60-120 mesh) using 0-50% ethyl acetate in n-hexane as the eluent to give pure tert-butyl (2-((diethoxyphosphoryl)thio)ethyl)carbamate as a colorless liquid 110 (2.2 g, 49%). Chemical formula: C 11 H 24 NO5PS. 1 H-NMR(400MHz,DMSO-d6)δ:5.11(bs,1H),4.23-4.12(m,4H),3.42(d,J=6.0MHz, 2H), 3.00-2.35 (m, 2H), 1.50 (s, 9H), 1.38-1.35 (m, 6H), HPLC: Rt = 4.17 min (99.9%).

[0183] Example 12: S-(2-aminoethyl) O,O-diethyl phosphorothioate (TFA salt) (1) [ka]

[0184] To a stirred solution of tert-butyl (2-((diethoxyphosphoryl)thio)ethyl)carbamate (110) (2.2 g, 7.02 mmol) in CHCl (30.0 mL) at 0° C., trifluoroacetic acid (2.68 mL, 35.08 mmol) was added dropwise over 10 min. After the addition was complete, the reaction mixture was gradually warmed to room temperature and stirring was continued at room temperature for 24 h. The progress of the reaction was monitored by TLC (10% methanol in CHCl, ninhydrin was used to visualize the spots). After completion of the reaction, the solution was concentrated under reduced pressure at 35° C. to provide crude S-(2-aminoethyl)O,O-diethyl phosphorothioate (18) as a thick gummy liquid (2.0 g, TFA salt, 92%). Chemical formula: CH 16 NO3PS. 1 H-NMR (400MHz, DMSO-d6) δppm: 4.10-4.02 (m, 4H), 2.80-2.73 (m, 4H), 2.35 (bs, 2H), 1.28-1.23 (m, 6H), HPLC: Rt = 6.18 min (96.7%).

[0185] Example 13: S-(2-aminoethyl) O,O-diethyl phosphorothioate (fumarate salt) (19) [ka]

[0186] S-(2-aminoethyl)O,O-diethyl phosphorothioate TFA salt (18) (4.0 g, 12.88 mmol) was dissolved in water (10 mL) and cooled to 0-5 °C. Aqueous NaHCO3 solution was then added until the pH was 7.5-8.0. After stirring at 0-5 °C for 15 min, 10% MeOH in CHCl2 (200 mL) was added to the reaction and the layers were separated. The aqueous layer was re-extracted with 10% MeOH in CHCl2 (200 mL) and the combined organic layers were dried over anhydrous NaSO4 and concentrated under reduced pressure to give a residue (2.8 g). The residue (2.8 g, 9.38 mmol) was dissolved in diethyl ether (10 Vol) and cooled to 0-5 °C. Fumaric acid (0.547 g, 4.71 mmol) was added and the reaction mixture was stirred at room temperature for 6 h. The solid was isolated by filtration and dried under vacuum at 45° C. to provide S-(2-aminoethyl) O,O-diethyl phosphorothioate fumarate salt (19) as an off-white solid (1.8 g, 85%). Chemical formula: CH 16 NO3PS. 1 H-NMR (500MHz, DMSO-d6) δppm: 8.53 (bs, 2H), 6.46 (s, 2H), 4.13-4.05 (m, 4H), 2.94-2.89 (m, 4H), 1.29-1.25 (m, 6H), HPLC: Rt = 4.17 min (99.9%).

[0187] Scheme 5 illustrates the preparation of compounds 21 and 22. [ka]

[0188] Methyl ((((R)-1-methoxy-1-oxopropan-2-yl)amino)(perfluorophenoxy)phosphoryl)-L-alaninate (114)

[0189] To a stirred solution of 2,3,4,5,6-pentafluorophenol (111) (30.0 g, 162.98 mmol) in anhydrous CHCl (500 mL) was added POCl (15.23 mL, 162.98 mmol) dropwise over 20 min at room temperature. After the addition was complete, stirring was continued at room temperature for 20 min. The reaction mixture was then cooled to −78° C. and trimethylamine (45.83 mL, 326.08 mmol) was added dropwise over 20 min and the reaction mixture was maintained at −78° C. for 1 h. After 1 h, L-alanine methyl ester hydrochloride (113) (45.5 g, 325.97 mmol) was added and the reaction mixture was stirred for 10 min. The reaction mixture was then maintained at −78° C. and trimethylamine (45.83 mL, 326.08 mmol) was added dropwise over 20 min. After the addition was complete, the reaction mixture was gradually warmed to room temperature and maintained at room temperature for 16 h. After completion of the reaction, water (100 mL) was added and the product was extracted into ethyl acetate (2×300 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure below 45° C. to give the crude compound as an off-white gummy liquid. The crude compound was purified on silica gel (100-200 mesh) by using 40% ethyl acetate in n-hexane as the eluent to give the pure compound as an off-white solid (114) (15.0 g, 21%). Chemical formula: C 15 H 30 N3O7PS. 1 H-NMR(400MHz,DMSO-d6)δ:4.16-4.09(m,2H),3.77(s,6H),3.74-3.69(m,2H),1.46(t,J=4.8MHz,6H),HPLC:Rt=5.51min(98.9%),

[0190] Methyl (((2-((tert-butoxycarbonyl)amino)ethyl)thio)(((R)-1-methoxy-1-oxopropan-2-yl)amino)phosphoryl)-L-alaninate (115) [ka]

[0191] To a stirred solution of methyl (2-mercaptoethyl)carbamate (6.12 g, 34.54 mmol) in THF (60 mL) was added sodium hydride (1.38 g, 57.5 mmol) in portions over 30 min at 0° C. After the addition was complete, the reaction mixture was allowed to warm gradually to room temperature and was maintained at room temperature for 30 min. After 30 min, the reaction mixture was cooled to 0° C. and a solution of methyl ((((R)-1-methoxy-1-oxopropan-2-yl)amino)(perfluorophenoxy)phosphoryl)-L-alaninate (114) (15.0 g, 34.54 mmol) in THF (200 mL) was added dropwise over 30 min at 0° C. After the addition was complete, the reaction mixture was allowed to warm gradually to room temperature and was maintained at room temperature for 16 h. After completion of the reaction, the reaction mixture was cooled to 0°C, quenched with ice-cold water (20.0 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure at 40°C to give the crude compound as a yellow liquid (5.1 g). The crude compound was purified on silica gel (60-120 mesh) by using 0-70% ethyl acetate in n-hexane as eluent to give the pure compound as an off-white solid (115) (3.8 g, 25%). Chemical formula: C 15 H 30 N3O7PS. 1 H-NMR(400MHz,DMSO-d6)δ:7.01(bs,1H),5.40-5.31(m,2H),3.89-3.81(m,2H),3.64(s,6H),3.16- 3.13 (m, 2H), 2.73-2.66 (m, 2H), 1.37 (s, 9H), 1.28 (d, J = 7.2Hz, 6H), ELSD-LS-MS: Rt = 1.84 min (98.2%).

