WO2015179293A1 - Small molecule activators and inhibitors of lecithin: cholesterol acyltransferase - Google Patents

Abstract

The disclosure includes compounds and salts of Formula I, II, and III. The variables R, R₀, R₁, R₁₀, R₁₁, and R₂ are defined herein. Compounds and salts of Formula I, II, and III are useful as modulators of Lecithin: cholesterol acyltransferase (LCAT), a protein that mediates the transfer of fatty acids from lecithin to cholesterol to form cholesterol ester and lysolecithin. LCAT activators of Formula I, II, and III are useful for modulating HDL cholesterol levels and for treating genetic disorders caused by LCAT mutations such as familial LCAT deficiency. Some compounds and salts of Formula I, II, and III are also useful for treating diseases in which LCAT inhibition is desirable, such as lysosomal acid lipase deficiency and Wolman's disease. The disclosure also includes pharmaceutical compositions and method of treatment employing a compound of Formula I, II, or III.

Description

SMALL MOLECULE ACTIVATORS AND INHIBITORS OF LECITHIN: CHOLESTEROL

ACYLTRANSFERASE

CROSS REFERENCE TO RELATED APPLICATION

This application claims priority from U.S. Provisional Application No. 61/994,987, filed May 18, 2014, which is hereby incorporated by reference in its entirety.

STATEMENT OF GOVERNMENT SUPPORT

[0001] This invention was made in part with government support from the National Institutes of Health. The government has certain rights in this invention.

BACKGROUND

[0002] Lecithin:cholesterol acyltransferase (LCAT) mediates the transfer of a fatty acid from phosphatidylcholine (lecithin) to cholesterol to form cholesterol ester and lysolecithin. LCAT mediates this reaction via a two-step reaction. First, it preferentially cleaves fatty acids from the sn-2 position of phospholipids by a phospholipase A-2 activity. LCAT also has an acyltransferase activity and transesterifies the cleaved fatty acid onto the hydroxyl group onto the A-ring of cholesterol to produce cholesterol ester. It performs both of these steps in absence of an external energy source, such as ATP. Phosphatidylcholine is the preferred phospholipid substrate for LCAT, but it can also act on other phospholipids, such as phosphatidylethanolamine. LCAT also has a preference for unsaturated fatty acids in the sn-2 position, and the preferred length of the fatty acid can vary depending on the species. Cholesterol is the preferred sterol substrate for LCAT, but it can also esterify other closely related sterols.

[0003] LCAT esterifies cholesterol in high density lipoproteins (HDL) to a greater extent than low density lipoproteins (LDL). LCAT is activated by apoA-I, the main protein component on HDL, and then utilizes the lipids on HDL, namely cholesterol and phospholipids, as its substrates. Discoidal HDL, which is sometimes called pre -beta HDL based on its electrophoretic migration position, is newly formed HDL and is particularly efficient in promoting the LCAT reaction.

Esterification of cholesterol converts discoidal HDL into a spherical shaped HDL. Cholesterol esters are much more hydrophobic than free cholesterol, causing the esterified cholesterol to partition from the surface of a discoidal HDL into the core, leading to the transformation of discoidal HDL into spherical HDL.

[0004] LCAT can also be found on LDL particles but it is not as active on LDL as on HDL. The affinity of human LCAT for LDL is 2- 4 fold lower than for HDL. More mature spherical forms of HDL are also relatively poor substrates compared to discoidal HDL. Nonetheless, a substantial fraction, sometimes as much as 30%, of the overall cholesterol esterification is thought to occur directly on LDL. Activity on LDL is referred to as β-LCAT activity, whereas activity on HDL is termed a-LCAT activity. Some mutations in LCAT are thought to preferentially affect esterification on HDL, and these mutations may lead to preferential loss of a-LCAT activity and partial retention of β-LCAT activity.