[0192] Example 14: Methyl (((2-aminoethyl)thio) (((R)-1-methoxy-1-oxopropan-2-yl) amino) phosphoryl)-L-alaninate TFA salt (20) [ka]

[0193] To a stirred solution of methyl (((2-((tert-butoxycarbonyl)amino)ethyl)thio)(((R)-1-methoxy-1-oxopropan-2-yl)amino)phosphoryl)-L-alaninate (115) (3.8 g, 8.88 mmol) in CHCl (50.0 ml) was added trifluoroacetic acid (1.36 ml, 17.77 mmol) dropwise over 10 min at 0° C. After the addition was complete, the reaction mixture was gradually warmed to room temperature and stirring was continued at room temperature for 24-30 h. After completion of the reaction, the solvent was removed under reduced pressure at 35° C. to give the crude compound as a thick gummy liquid (20), TFA salt, 4.0 g, 92%. Chemical formula: C 10 H 22 N3O5PS. 1 HNMR(400MHz,DMSO-d6)δppm:7.88(bs,2H),5.62-5.56(s,3H),3.96-3.84(m,2H),3.64(s, 6H), 3.10-3.07 (m, 2H), 2.98-2.85 (m, 2H), 1.38 (d, J = 7.2Hz, 6H), HPLC: Rt = 4.21 min (99.9%).

[0194] Example 15: Methyl (((2-aminoethyl)thio) (((R)-1-methoxy-1-oxopropan-2-yl) amino) phosphoryl)-L-alaninate fumarate (21) [ka]

[0195] Methyl (((2-aminoethyl)thio)(((R)-1-methoxy-1-oxopropan-2-yl)amino)phosphoryl)-L-alaninate TFA salt (21) (1.0 g, 2.35 mmol) was dissolved in water (10 mL), cooled to 0-5 °C, and then added to aqueous NaHCO3 solution until the pH was 7.5-8.0. After stirring at 0-5 °C for 15 min, 10% MeOH in CHCl2 (200 mL) was added to the reaction mixture and the layers were separated. The aqueous layer was re-extracted with 10% MeOH in CHCl2 (200 mL) and the combined organic layers were dried over anhydrous NaSO4 and concentrated under reduced pressure to provide a residue (0.6 g). The residue was dissolved in diethyl ether (30.0 mL) and cooled to 0-5 °C. Fumaric acid (0.22 g, 1.88 mmol) was added, the reaction mixture was stirred at room temperature for 16 h, and the solvent was removed under reduced pressure. The solid residue was washed twice with diethyl ether and dried. The gummy solid was lyophilized to give the compound methyl(((2-aminoethyl)thio)(((R)-1-methoxy-1-oxopropan-2-yl)amino)phosphoryl)-L-alaninate (fumarate salt) (21) as an off-white hygroscopic solid (0.29 g, 28%). Chemical formula: C 10 H 22 N3O5PS. 1 H-NMR(400MHz,DMSO-d6)δppm:8.96(bs,2H),6.44(s,3H),5.58-5.53(m,2H),3.90-3.85(m,2H),3 .63(s,6H),3.16-2.89(m,2H),2.87-2.81(m,2H),1.29(d,J=7.2Hz,6H),HPLC:Rt=5.87min(95.5%).

[0196] Scheme 6 illustrates the preparation of compound 22. [ka]

[0197] Example 16: Isopropyl ((R)-((2-guanidinoethyl)thio(phenoxy)phosphoryl)-L-alaninate (22) [ka]

[0198] To a stirred solution of isopropyl(((2-aminoethyl)thio)(phenoxy)phosphoryl)-L-alaninate TFA salt (13) (4.0 g, 4.5 mmol) in DMF (10 mL) was added N,N-diisopropylethylamine (3.91 ml, 22.44 mmol) at 0° C. After stirring for 10 min, 1H-pyrazole-1-carboximidamide hydrochloride (1.319 g, 9.0 mmol) was added in portions over 20 min at 0° C. After complete addition, the reaction mixture was allowed to warm to room temperature and stirring was continued for 24 h. The progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was concentrated under vacuum at 45° C. to provide the crude compound as a gummy liquid (5.38 g). The crude compound was purified using reversed phase Prep-HPLC {Column: -X-SELECT CSH C18 (25*150mm), 10um Buffer A: 0.1% formic acid Buffer B: ACN, Solubility: -ACN-H2O Mobile phase conditions (%B): -0 / 5, 2 / 5, 12 / 40, 14 / 40, 14.01 / 99 Flow rate -19ml / min} to give the formate salt (22) (0.548g, 31.49%) isopropyl((R)-((2-guanidinoethyl)thio(phenoxy)phosphoryl)-L-alaninate as a colorless gummy liquid. 15 H 25 N4O4PS. 1 H-NMR(400MHz,DMSO-d6)δ=8.58(s,1H),7.69(bs,4H),7.39(t,J=7.2MHz,1H),7.24-7.19(m,3H),6.69-6.63(m,1H),4 .93-4.87(m,1H),3.92-3.85(m,1H),3.46-3.32(m,2H),2.93-2.85(m,2H),1.27(d,J=6.8MHz,3H),1.20-1.18(m,6H). HPLC-97.7%, LC-MS:389.21[M+H] + .

[0199] Scheme 7 illustrates the preparation of compounds 16 and 23. [ka]

[0200] Example 17: Isopropyl ((S)-ethoxy(perfluorophenoxy)phosphoryl)-L-alaninate (119) [ka]

[0201] To a solution of ethyl phosphorodichloridate (105) (34 mL, 298.3 mmol) in CHCl at −78° C., L-alanine isopropyl ester hydrochloride (102) (50 g, 298.3 mmol) in CHCl (300 mL) was added dropwise (approximately 30 min) and stirred for 10 min. Triethylamine (84 mL, 596.68 mmol) was then added over 30 min at the same temperature and stirred for 1 h at the same temperature. The reaction mixture was then warmed to 0° C. A solution of 2,3,4,5,6-pentafluorophenol (116) (32 mL, 298.3 mmol) in 200 mL of dichloromethane and triethylamine (46 mL, 328.1 mmol) were added simultaneously at 0° C. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with ice-cold water and extracted into CHCl (2×200 mL). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure. The residue (117) was crystallized from MTBE (100 mL). The white solid was isolated by filtration and the cake was washed with MTBE (3×50 mL). The filtrate was concentrated and the resulting crude solid was isolated by crystallization from 20% ethyl acetate in hexane (100 mL). The solid was collected by filtration and dried under high vacuum for 5-6 h to give isopropyl((S)-ethoxy(perfluorophenoxy)phosphoryl)-L-alaninate (119) (99% single isomer) as two lots. 73 g, 60%, HPLC-95%, Chiral HPLC-99%). Chemical formula: C 14 H 17 F5NO5P. 1H-NMR(400MHz,CDCl3)δppm:5.09-5.03(m,1H),4.31-4.28(m,2H),4.05-3.97(m,2H),3.70(t,J=5.6Hz,1H ),1.45(d,J=6.8Hz,3H),1.40-1.36(m,3H),1.27(t,J=6.0Hz,6H),HPLC:Rt=4.28min(95%),m / z406.13[M+H] + The structure was supported by single crystal X-rays.

[0202] Isopropyl ((R)-((2-((tert-butoxycarbonyl)amino)ethyl)thio)(ethoxy)phosphoryl)-L-alaninate (120) [ka]

[0203] To a stirred solution of tert-butyl (2-mercaptoethyl)carbamate (7.2 g, 61.72 mmol) in THF (400 mL) was added sodium hydride (2.2 g, 92.59 mmol) in portions over 30 min at 0 °C. The reaction mixture was gradually warmed to room temperature and maintained at room temperature for 30 min. The reaction mixture was cooled to 0 °C and a solution of isopropyl ((R)-ethoxy(perfluorophenoxy)phosphoryl)-L-alaninate (119) (25 g, 61.72 mmol) in THF (200 mL) was added over 30 min. After the addition was complete, the reaction mixture was gradually warmed to room temperature and maintained at room temperature for 16 h. The reaction mixture was cooled to 0 °C, quenched with ice-cold water (500.0 mL) and extracted with ethyl acetate (2 x 500 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure at 40 °C to give a gummy liquid. The crude compound was purified on silica gel (100-200 mesh) using 0-80% ethyl acetate in n-hexane as eluent to give the pure compound as an off-white solid (120) (12 g, 48%). Chemical formula: C 15 H 31 N2O6PS: 1HNMR(400MHz,CDCl3)δppm:5.33(bs,1H),5.08-5.01(m,1H),4.19-4.10(m,2H),3.95-3.74(m,1H),3.79-3.74(m,1H),3.48-3.41(m ,2H),3.00-2.87(m,2H),1.60(s,9H),1.44-1.39(m,3H),1.36-1.33(m,3H),1.28-1.21(m,6H),HPLC:Rt=4.46min(95%),m / z400[M+H] + .

[0204] Example 18: Isopropyl ((R)-((2-((tert-butoxycarbonyl)amino)ethyl)thio)(ethoxy)phosphoryl)-L-alaninate TFA salt (16) [ka]

[0205] To a stirred solution of (120) (12 g, 30.15 mmol) in CHCl (100 mL) was added trifluoroacetic acid (11.59 mL, 150.75 mmol) dropwise at 0-5 °C. After the addition was complete, the temperature was allowed to rise to room temperature and stirring was continued at room temperature for 24 h. The progress of the reaction was monitored by TLC (10% methanol in CHCl, ninhydrin was used to visualize the spots. Rf values ​​of starting material and product are 0.8 and 0.1, respectively). After completion of the reaction, the solvent was removed under reduced pressure at 35 °C to give the crude compound as a thick gummy liquid, 11 g TFA salt (16), 92%. Chemical formula: C 12 H 23 F3N2O5PS. 1 H-NMR(400MHz,DMSO-d6):δ:7.94(bs,3H),4.93-4.86(m,1H),4.09-4.02(m,2H),3.81-3.7 4(m,1H), 3.11-3.06(m,2H), 2.95-2.87(m,2H), 1.29-1.18(m,12H), HPLC: Rt=5.70 min (98%).

[0206] Example 19: Isopropyl ((R)-((2-aminoethyl)thio)(ethoxy)phosphoryl)-L-alaninate fumarate salt (23) [ka]

[0207] Isopropyl ((R)-((2-((tert-butoxycarbonyl)amino)ethyl)thio)(ethoxy)phosphoryl)-L-alaninate TFA salt (16) (3.6 g, 9.1 mmol) (95% by HPLC) was dissolved in water (18 mL) and cooled to 0-5 °C. Aqueous NaHCO3 solution was then added until the pH was 7.5-8.0. After stirring at 0-5 °C for 15 min, 10% MeOH in CHCl2 (200 mL) was added to the reaction and the layers were separated. The aqueous layer was re-extracted with 10% MeOH in CHCl2 (200 mL) and the combined organic layers were dried over anhydrous NaSO4 and concentrated under reduced pressure to give a residue (2.8 g). The residue (2.8 g, 9.38 mmol) was dissolved in diethyl ether (5 Vol) and cooled to 0-5 °C. Fumaric acid (0.87 g, 7.49 mmol) was added to the above reaction mixture and the reaction mixture was stirred at room temperature for 16 h. The solvent was removed under vacuum and the semi-solid was washed with diethyl ether and dried under vacuum. The semi-solid was lyophilized to give compound (23) as an off-white solid (3.3 g, 90% hygroscopic). Chemical formula: C 10 H 23 N2O4PS. 1 H-NMR(400MHz,DMSO-d6):δ:6.41(s,1H),6.1(bs,1H),4.92-4.86(m,1H),4.07-3.99(m,2H),3 .76-3.75(bs,1H),2.93-2.91(t,2H),2.86-2.79(m,2H),1.28-1.23(m,6H),1.21-1.85(m,6H). HPLC: Rt=7.2 min (97.57%).

[0208] Scheme 8 illustrates the preparation of compounds 24 and 25. [ka]

[0209] Ethyl ((((R)-1-ethoxy-1-oxopropan-2-yl)amino)(perfluorophenoxy)phosphoryl)-L-alaninate (123)

[0210] To a stirred solution of 2,3,4,5,6-pentafluorophenol (116) (50.0 g, 271.63 mmol) in anhydrous CHCl (750 mL) was added POCl (25.39 mL, 271.63 mmol) dropwise over 20 min at room temperature. After addition, stirring was continued for 20 min at room temperature. The reaction mixture was then cooled to −78° C. and trimethylamine (76.34 mL, 543.18 mmol) was added dropwise over 20 min to form intermediate (121). The reaction mixture was held at −78° C. for 1 h. After 1 h, L-alanine ethyl ester hydrochloride (122) (83.45 g, 543.2 mmol) was added and the reaction mixture was stirred for 10 min. The reaction mixture was cooled to −78° C. and trimethylamine (76.34 mL, 543.18 mmol) was added dropwise over 20 min. After the addition was complete, the reaction mixture was gradually warmed to room temperature and maintained at room temperature for 16 h. After completion of the reaction, water (200 mL) was added to the reaction mixture and the product was extracted into CHCl (2×500 mL). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure below 45° C. to give the crude compound as an off-white gummy liquid. The crude compound was purified on silica gel (100-200 mesh) by using 40% ethyl acetate in n-hexane as eluent to give the pure compound as an off-white solid (123) (20.0 g, 16%). Chemical formula: C 16 H 20 F5N2O6P. 1 H-NMR(400MHz,DMSO-d6)δ:4.23(q,J=7.2MHz,4H),4.15-4.06(m,2H),3.76(q,J=6. 0MHz, 2H), 1.47 (q, J = 6.8MHz, 6H), 1.30 (t, J = 6.8MHz, 6H), HPLC: Rt = 8.28 minutes (99.5%).