[0005] LCAT also participates in the removal of excess cellular cholesterol in peripheral cells by the reverse cholesterol transport (RCT) pathway. While recent studies have revealed that cholesterol homeostasis by most peripheral tissues is relatively unaffected by HDL and the RCT pathway, efflux of cholesterol from certain cell types, such as macrophages in the vessel wall, appears to be critical in preventing foam cell formation and inflammation, during the process of

atherosclerosis. Simple removal of excess cholesterol from macrophages by HDL and its redistribution of cholesterol among other tissues may be sufficient for reducing atherosclerosis rather than the necessity for delivering it to the liver for excretion. LCAT is thought to help facilitate the RCT pathway largely because without LCAT, mature spherical shaped HDL cannot be adequately formed. Discoidal HDL, perhaps because of its small size and/or instability is rapidly catabolized by the kidney. The majority of cholesterol esters formed by LCAT in the plasma are removed by the liver. Because it is more polar, free cholesterol removed from peripheral cells by HDL can also readily exchange back and be taken up by other peripheral cells. However, once cholesterol is esterified and is trapped in the core of a lipoprotein, it is more likely to be removed from the body by hepatic excretion.

[0006] Other properties of LCAT can potentially affect HDL metabolism and

atherosclerosis. For example, LCAT also hydrolyses oxidized phospholipids and may help protect against oxidized LDL, it can possibly modulate the binding of thrombin and platelet aggregation, enhance insulin sensitivity, and regulate glucocorticoid levels, by providing a source of sterols for steroid synthesis in the adrenal glands. Besides modulating the level of HDL-cholesterol (HDL-C), the level of LDL-cholesterol (LDL-C) is also affected by LCAT. This may be due in part to the direct esterification of cholesterol that can occur on LDL, but is most likely due to a significant fraction of cholesterol on LDL being derived from HDL after transfer of cholesterol esters by Cholesterol Ester Transfer Protein (CETP) or by simple exchange of free cholesterol from HDL.

[0007] In addition to its role in LCAT metabolism, LCAT also plays a role in several genetic disorders. Mutations in the LCAT protein which cause loss or reduction of LCAT activity are responsible for Familial LCAT deficiency (FLD) or Fish Eye Disease (FED). Genetic LCAT deficiency is a rare autosomal recessive disorder with an incidence of less than 1 in 200,000, although the frequency is likely to be higher because of misdiagnosis or under diagnosis. FLD is characterized by the absence of LCAT activity for both HDL and LDL. FED is characterized by the absence of LCAT activity toward HDL only.

[0008] Originally, it was thought the different manifestation of FLD and FED may be due to the residual amount of LCAT activity present on either on HDL or LDL particles. It is understood that these two disorders represent a continuum of LCAT deficiency with FLD patients having a more profound decrease in total LCAT activity. Clinically, the absence of proteinuria and other signs of renal damage are often used to distinguish between these two disorders, although the development of renal disease often takes decades and thus the prognosis of a patient with a new LCAT mutation may remain uncertain.

[0009] FLD is characterized by extremely low or absent HDL, mild to moderate

hypertriglyceridemia, the development of cloudy cornea in the teenage years, followed by early asymptomatic proteinuria. Normochromic anemia often develops over the next decade, but it is typically mild. Proteinuria often steadily progresses to nephrotic syndrome, resulting in end stage renal disease in the fourth or fifth decade of life. The clinical features of FED are also extremely low or absent HDL and development of cloudy corneas in the teenage years, but the absence of any significant proteinuria and renal disease. Heterozygotes for FLD or FED have no outward clinical symptoms and only have a mildly reduced HDL-C (20-30 mg/dL, 0.52-0.78 mmole/L) and may be at an increased risk for cardiovascular disease.

[0010] Patients with a genetic defect in LCAT form Lipoprotein X (LpX), an abnormal cholesterol and phospholipid rich lipoprotein particle that is poor in neutral lipids (cholesterol esters and triglycerides). Unlike normal lipoproteins, which have a micellar-like arrangement of a single layer of phospholipids surrounding a hydrophobic core of cholesterol ester and triglylcerides, LpX has a vesicular structure. Because of the high ratio of amphipathic surface lipids (unesterified cholesterol and phospholipids) to neutral core lipids, LpX forms a bilayer of phospholipids or even a

multilamellar phospholipid arrangement, which results in its "onion-like" appearance on electron microscopy. LpX particles are heterogeneous in size (30-100 nm) and can have a density between LDL and VLDL. The genesis of LpX in patients with FLD is not known, but the low level of plasma cholesterol esters most likely contributes to its formation in this disorder. The presence of LpX particles in FLD is likely a major causative factor in the development of renal disease in FLD patients.

[0011] In certain instances LCAT inhibition is clinically desirable. Lysosomal Acid Lipase (LAL) deficiency is a rare autosomal recessive disorder. Children born with mutations in both copies of the gene for the lysosomal acid lipase enzyme are unable to process cholesterol esters and triglycerides. LAL deficiency causes liver fibrosis, cirrhosis, and liver failure. In the most severe form of LAL deficiency, Wolman' s disease, the lack of LAL activity results in the rapid buildup of fatty materials in the liver, gut, and blood vessels. Wolman' s disease is fatal in the first year of life. A more prevalent and benign form of LAL-deficiency is Cholesterol ester storage disorder CESD. Individuals affected with this disorder have only a partial loss of LAL activity and present with hepatomegaly in early childhood or adulthood and often go on to develop liver cirrhosis and failure. Patients with CESD are also at increased risk for developing premature atherosclerosis, due to hypercholesterolemia and increased atheroma foam cell formation. LCAT inhibition prevents the formation of cholesterol esters and would likely extend the life of patients suffering from LAL deficiency. While inhibiting LCAT may lead to the problems associated with FLD, the symptoms of FLD do not present until middle age. Thus, LCAT inhibition is a reasonable treatment option for LAL deficiency patients.

[0012] Because LCAT activators are useful for treating atherosclerosis, FLD, and FED and LCAT inhibitors are useful for treating LAL deficiency, there is a need for molecules that modulate LCAT activity. This disclosure fulfills this need and provides additional advantages described herein,

SUMMARY

[0013] The disclosure provides compounds of Formula I, II, and III, and pharmaceutically acceptable salts thereof, that act as LCAT modulators. Certain compounds and salts of Formula I, II, and III act as LCAT inhibitors or LCT activators.

(Formula

III).

[0014] Within Formula I the variables R, R₀, Ri, and R₂ carry the following definitions.

[0015] R is chosen from hydrogen and Ci-C₄alkyl.

[0016] Ro is hydrogen, Ci-C₄alkyl, or -ORx, where Rx is d-Qalkyl, -C(0)CH₃, Ar_{1 ;} or - CH₂phenyl.

[0017] Ri is -Li-Ari or, for Formula II, Ri may also be -Qi, where

Li is NH, O, Se, or S(0)m, where m is 0, 1 , or 2.

[0018] Qi is C₂-C₆ alkenyl or alkynyl.

[0019] Rio and Rn are in dependently chosen from H and -L Rz, where Li is N, O, Se, or S(0)m, where m is 0, 1 , or 2 and Rz is Ci-Cealkyl.

[0020] Ari is independently chosen at each occurrence from phenyl, naphthyl, and 5- or 6- membered heteroaryl groups having from 1 to 3 heteroatoms independently chosen from N, O, and S, each of which Ari is unsubstituted or substituted with 1 or more substituents independently chosen from halogen, hydroxyl, amino, cyano, nitro, -CHO, -COOH, -SH, Ci-C₈alkyl, C₂-C₈alkenyl, C₂- C₆alkanoyl, (Ci-C₆alkoxy)C₀-C₄alkyl, (Ci-C₆alkylthio)C₀-C₄alkyl, (mono- and di-Ci- C₆alkylamino)C₀-C₄alkyl, (C₃-C₆cycloalkyl)C₀-C₄alkyl, mono- and di-Ci-C₆alkylcarboxamide, mono- and di-Ci-C₆alkylester, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy.

[0021] Q_! is C₂-C₆alkenyl or C₂-C₆ alkynyl.

[0022] R₂ is hydrogen, d-Csalkyl, SRy, where Ry is d-Csalkyl, or S0₃H; or R₂ is

-L₂-Ar₂.

[0023] L₂ is -S-, -C(0)NR₃(CR4R₅)n- or -C(0)0(CR4R₅)n-, where n is 0, 1 , or 2.

[0024] R₃ is hydrogen, Ci-C₄alkyl, or phenyl. [0025] R4 and R₅ are independently chosen from hydrogen, halogen, Ci-C₄alkyl, or d- C₄alkoxy.

[0026] Ar₂ is phenyl, naphthyl, or a 5- or 6-membered heteroaryl group having from 1 to 3 heteroatoms independently chosen from N, O, and S, each of which Ar₂ is unsubstituted or substituted with 1 or more substituents independently chosen from halogen, hydroxyl, amino, cyano, nitro, -CHO, -COOH, -SH, Ci-Cgalkyl, C₂-C₈alkenyl, C₂-C₆alkanoyl, (C₁-C₆alkoxy)Co-C₄alkyl, (Q- C₆alkylthio)C₀-C₄alkyl, (mono- or di-Ci-C₆alkylamino)C₀-C alkyl, (C₃-C₆cycloalkyl)C₀-C alkyl, mono- or di-Ci-Cealkylcarboxamide, Ci-Cealkylester, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy.