[0211] Ethyl (((2-((tert-butoxycarbonyl)amino)ethyl)thio)(((R)-1-ethoxy-1-oxopropan-2-yl)amino)phosphoryl)-L-alaninate (124) [ka]

[0212] To a stirred solution of methyl (2-mercaptoethyl)carbamate (5.36 g, 30.28 mmol) in THF (50 mL) was added sodium hydride (1.211 g, 50.47 mmol) in portions over 30 min at 0° C. After the addition was complete, the reaction mixture was allowed to warm gradually to room temperature and was maintained at room temperature for 30 min. After 30 min, the reaction mixture was cooled to 0° C. and a solution of ethyl ((((R)-1-ethoxy-1-oxopropan-2-yl)amino)(perfluorophenoxy)phosphoryl)-L-alaninate (123) (14.0 g, 30.28 mmol) in THF (200 mL) was added dropwise over 30 min at 0° C. After the addition was complete, the reaction mixture was allowed to warm gradually to room temperature and was maintained at room temperature for 16 h. After completion of the reaction, the reaction mixture was cooled to 0°C, quenched with ice-cold water (30.0 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure at 40°C to give the crude compound as a yellow liquid (5.1 g). The crude compound was purified on silica gel (60-120 mesh) by using 0-70% ethyl acetate in n-hexane as eluent to give the pure compound as an off-white solid (124) (6.0 g, 43.5%). Chemical formula: C 17 H 34 N3O7PS. 1 H-NMR(400MHz,DMSO-d6)δ:4.22(q,J=7.2MHz,4H),4.08-4.00(m,2H),3.78-3.67(m,2H)3.42 (bs, 2H), 2.98-2.90 (m, 2H), 1.48-1.40 (m, 15H), 1.30-1.25 (m, 6H), HPLC: Rt = 5.53 min (91.5%).

[0213] Example 20: Step 4: Ethyl (((2-aminoethyl)thio)(((R)-1-ethoxy-1-oxopropan-2-yl)amino)phosphoryl)-L-alaninate TFA salt (24) [ka]

[0214] To a stirred solution of ethyl (((2-((tert-butoxycarbonyl)amino)ethyl)thio)(((R)-1-ethoxy-1-oxopropan-2-yl)amino)phosphoryl)-L-alaninate (124) (1.0 g, 2.19 mmol) in CHCl (20.0 ml) was added trifluoroacetic acid (0.33 ml, 4.38 mmol) dropwise over 10 min at 0° C. After addition, the reaction mixture was gradually warmed to room temperature and stirring was continued at room temperature for 24 h. After completion of the reaction, the solvent was removed under reduced pressure at 35° C. to give the crude compound as a thick gummy liquid (24) (TFA salt, 1.2 g). Chemical formula: C 12 H 26 N3O5PS. 1 H-NMR(400MHz,DMSO-d6)δ:7.88(bs,3H),5.54(t,J=11.2MHz,2H),4.13-4.05(m,4H),3.92-3.81(m,2H),3. 12-3.07(s,2H),2.92-2.86(m,2H),1.30(d,J=6.8MHz,6H),1.21(t,J=7.2Hz,6H),HPLC:Rt=5.48min(99.8%).

[0215] Example 21: Ethyl (((2-aminoethyl)thio)(((R)-1-ethoxy-1-oxopropan-2-yl)amino)phosphoryl)-L-alaninate fumarate salt (25) [ka]

[0216] Ethyl (((2-aminoethyl)thio)(((R)-1-ethoxy-1-oxopropan-2-yl)amino)phosphoryl)-L-alaninate TFA salt (24) (0.5 g, 1.102 mmol) was dissolved in water (5 mL) and cooled to 0-5 °C. Aqueous NaHCO3 solution was then added until the pH was 7.5-8.0. After stirring at 0-5 °C for 15 min, 10% MeOH in CHCl2 (200 mL) was added to the reaction mixture and the layers were separated. The aqueous layer was re-extracted with 10% MeOH in CHCl2 (200 mL) and the combined organic layers were dried over anhydrous NaSO4 and concentrated under reduced pressure to give a residue (0.3 g). The residue was dissolved in diethyl ether (30.0 mL) and cooled to 0-5 °C. Fumaric acid (0.102 g, 0.87 mmol) was added to the above reaction mixture and the reaction mixture was stirred at room temperature for 16 hours. After 16 hours, the solvent was removed by distillation and the semi-solid was washed twice with diethyl ether and dried. The gummy solid was lyophilized to give the compound ethyl (((2-aminoethyl)thio)(((R)-1-ethoxy-1-oxopropan-2-yl)amino)phosphoryl)-L-alaninate fumarate (25) as an off-white hygroscopic solid (0.35 g, 67.4%). Chemical formula: C 12 H26N3O5PS. 1 H-NMR(400MHz,DMSO-d6)δ:8.57(bs,2H),6.46(s,2H),5.56-5.53(m,2H),4.12-4.04(m,4H),3.88-3.84(m,2H) ,3.27-3.16(m,2H),3.04-2.83(m,2H),1.29(d,J=6.4Hz,6H),1.18(t,J=6.8Hz,6H),HPLC:Rt=7.04min(96.83%).

[0217] Scheme 9 illustrates the preparation of compound 26. [ka]

[0218] Isopropyl((S)-ethoxy((2-(N-(2-methoxy-2-oxoethyl)cyanamid)ethyl)thio)phosphoryl)-L-alaninate (125) [ka]

[0219] To a stirred solution of isopropyl (R)-ethoxy((2-((2,2,2-trifluoroacetyl)-14-azaneyl)ethyl)thio)phosphoryl)-L-alaninate (16), 3.0 g, 7.58 mmol, in THF (20 mL) was added DBU at 0° C. The reaction was warmed to room temperature and stirred for 30 min. After 30 min, the reaction mixture was cooled to 0° C. and methyl bromoacetate (1.08 mL, 11.38 mmol) was added. After stirring at 0° C. for 20 min, cyanogen bromide (1.2 g, 11.38 mmol) was added in portions. After the addition was complete, the reaction mixture was gradually warmed to room temperature and stirring was continued at room temperature for more than 16 h. The progress of the reaction was monitored by LC-MS. LC-MS indicated 62% desired product and 29% remaining starting material. Water was added, the product was extracted into ethyl acetate (2 x 100 mL), and the solvent was removed by distillation under reduced pressure. The crude compound was purified on silica gel (100-200 mesh) using 0-80% ethyl acetate in n-hexane as the eluent to give pure compound 125 as a pale yellow liquid (0.7 g, 23%). Chemical formula: C 13 H 24 N3O6PS. 1 H-NMR(400MHz,DMSO-d6):δ:6.17-6.11(m,1H),4.92-4.86(m,1H),4.07-3.99(m, 5H), 3.77-3.70(m, 4H), 3.38-3.32(m, 2H), 2.94-2.86(m, 2H), 1.35-1.17(m, 9H). ELSD-LC-MS: Rt=1.65 min (99.84%).