[0027] The variables in Formula II carry the same definitions as set forth for Formula I except R₂ is- L₂-Ar₂; where L₂ is -S-, -(CR R5)n- or -C(0)0(CR R5)n-, where n is 0, 1, or 2.

[0028] The variables in Formula III, except Ri₀ and Rn which are not defined in Formula I, carry the same definitions as set forth for Formula I.

[0029] The disclosure also comprises a pharmaceutical composition comprising a compound or salt of Formula I, II, or III together with a pharmaceutically acceptable carrier.

[0030] The disclosure also provides methods of treatment in which LCAT is activated or inhibited in a patient by administering a therapeutically effective amount of a compound or salt of Formula I , II, or III to the patient.

DETAILED DESCRIPTION

TERMINOLOGY

[0031] Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.

[0032] The terms "a" and "an" do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. The term "or" means "and/or". The open-ended transitional phrase "comprising" encompasses the intermediate transitional phrase "consisting essentially of and the close-ended phrase "consisting of." Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are included within the range and independently combinable. All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as"), is intended merely for illustration and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention. [0033] Compounds of Formula I include other formulae disclosed herein within the scope of Formula I. These include, for example, compounds 2-56 and 62-79. Compounds of Formula II include all other formulae disclosed herein within the scope of Formula II. These include, for example, compounds 57-61. Compounds of Formula III include other formulae disclosed herein within the scope of Formula III, for example compound 80.

[0034] Compounds of Formula I , II, and III include compounds of these formulae having isotopic substitutions at any position. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example, and without limitation, isotopes of hydrogen include tritium and deuterium and isotopes of carbon include ⁿC, ¹³C, and ¹⁴C. Compounds of Formula I, II, and III also require enrichment of deuteration (substitution of a hydrogen atom with deuterium) at identified positions.

[0035] An "active agent" is a compound (including a compound disclosed herein), element, or mixture that when administered to a patient, alone or in combination with another compound, element, or mixture, confers, directly or indirectly, a physiological effect on the patient. The indirect physiological effect may occur via a metabolite or other indirect mechanism.

[0036] The term "substituted", as used herein, means that any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded.

[0037] A "dosage form" means a unit of administration of an active agent. Non-limiting examples of dosage forms include tablets, capsules, injections, suspensions, liquids, intravenous fluids, emulsions, creams, ointments, suppositories, inhalable forms, transdermal forms, and the like.

[0038] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -(C=0)NH₂ is attached through carbon of the keto (C=0) group.

[0039] "Alkyl" is a branched or straight chain saturated aliphatic hydrocarbon group, having the specified number of carbon atoms, generally from 1 to about 12 carbon atoms. The term d- C₆alkyl as used herein indicates an alkyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms. Other embodiments include alkyl groups having from 1 to 8 carbon atoms, 1 to 4 carbon atoms or 1 or 2 carbon atoms, e.g. Ci-C₈alkyl, Ci-C₄alkyl, and Ci-C₂alkyl. When C₀-C_n alkyl is used herein in conjunction with another group, for example, (C₃.C₇cycloalkyl)Co-C4 alkyl, the indicated group, in this case cycloalkyl, is either directly bound by a single covalent bond (C₀alkyl), or attached by an alkyl chain having the specified number of carbon atoms, in this case 1, 2, 3, or 4 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, 3- methylbutyl, t-butyl, n-pentyl, and sec-pentyl.

[0040] "Alkenyl" is a branched or straight chain aliphatic hydrocarbon group having one or more double carbon-carbon bonds that may occur at any stable point along the chain, having the specified number of carbon atoms. Examples of alkenyl include, but are not limited to, ethenyl and propenyl.

[0041] "Alkynyl" is a branched or straight chain aliphatic hydrocarbon group having one or more triple carbon-carbon bonds that may occur at any stable point along the chain, having the specified number of carbon atoms. Examples of alkynyl include, but are not limited to, ethynyl and propynyl.

[0042] "Alkoxy" is an alkyl group as defined above with the indicated number of carbon atoms covalently bound to the group it substitutes by an oxygen bridge (-0-). Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3- pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and 3- methylpentoxy.

[0043] "Alkylthio" is an alkyl group as defined above with the indicated number of carbon atoms covalently bound to the group it substitutes by an sulfur bridge (-S-).

[0044] "Alkanoyl" is an alkyl group as defined above with the indicated number of carbon atoms covalently bound to the group is substitutes through a carbonyl (C=0) bridge. The carbonyl carbon is included in the number of carbons, that is C₂alkanoyl is a CH₃(C=0)- group.

[0045] "Alkylester" is an alkyl group as defined herein covalently bound to the group it substitutes by an ester linkage. The ester linkage may be in either orientation, e.g., a group of the formula -0(C=0)alkyl or a group of the formula -(C=0)Oalkyl.

[0046] The term "mono- and/ or di-alkylamino" indicates secondary or tertiary alkyl amino groups, wherein the alkyl groups are independently chosen alkyl groups, as defined herein, having the indicated number of carbon atoms. The point of attachment of the alkylamino group is on the nitrogen. Examples of mono- and di-alkylamino groups include ethylamino, dimethylamino, and methyl-propyl-amino.

[0047] "Mono- and/or di-alkylcarboxamide" includes mono-alkylcarboxamide groups of formula (alkyl_!)0(C=0)NH- or a dialkylcarboxamide groups of the formula

(alkyl₁)0(C=0)N(alkyl₂)- in which the point of attachment of the mono- or dialkylcarboxamide substituent to the molecule it substitutes is on the nitrogen of the carboxamide amino.

[0048] "Aryl" indicates aromatic groups containing only carbon in the aromatic ring or rings. Aryl groups include, for example, phenyl and naphthyl, including 1- naphthyl and 2-naphthyl.

[0049] "Cycloalkyl" is a saturated hydrocarbon ring group, having the specified number of carbon atoms. Monocyclic cycloalkyl groups typically have from 3 to about 8 carbon ring atoms or from 3 to 7 (3, 4, 5, 6, or 7) carbon ring atoms. Cycloalkyl substituents may be pendant from a substituted nitrogen or carbon atom, or a substituted carbon atom that may have two substituents may have a cycloalkyl group, which is attached as a spiro group. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. [0050] "Haloalkyl" indicates both branched and straight-chain alkyl groups having the specified number of carbon atoms, substituted with 1 or more halogen atoms, up to the maximum allowable number of halogen atoms. Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl.

[0051] "Haloalkoxy" indicates a haloalkyl group as defined herein attached through an oxygen bridge (oxygen of an alcohol radical).

[0052] "Halo" or "halogen" indicates any of fluoro, chloro, bromo, and iodo.

[0053] "Heteroaryl" indicates a stable monocyclic aromatic ring having the indicated number of ring atoms which contains from 1 to 3, or in some embodiments from 1 to 2, heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon, or a stable bicyclic or tricyclic system containing at least one 5- to 7-membered aromatic ring which contains from 1 to 3, or in some embodiments from 1 to 2, heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon. Monocyclic heteroaryl groups typically have from 5 to 7 ring atoms. In some embodiments bicyclic heteroaryl groups are 9- to 10-membered heteroaryl groups. It is preferred that the total number of S and O atoms in the heteroaryl group is not more than 2. Examples of heteroaryl groups include thienyl, pyridyl, pyrimidinyl, and pyrrolyl.

[0054] "Pharmaceutical compositions" are compositions comprising at least one active agent, such as a compound or salt of one of the active compounds disclosed herein, and at least one other substance, such as a carrier. Pharmaceutical compositions optionally contain one or more additional active agents.

[0055] "Pharmaceutically acceptable salts" includes derivatives of the disclosed compounds in which the parent compound is modified by making inorganic and organic, non-toxic, acid or base addition salts thereof. The salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. The pharmaceutically acceptable salt can be in the form of a pure crystal, or single polymorphic form, or can be used in non-crystalline or amorphic, glassy, or vitreous form, or a mixture thereof. In an alternative embodiment, the active compound can be provide in the form of a solvate.

[0056] Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional nontoxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH₂)_n-COOH where n is 0-4, tetrabutylammonium, and the like. Lists of additional suitable salts may be found, e.g., in

Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).

[0057] The term "carrier" applied to pharmaceutical compositions/ combinations means a diluent, excipient, or vehicle with which an active compound is provided.