[0220] Example 22: Isopropyl ((S)-ethoxy((2-(2-imino-4-oxoimidazolidin-1-yl)ethyl)thio)phosphoryl)-L-alaninate (26) [ka]

[0221] A solution of isopropyl((s)-ethoxy((2-(N-2-methoxy-2-oxoethyl)cyanamid)ethyl)thio)phosphoryl)-L-alaninate (125) (700 mg, 1.77 mmol) in aqueous ammonia (1 mL) (30%, specific gravity = 0.89) was stirred at room temperature for 30 min. After 30 min, lyophilization provided isopropyl((S)-ethoxy((2-(N-(2-methoxy-2-oxoethyl)cyanamid)ethyl)thio)phosphoryl)-L-alaninate (26) as an off-white solid (500 mg, 74%). Chemical formula: C 13 H 25 N4O5PS. 1 H-NMR(400MHz,DMSO-d6):δ:7.53(bs,2H),6.18(dd,J=10.0Hz,J=10.0Hz,1H),4.92-4.86(m,1H),4.07-3. 97(m,2H),3.80-3.71(m,3H),3.62-3.47(m,2H),2.92-2.85(m,2H),1.28-1.22(m,6H),1.20-1.55(m,6H). ELSD-LC-MS: Rt=1.30 min (97.7%).

[0222] Scheme 10 illustrates the preparation of compounds 27 and 28. [ka]

[0223] Ethyl ((S)-(perfluorophenoxy)(phenoxy)phosphoryl)-L-alaninate (127b) [ka]

[0224] Ethyl L-alaninate hydrochloride (122) (50 g, 325.5 mmol) in CHCl (200 mL) was added dropwise (about 30 min) to a stirred solution of phenyl phosphorodichloridate (68.67 mL, 325.5 mmol) in dichloromethane (100 mL) at -78 °C and stirred for 10 min. Then, triethylamine (65.88 mL, 650.9 mmol) was added over 30 min at the same temperature and stirred for 1 h at the same temperature. The reaction mixture obtained above was then allowed to reach 0 °C. A solution of 2,3,4,5,6-pentafluorophenol (59.9 g, 325.5 mmol) in dichloromethane (200 mL) and triethylamine (36.23 mL, 358 mmol) were added simultaneously to the reaction mixture. The reaction mixture obtained was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was diluted with ice-cold water (250 mL) and extracted with CHCl (2×200 mL). The combined organic layers were dried over anhydrous NaSO, concentrated under reduced pressure, and the residue was recrystallized from MTBE (100 mL). The white solid was collected by filtration and washed with MTBE (3×50 mL) to give pure 127b. The filtrate (containing 4a and 4b) was concentrated, and the resulting crude solid was recrystallized again from 20% ethyl acetate in hexane (100 mL). The solid was collected by filtration and dried under high vacuum for 30 min to give an additional amount of 127b. Finally, the two recrystallized batches were combined and collected to give 70 g (49% yield) of ethyl ((S)-(perfluorophenoxy)(phenoxy)phosphoryl)-L-alaninate 127b as a white solid as a single diastereomer (absolute stereochemistry not confirmed). 1 H-NMR(400MHz,CDCl3)δ:7.38-7.34(m,2H),7.27-7.20(m,3H),4.22-4.14(m,3H),3.97-3 .94(m,1H),1.47(d,J=6.8Hz,3H),1.27(t,J=7.2Hz,3H), LC-MS:87.58%, m / z440.22[M+H] + , Chiral purity: 90.90% (by SFC method).

[0225] Ethyl ((R)-((2-((tert-butoxycarbonyl)amino)ethyl)thio)(phenoxy)phosphoryl)-L-alaninate (128) [ka]

[0226] To a stirred solution of tert-butyl (2-mercaptoethyl)carbamate (10 g, 56.91 mmol) in THF (500 mL) was added sodium hydride (50%) (2.04 g, 85.36 mmol) in portions over 30 min at 0 °C. The reaction mixture was gradually warmed to room temperature and stirred for an additional 30 min. Again, the reaction mixture was cooled to 0 °C and a solution of ethyl ((R)-(perfluorophenoxy)(phenoxy)phosphoryl)-L-alaninate 127b (25 g, 56.91 mmol) in THF (100 mL) was added to the mixture over 30 min at 0 °C. After the addition was complete, the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was cooled to 0 °C and quenched with ice-cold water (400.0 mL). The reaction mixture was extracted with ethyl acetate (2 x 400 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure at 40 °C to give a gummy liquid. The crude compound was purified by silica gel (100-200 mesh) column chromatography using 0-40% ethyl acetate in n-hexane as eluent to give compound 128 (3 g, 12.5%) as a yellow liquid. LCMS: 99.33%, m / z 433.36 [M+H] + HPLC purity: 98.88%.

[0227] Example 23: Ethyl ((R)-((2-aminoethyl)thio)(phenoxy)phosphoryl)-L-alaninate (27) [ka]

[0228] To a stirred solution of ethyl ((R)-((2-((tert-butoxycarbonyl)amino)ethyl)thio)(phenoxy)phosphoryl)-L-alaninate 128 (4 g, 9.25 mmol) in CHCl (80 mL) was added trifluoroacetic acid (3.63 mL, 46.22 mmol) dropwise at 0° C. The resulting reaction mixture was stirred at room temperature for 24 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure at 35° C. to give crude compound 27 (3.5 g, TFA salt) as a thick yellow liquid. 1 H-NMR(400MHz,DMSO-d6)δ:7.87(brs,3H),7.43-7.39(m,2H),7.25-7.21(m,3H),6.67(dd,J=10,14.4Hz,1H),4.14-4.08( m,2H),4.01-3.90(m,1H),3.10-2.94(m,4H),1.29(d,J=7.2Hz,3H),1.19(t,J=7.2Hz,3H),LCMS:99.41%,m / z333.47[M+H] + , HPLC: 99.15%.

[0229] Example 24: Ethyl ((R)-((2-aminoethyl)thio)(phenoxy)phosphoryl)-L-alaninate-fumarate (28) [ka]

[0230] Ethyl ((R)-((2-aminoethyl)thio)(phenoxy)phosphoryl)-L-alaninate TFA salt 27 (2.5 g, 7.53 mmol) was dissolved in water (30 mL) and cooled to 0 °C. An aqueous solution of NaHCO3 was then added until the pH was 8.0-10.0. After stirring at 0 °C for 30 min, diethyl ether (50 mL) was added to the reaction mixture and the organic layer was separated. The aqueous layer was extracted with diethyl ether (2 × 25 mL) and the combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the free base of 29 (1.2 g). The residue (1.2 g) was dissolved in diethyl ether (5 vol) and cooled to 0 °C. Fumaric acid (0.53 g, 4.566 mmol) was added to the above reaction mixture. The resulting reaction mixture was stirred at room temperature for 16 h. The reaction mixture was distilled in vacuum, washed with diethyl ether and dried under vacuum to give a solid residue which was washed with pentane and dried under vacuum to give 28 (400 mg, 14%) as an off-white solid. 1 H-NMR(400MHz,DMSO-d6)δ:7.42-7.38(m,2H),7.25-7.20(m,3H),6.49(s,2H),4.10(q,J=7.2Hz,2H),3.97- 3.92(m,1H),3.05-2.91(m,4H),1.29(d,J=6.8Hz,3H),1.18(t,J=7.2Hz,3H), LCMS:99.82%, m / z333.25[M+H] + , HPLC: 99.70%.