[0058] A "pharmaceutically acceptable excipient" means an excipient that is useful in preparing a pharmaceutical composition/ combination that is generally safe, is sufficiently non-toxic, and neither biologically nor otherwise undesirable. A "pharmaceutically acceptable excipient" as used in the present application includes both one and more than one such excipient.

[0059] A "therapeutically effective amount" of a pharmaceutical composition/ combination of this disclosure means an amount effective, when administered to a patient, to provide a therapeutic benefit such as an amelioration of symptoms, e.g., an amount effective to decrease the symptoms of an LCAT mediated disorder, or in some embodiments a therapeutically effective amount is an amount sufficient to prevent or prophylactically treat an LCAT mediated disorder. In certain embodiments a therapeutically effect amount is thus an amount sufficient to provide a significant increase in HDL levels.

[0060] A "patient" or "host" is a human or non-human animal in need of medical treatment. Medical treatment can include treatment of an existing condition, such as a disease or disorder, prophylactic or preventative treatment, or diagnostic treatment. Unless otherwise stated, the patient or host is a human patient.

CHEMICAL DESCRIPTION

[0061] Formula I, II, and III includes all subformulae thereof. In certain situations, the compounds of Formula I and II may contain one or more asymmetric elements such as stereogenic centers, stereogenic axes and the like, e.g. asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates or optically active forms. For compounds with two or more asymmetric elements, these compounds can additionally be mixtures of diastereomers. For compounds having asymmetric centers, it should be understood that all of the optical isomers and mixtures thereof are encompassed. In addition, compounds with carbon-carbon double bonds may occur in Z- and E-forms, with all isomeric forms of the compounds being included in the present disclosure. In these situations, single enantiomers, i.e., optically active forms, can be obtained by asymmetric synthesis, synthesis from optically pure precursors, or by resolution of the racemates. Resolution of the racemates can also be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example using a chiral HPLC column.

[0062] Where a compound exists in various tautomeric forms, the invention is not limited to any one of the specific tautomers, but rather includes all tautomeric forms.

[0063] Compounds of Formula I particularly may be diastereomers. For example the following four diastereomers exist for compounds of Formula I when R₂ is -C(0)NHCH(R₃)Ar₂:

[0064] In Formula IA-ID Ri is a non-hydrogen substituent. Diastereomers may be separated by conventional methods such as column chromatography. The disclosure includes both mixtures of diastereomers and purified forms containing a single diastereomer.

[0065] The procedures for generating the various C4-substituted beta-lactams are

summarized in Scheme 1. These compounds were either unsubstituted or carbamylated at Nl

(Scheme 1).

Scheme 1

Ar-_| = PhY, nap tyl, thiop enyl

n = 0 or 1

Y = H, F, CI, N0₂, CF₃, SH, SCH₃, OCH₃

Ar₂ = Ph, C₆H₅F,

C₆H₅N0₂, C₆H₅OCH₃, naphtyl

[0066] Beta-Lactams unsubstituted at Nl are prepared from the commercially available beta- lactam 1 in the presence of NaHC0₃ in acetone/water. Beta-Lactams substituted with aryl

carboxamide at Nl were prepared from beta-lactams unsubstituted at Nl using aryl isocyanates and Et₃N in methylene chloride at room temperature, or by using a CEM microwave apparatus at 300W, 30 °C for 20-45 minutes. [0067] In addition to the compounds and salts of Formula I, II, and III set forth in the SUMMARY section the disclosure also includes compounds and salts of Formula I , II, and III in which the variables (e.g. R, R₀, Ri_, and R₂) carry the definitions set forth below. Any combination of variable II, or III results.

(Formula III)

[0068] The disclosure includes embodiments (i)-(xiv).

[0069] (i) R and R₀ are each hydrogen or methyl.

[0070] (ii) R and R₀ are both hydrogen.

[0071] (iii) R and R₀ are both hydrogen or methyl.

[0072] (iv) R is hydrogen and R₀ is phenyl, which phenyl is unsubstituted or substituted with 1 or more substituents independently chosen from halogen, hydroxyl, amino, cyano, nitro, -CHO, - COOH, Ci-Cgalkyl, C₂-C₈alkenyl, C₂-C₆alkanoyl, (C₁-C₆alkoxy)Co-C₄alkyl, (Ci-C₆alkylthio)C₀- C₄alkyl, (mono- or di-Ci-C₆alkylamino)Co-C₄alkyl, (C₃-C₆cycloalkyl)Co-C₄alkyl, mono- or di-Ci- Cealkylcarboxamide, Ci-Cealkylester, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy.

[0073] (v) R is hydrogen and R₀ is phenyl, which phenyl is substituted with one or more substituents independently chosen halogen substituents.

[0074] (vi) is S(0)m; and

Ari is phenyl, thienyl, or naphthyl; each of which Ari is unsubstituted or substituted with 1 or more substituents independently chosen from halogen, hydroxyl, amino, cyano, nitro, -CHO, -COOH, -SH, d-Qalkyl, C₂-C₈alkenyl, C₂-C₆alkanoyl, (C₁-C₆alkoxy)C₀-C₄alkyl, (C₁-C₆alkylthio)C₀-C₄alkyl, (mono- or di-Ci-C₆alkylamino)C₀-C alkyl, (C₃-C₆cycloalkyl)C₀-C alkyl, mono- or di-Ci- Cealkylcarboxamide, Ci-Cealkylester, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy.

[0075] (vii) R and R₀ and both hydrogen;

Ari is phenyl, thienyl, or naphthyl, each of which is unsubstituted.

[0076] (viii) R and R₀ and both hydrogen;

Ari is phenyl, substituted at the ortho and/ or para positions with a substituents independently chosen from halogen, cyano, nitro, -CHO, -COOH, -SH, Ci-C₃alkylthio, Ci-C₃alkoxy, C₂-C₄alkanoyl, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy and optionally substituted with 1 or more substituents independently chosen from halogen, hydroxyl, amino, cyano, nitro, -CHO, -COOH, Ci-C₈alkyl, C₂- C₈alkenyl, C₂-C₆alkanoyl, (Ci-C₆alkoxy)C₀-C₄alkyl, (Ci-C₆alkylthio)C₀-C₄alkyl, (mono- or di-Ci- C₆alkylamino)C₀-C₄alkyl, (C3-C₆cycloalkyl)Co-C₄alkyl, mono- or di-Ci-C₆alkylcarboxamide, d- C₆alkylester, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy.

[0077] (ix) Ar_! is phenyl substituted at one or more of the ortho or para positions with substituents independently chosen from fluoro, chloro, nitro, -SH, methylthio, trifluoromethyl, methoxy, and optionally substituted with one or more additional methyl or ethyl substituents.

[0078] (x) L₂ is -CONHR₄R₅- where R₄ and R₅ are independently hydrogen or methyl.

[0079] (xi) L₂ is -CONH-.

[0080] (xii) L₂ is -CR₄R5-.

[0081] (xiii) L₂ is -CR₄R₅-and R₄ and R₅ are independently hydrogen or methyl.

[0082] (xiv) Ar₂ is phenyl or naphthyl, each of which is unsubstituted.

[0083] (xv) R₂ is hydrogen.

[0084] (xvi) Ar₂ is phenyl, naphthyl, thienyl, or pyridyl, each of which Ar₂ is unsubstituted or substituted with 1 to 3 substituents independently chosen from halogen, hydroxyl, amino, cyano, nitro, -CHO, -COOH, -SH, d-C₆alkyl, C₂-C₆alkanoyl, (C₁-C₄alkoxy)C₀-C₂alkyl, (Ci-C₄alkylthio)C₀- C₂alkyl, (mono- or di-Ci-C₄alkylamino)C₀-C₂alkyl, (C₃-C₆cycloalkyl)C₀-C₂alkyl, mono- or di-Ci- C₆alkylcarboxamide, Ci-C₆alkylester, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy.