[0231] Scheme 11 illustrates the preparation of compounds 29 and 30. [ka]

[0232] Ethyl (((2-((tert-butoxycarbonyl)amino)ethyl)thio)(ethoxy)phosphoryl)-L-alaninate (129) [ka]

[0233] To a stirred solution of tert-butyl (2-mercaptoethyl)carbamate (3.62 g, 20.44 mmol) in THF (100 mL) was added sodium hydride (60%) (736.3 mg, 30.69 mmol) in portions over 30 min at 0 °C. The reaction mixture was gradually warmed to room temperature and stirred for 30 min. Again, the reaction mixture was cooled to 0 °C and ethyl (ethoxy(perfluorophenoxy)phosphoryl)-L-alaninate 126 (8 g, 20.46 mmol) in THF (100 mL) was added dropwise over 30 min. After completion of the addition, the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was cooled to 0 °C, quenched with ice-cold water (100 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure at 30 °C to give the crude compound. The crude compound was purified on silica gel (100-200 mesh) by using 0-60% ethyl acetate in n-hexane as the eluent to give compound 129 (5 g, 63%) (diastereomeric mixture) as a yellow gummy liquid. 1 H-NMR(400MHz,DMSO-d6)δ:6.96(m,1H),6.10-6.03(m,1H),4.12-4.07(m,2H),4.07-3.95(m,2H),3.82 -3.75(m,1H),3.17-3.12(m,2H),2.78-2.71(m,2H),1.38(s,9H),1.34-1.24(m,3H),1.22-1.16(m,6H).

[0234] Example 25: Ethyl (((2-aminoethyl)thio)(ethoxy)phosphoryl)-L-alaninate (29) [ka]

[0235] To a stirred solution of ethyl (((2-((tert-butoxycarbonyl)amino)ethyl)thio)(ethoxy)phosphoryl)-L-alaninate 129 (5 g, 13.02 mmol) in CHCl (50 mL) was added trifluoroacetic acid (5.3 mL, 65.1 mmol) dropwise at 0° C. The resulting reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure at 35° C. to provide compound 29 (4.5 g, TFA salt, 90%) (diastereomeric mixture) as a thick gummy liquid. 1 H-NMR(400MHz,DMSO-d6)δ:8.33-8.20(m,1H),8.00-7.82(m,3H),6.26-6.20(m,1H),4.13-4.01(m,4H) ,3.99-3.78(m,1H),3.10-3.08(m,2H),2.98-2.90(m,2H),1.31-1.17(m,9H),HPLC:(81.57% and 16.77%).

[0236] Example 26: Ethyl (((2-aminoethyl)thio)(ethoxy)phosphoryl)-L-alaninate fumarate (30) [ka]

[0237] Ethyl (((2-aminoethyl)thio)(ethoxy)phosphoryl)-L-alaninate TFA salt 29 (4.0 g, 10.46 mmol) was dissolved in water (100 mL) and cooled to 0 °C. Aqueous NaHCO3 solution was then added until the pH was 7.5-8.0. After stirring at 0 °C for 15 min, 10% MeOH in CHCl2 (100 mL) was added into the reaction mixture and the organic layer was separated. The aqueous layer was extracted with 10% MeOH in CHCl2 (2 × 100 mL) and the combined organic layers were dried over anhydrous NaSO4 and concentrated under reduced pressure to provide a residue. The residue was dissolved in diethyl ether (50 mL) and cooled to 0 °C. Fumaric acid (0.68 g, 5.85 mmol) was then added to the above solution and the reaction mixture was stirred at room temperature for 16 h. The reaction mass was vacuum distilled, washed with diethyl ether and dried under vacuum to give 30 (2.72 g, 65%) (diastereomeric mixture) as an off-white material. 1 H-NMR(400MHz,DMSO-d6)δ:8.80(brs,1H),6.47(s,2H),6.24(m,1H),4.13-3.98(m,4H),3.81(m,1H),3.02 -2.98(m,2H),2.94-2.86(m,2H),1.30-1.18(m,9H), HPLC:(86.7% and 13.3%), LCMS:(80.58% and 18.96%)(m / z 285.22[M+H] + ).

[0238] Scheme 12 illustrates the preparation of compound 31. [ka]

[0239] Isopropyl ((R)-((2-((tert-butoxycarbonyl)(methyl)amino)ethyl)thio)(ethoxy)phosphoryl)-L-alaninate (130) [ka]

[0240] To a stirred solution of tert-butyl (2-mercaptoethyl) (methyl) carbamate (10 g, 52.3 mmol) in THF (100 mL) was added sodium hydride (2.0 g, 78.53 mmol) in portions over 30 min at 0 °C. The resulting reaction mixture was gradually warmed to room temperature and stirred for 30 min. The reaction mixture was cooled back to 0 °C and a solution of isopropyl ((R)-ethoxy(perfluorophenoxy)phosphoryl)-L-alaninate (118) (25.4 g, 62.8 mmol) in THF (130 mL) was added over 30 min. The resulting reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was quenched with ice-cold water (300.0 mL) and extracted with ethyl acetate (2 x 250 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure at 40 °C to give a gummy liquid. The crude compound was purified by silica gel column chromatography (100-200 mesh) using 0-80% ethyl acetate in n-hexane as the eluent to give compound 130 as a gummy liquid (9.5 g, 44.02%). LC-MS: 95.28% (m / z 413.41 [M+H] + ).

[0241] Example 27: Isopropyl ((R)-ethoxy((2-(methylamino)ethyl)thio)phosphoryl)-L-alaninate (34) [ka]

[0242] To a stirred solution of isopropyl ((R)-((2-((tert-butoxycarbonyl)(methyl)amino)ethyl)thio)(ethoxy)phosphoryl)-L-alaninate 130 (9.58 g, 23.2 mmol) in CHCl (50 mL) was added trifluoroacetic acid (7.16 mL, 93.0 mmol) dropwise at 0-5° C. The resulting reaction mixture was stirred at room temperature for 24 h. After completion of the reaction (monitored by TLC), the reaction mass was concentrated under reduced pressure at 35° C. to give crude compound 34 (9.5 g, TFA salt, 98%) as a thick gummy liquid, which was used in the next reaction without further purification. LCMS: 99% m / z 313.39% [M+H] + .

[0243] Example 28: Isopropyl ((R)-((2-(3-carbamimidoyl-1-methylguanidino)ethyl)thio)(ethoxy)phosphoryl)-L-alaninate (31) [ka]

[0244] To a stirred solution of isopropyl((R)-ethoxy((2-(methylamino)ethyl)thio)phosphoryl)-L-alaninate (TFA salt) 34 (1 g, 2.44 mmol) in THF (18 mL) was added N-carbamimidoyl-1H-pyrazole-1-carboximidamide (408 mg, 2.44 mmol) and TEA (1.34 mL, 9.6 mmol) at room temperature. The resulting reaction mixture was heated at 60° C. for 6 h. After completion of the reaction (monitored by LC-MS), the reaction mixture was concentrated under reduced pressure to give compound 31, which was purified by prep-HPLC to give a pale yellow semi-solid compound 31 (220 mg, 22%). 1H-NMR(400MHz,DMSO-d6)δ:7.24(brs,2H),6.71(brs,3H),6.12(m,1H),4.93-4.86(m,1H),4.07-4.01(m,2H),3.78-3.71(m,1H),3.5 7-3.53(m,2H),2.97(s,3H),2.90-2.86(m,2H),1.29-1.24(m,6H),1.20-1.19(m,6H), HPLC purity:99.53%, LCMS:99.33%(m / z397.55[M+H] + ).

[0245] Scheme 13 illustrates the preparation of compounds 32 and 33. [ka]

[0246] Ethyl ((S)-((2-((tert-butoxycarbonyl)amino)ethyl)thio)(ethoxy)phosphoryl)-L-alaninate (131) [ka]

[0247] To a stirred solution of tert-butyl (2-mercaptoethyl)carbamate (1.61 g, 9.11 mmol) in THF (40 mL) was added sodium hydride (0.32 g, 13.67 mmol, 60%) in portions over 30 min at 0 °C. The reaction mixture was gradually warmed to room temperature and stirred for 30 min. The reaction mixture was then cooled to 0 °C and a solution of ethyl ((R)-ethoxy(perfluorophenoxy)phosphoryl)-L-alaninate 130 (3.5 g, 9.11 mmol) in THF (50 mL) was added to the reaction mixture over 30 min. The resulting reaction mixture was stirred at room temperature for 16 h. The reaction was quenched with ice-cold water (50 mL) and extracted with ethyl acetate (2 x 60 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure at 40 °C to give a yellow gummy liquid. The crude compound was purified on silica gel (100–200 mesh) by using 0–60% ethyl acetate in n-hexane as the eluent to give ethyl ((S)-((2-((tert-butoxycarbonyl)amino)ethyl)thio)(ethoxy)phosphoryl)-L-alaninate 131 (1.9 g, 55%) as a yellow gummy liquid. 1 H-NMR(400MHz,CDCl3)δ:5.32(brs,1H),4.24-4.11(m,4H),4.00-3.93(m,1H),3.80-3.75(m,1H),3.44 -3.40(m,2H),3.00-2.87(m,2H),1.44-1.42(m,12H),1.39-1.24(m,6H), LCMS:99.67%, m / z385.31[M+H] + ,

[0248] Example 29: Ethyl ((S)-((2-aminoethyl)thio)(ethoxy)phosphoryl)-L-alaninate TFA salt (32) [ka]

[0249] To a stirred solution of ethyl ((S)-((2-((tert-butoxycarbonyl)amino)ethyl)thio)(ethoxy)phosphoryl)-L-alaninate 131 (1.9 g, 4.94 mmol) in CHCl (20 mL) was added trifluoroacetic acid (2.25 mL, 19.73 mmol) dropwise at 0° C. The resulting reaction mixture was stirred at room temperature for 24 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure at 35° C. to provide compound 32 (2.5 g as TFA salt) as a thick gummy liquid. LC-MS: 99.22% (m / z 285.25 [M+H] + ).

[0250] Example 30: Ethyl ((S)-((2-aminoethyl)thio)(ethoxy)phosphoryl)-L-alaninate fumarate salt (33) [ka]

[0251] Ethyl ((S)-((2-aminoethyl)thio)(ethoxy)phosphoryl)-L-alaninate TFA salt 32 (1.5 g, 3.92 mmol) was dissolved in water (10 mL) and aqueous NaHCO3 solution was added until the pH was 7.5-8.0. After stirring at 0 °C for 15 min, 10% MeOH in CHCl2 (40 mL) was added to the reaction mixture and the organic layer was separated. The aqueous layer was extracted with 10% MeOH in CHCl2 (2 × 20 mL) and the combined organic layers were dried over anhydrous NaSO4 and concentrated under reduced pressure to provide a residue. The residue was dissolved in diethyl ether (20 mL) and cooled to 0 °C. Fumaric acid (0.415 g, 3.52 mmol) was then added to the above reaction mixture and stirred at room temperature for 16 h. The reaction mixture was vacuum distilled, washed with diethyl ether and dried under vacuum to provide 33 (1.46 g, 93%) as an off-white solid (slightly hygroscopic). 1H-NMR(400MHz,DMSO-d6)δ:9.41(brs,2H),6.48(s,2H),6.26-623(m,1H),4.13-4.01(m,4H ),3.82-3.81(m,1H),3.04-2.87(m,4H),1.31-1.18(m,9H), LC-MS:99.87%, m / z285.31[M+H] + , HPLC: 99.13%.

[0252] Scheme 14 illustrates the preparation of compound 35. [ka]

[0253] Example 31: Isopropyl ((R)-((2-(2,4 dioxoimidazolidin-1-yl)ethyl)thio)(ethoxy)phosphoryl)-L-alaninate (35) [ka]

[0254] Isopropyl((R)-ethoxy((2-(N-(2-methoxy-2-oxoethyl)cyanamid)ethyl)thio)phosphoryl)-L-alaninate 125 (500 mg, 1.26 mmol) was treated with dibutyl phosphate (510 mg, 2.53 mmol) and heated at 100° C. for 2 h. The reaction mixture was then cooled to room temperature and washed with petroleum ether (2×50 mL) to provide the solid as crude compound. The crude compound was purified by mass-directed reverse-phase prep-HPLC (column: X-SELECT-CSH C18 (25×150 mm), 10μ, mobile phase A: water containing 0.1% FA, mobile phase B: acetonitrile, gradient: (T / %B): 0 / 20, 2 / 20, 10 / 60, 10.1 / 98, 13 / 98, 13.11 / 20, 15 / 20 Flow rate: 19 mL / min to provide 35 (150 mg, 31%) as an off-white solid. 1HNMR(400MHz,DMSO-d6)δ:10.76(brs,1H),6.07(dd,J=13.6Hz,1H),4.92-4.86(m,1H),4.06-3.97(m,4H), 3.78-3.71(m,1H),3.51-3.43(m,2H),2.91-2.84(m,2H),1.28-1.18(m,12H), LCMS:99.7%(m / z382.26[M+H] + ).

[0255] Scheme 15 illustrates the preparation of 36: [ka]

[0256] Example 32: Isopropyl ((R)-((2-(1,3-dioxoisoindolin-2-yl)ethyl)thio)(ethoxy)phosphoryl)-L-alaninate (36) [ka]

[0257] To a stirred solution of 2-(2-mercaptoethyl)isoindoline-1,3-dione (511 mg, 2.46 mmol) in THF (10 mL) was added sodium hydride (60% in mineral oil) (88 mg, 3.70 mmol) in portions over 30 min at 0 °C. The resulting reaction mixture was gradually warmed to room temperature and stirred for 30 min. The reaction mixture was then re-cooled to 0 °C and a solution of isopropyl((S)-ethoxy(perfluorophenoxy)phosphoryl)-L-alaninate (119) (1 g, 2.46 mmol) in THF (20 mL) was added over 15 min and stirred at room temperature for 12 h. The reaction mixture was then quenched with ice-cold water (50 mL) and extracted with ethyl acetate (2 x 100 mL) and the combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure at 40 °C to give a freshly gummy liquid. The crude compound was purified by silica gel column chromatography (100-200 mesh) using 0-80% ethyl acetate in n-hexane as the eluent to give 36 as an off-white solid (600 mg, 57%). 1HNMR(400MHz,CDCl3)δ:7.91-7.83(m,4H),6.04(dd,J=14.0,13.6Hz,1H),4.87-4.81(m,1H),4.02-3.93(m,2H),3.85(t,J=7.2Hz,2H),3.77-3.70(m,1H),3.02-2.98(m,2H),1.26-1.15(m,12H)、LC-MS:76%(m / z429.31[M+H] + )。

Claims

1. Structural formula (I): 【Chemistry 1】 (In the formula, R １ is a thiol residue of molecular weight less than 1000 daltons, Y is -NR ２ R ３ and X is -OR ４ Or -SR １ and R ２ and R ３ is independently -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl; or R ２ and R ３ together with the atom to which they are attached form a cycloalkyl ring, a substituted cycloalkyl ring, a cycloalkenyl ring, a substituted cycloalkenyl ring, a heterocycloalkyl ring, a substituted heterocycloalkyl ring, a heterocycloalkenyl ring, or a substituted heterocycloalkenyl ring; and R ４ is alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, or substituted heteroarylalkyl; However, R ２ and R ３ are not both -H, and R ２ and R ３ are not included in the formula (I), unless R is an integer from 1 to 5, and R is an integer from 1 to 5, and R is an integer from 1 to 5, ２ and R ３ one of which is -H) or a pharma- ceutically acceptable salt, hydrate, or solvate thereof.

2. R １ is a thiol residue of molecular weight less than 500 daltons.

3. R １ but, 【Chemistry 2】 and R １０１ ~R １０３ , R １０６ , R １０９ , R １１６ ~ １１８ is independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, and R １０４ , R １０５ , R １０７ , R １０８ , R １１０ ~R １１５ , and R １１９ ~R １２９ is independently -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl.

4. R １０１ ~R １０３ , R １０６ , R １０９ , R １１６ ~ １１８ is independently alkyl or alkenyl, and R １０４ , R １０５ , R １０７ , R １０８ , R １１０ ~R １１５ , and R １１９ ~R １２９ The compound of claim 3, wherein is independently -H, alkyl, or alkenyl.

5. R ２ and R ３ is independently -H, substituted alkyl, substituted alkenyl, substituted arylalkyl, substituted arylalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, substituted heteroarylalkyl, or substituted heteroarylalkenyl.

6. R ２ and R ３ The compound of any one of claims 1 to 4, wherein is independently -H, substituted alkyl, substituted alkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, or substituted heteroalkenyl.

7. R ２ and R ３ The compound of any one of claims 1 to 4, wherein is independently -H, substituted alkyl, or substituted alkenyl.

8. R ２ and R ３ are independently -H or -CHR ５ CO ２ R ６ and R ５ is -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroaryl, or substituted heteroaryl, and R ６ The compound of any one of claims 1 to 4, wherein is alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, or substituted cycloheteroalkenyl.

9. R ２ and R ３ are independently -H or -CHR ５ CO ２ R ６ and R ５ is —H, alkyl, substituted alkyl, alkenyl, or substituted alkenyl, and R ６ The compound according to any one of claims 1 to 4, wherein is alkyl, alkenyl or arylalkenyl.

10. R ２ and R ３ are independently -H, or 【Chemistry 3】 10. The compound of claim 9,

11. R ２ and R ３ is -H, and R ２ and R ３ The other one is 【Chemistry 4】 10. The compound of claim 9,

12. R ４ is alkyl, alkenyl, cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, or substituted heteroarylalkyl.

13. R ４ The compound of any one of claims 1 to 11, wherein is alkyl, alkenyl, aryl, or substituted aryl.

14. The compound is 【Chemistry 5】 【change】 【change】 【change】 2. The compound of claim 1 selected from the group consisting of:

15. Structural formula: 【Chemistry 6】 and pharma- ceutically acceptable salts, hydrates, or solvates thereof.

16. 16. The compound of claim 15, wherein the pharma- ceutically acceptable salt is a trifluoroacetate salt.

17. Structural formula: 【Chemistry 7】 and pharma- ceutically acceptable salts, hydrates, or solvates thereof.

18. 18. The compound of claim 17, wherein the pharma- ceutically acceptable salt is a trifluoroacetate salt.

19. Structural formula: 【Chemistry 8】 and pharma- ceutically acceptable salts, hydrates, or solvates thereof.

20. 20. The compound of claim 19, wherein the pharma- ceutically acceptable salt is a trifluoroacetate salt.

21. 20. The compound of claim 19, wherein the pharma- ceutically acceptable salt is a fumarate salt.

22. Structural formula: 【Chemistry 9】 and pharma- ceutically acceptable salts, hydrates, or solvates thereof.

23. 23. The compound of claim 22, wherein the pharma- ceutically acceptable salt is a trifluoroacetate salt.

24. 23. The compound of claim 22, wherein the pharma- ceutically acceptable salt is a fumarate salt.

25. Structural formula: 【Chemistry 10】 and pharma- ceutically acceptable salts, hydrates, or solvates thereof.

26. 26. The compound of claim 25, wherein the pharma- ceutically acceptable salt is a trifluoroacetate salt.

27. 26. The compound of claim 25, wherein the pharma- ceutically acceptable salt is a fumarate salt.

28. A pharmaceutical composition comprising any of the compounds according to any one of claims 1 to 27 and a pharma- ceutically acceptable medium.

29. A method for treating cystinuria comprising administering to a patient in need thereof a therapeutically effective amount of any of the compounds according to any one of claims 1 to 27 or the pharmaceutical composition according to claim 28.

30. 29. A method for treating cystinosis, cystinuria, cancer neurodegenerative diseases, Parkinson's disease, Huntington's disease, malaria, non-alcoholic fatty liver disease, radiation poisoning, arsenic poisoning, radioprotection, Wilson's disease, or rheumatoid arthritis comprising administering to a patient in need thereof a therapeutically effective amount of any of the compounds of any one of claims 1 to 27 or the pharmaceutical composition of claim 28.

Images