[0085] (xvii) Compounds and salts of Formula I in which any one of the following conditions is met:

hi is S, Ατχ is 2,4-difluorophenyl, and R₂ is H;

Li is S, Ari is 4-nitrophenyl, and R₂ is H;

Li is S, Ari is 2,4-difluorophenyl, R₂ is -L₂-Ar₂, L₂ is -CONHCH₂-, and Ar₂ is phenyl;

Li is S, Ari is 2,4-difluorophenyl, R₂ is -L₂-Ar₂, L₂ is -CONHCH(CH₃)-, and Ar₂ is naphthyl; Li is S, Ari is 2,4-difluorophenyl, R₂ is -L₂-Ar₂, L₂ is -CONHCH₂-, and Ar₂ is 2- fluorophenyl;

hi is S, Ατχ is 2,4-difluorophenyl, R₂ is -L₂-Ar₂, L₂ is -CONHCH₂-, and Ar₂ is 2- methoxyphenyl;

hi is S, Ατχ is 2,4-difluorophenyl, R₂ is -L₂-Ar₂, L₂ is -CONH-, and Ar₂ is 2-fluorophenyl; hi is S, Ατχ is 2-chloro-4-fluorophenyl, and R₂ is H;

hi is S, Ατχ is 4-trifluoromethylphenyl, R₂ is -L₂-Ar₂, L₂ is -CONHCH₂-, and Ar₂ is phenyl; hi is S, Ατχ is 3-trifluoromethylphenyl, R₂ is -L₂-Ar₂, L₂ is -CONHCH₂-, and Ar₂ is phenyl; hi is S, Ατχ is 2,4-dichlorophenyl, R₂ is -L₂-Ar₂, L₂ is -CONHCH₂-, and Ar₂ is phenyl; or hi is S, Ατχ is 2-chloro-4-fluorophenyl, R₂ is -L₂-Ar₂, L₂ is -CONHCH(phenyl)-, and Ar₂ is phenyl.

[0086] (xviii) Compounds and salts of Formula II in which any one of the following conditions is met:

Li is S, Ari is 4-nitrophenyl, L₂ is CH₂, and Ar₂ is phenyl; or

Li is S, Ari is phenyl, L₂ is CH₂, and Ar₂ is phenyl. [0087] The disclosure also includes compounds and pharmaceutically acceptable salts of Formula III

(Formula III)

in which the variables R, R₀, Rio, Rn, and R₂ carry the following definitions.

[0088] R is chosen from hydrogen and Ci-C₄alkyl.

[0089] R₀ is hydrogen, Ci-C₄alkyl, or -ORx, where Rx is Ci-C₄alkyl, -C(0)CH₃, Ar_{1 ;} or - CH₂phenyl.

[0090] Rio and R_n are in dependently chosen from H and -I^-Rz, where hi is N, O, Se, or S(0)m, where m is 0, 1 , or 2.

[0091] Rz is d-Csalkyl.

[0092] R₂ is hydrogen, Ci-Cealkyl, or SRy, where Ry is Ci-C₄alkyl; or R₂ is -L₂-Ar₂.

[0093] L₂ is a bond, -C(0)NR₃(CR₄R₅)n- or -C(0)0(CR₄R₅)n-, where n is 0, 1 , or 2.

[0094] R₃ is hydrogen, Ci-C₄alkyl, or phenyl.

[0095] R and R₅ are independently chosen from hydrogen, halogen, Ci-C alkyl, or Ci- C alkoxy.

[0096] Ar₂ is phenyl, naphthyl, or a 5- or 6-membered heteroaryl group having from 1 to 3 heteroatoms independently chosen from N, O, and S, each of which Ar₂ is unsubstituted or substituted with 1 or more substituents independently chosen from halogen, hydroxyl, amino, cyano, nitro, -CHO, -COOH, -SH, Ci-Cgalkyl, C₂-C₈alkenyl, C₂-C₆alkanoyl, (Ci-C₆alkoxy)C₀-C₄alkyl, (d- C₆alkylthio)C₀-C alkyl, (mono- or di-Ci-C₆alkylamino)C₀-C alkyl, (C₃-C₆cycloalkyl)C₀-C alkyl, mono- and di-Ci-Cealkylcarboxamide, Ci-Cealkylester, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy.

[0097] The disclosure includes compounds and salts of Formula III in which the following conditions are met.

[0098] R is hydrogen.

[0099] Ro is -ORx.

[0100] R₁₀ and R_! i are each Li-Rz, wherein Li is S.

[0101] L₂ is a bond.

[0102] Ar₂ is phenyl which is unsubstituted or substituted with 1 or more substituents independently chosen from halogen, hydroxyl, amino, cyano, nitro, -CHO, -COOH, -SH, Ci-C₈alkyl, C₂-C₈alkenyl, C₂-C₆alkanoyl, (Ci-C₆alkoxy)C₀-C₄alkyl, (Ci-C₆alkylthio)C₀-C₄alkyl, (mono- or di-Ci- C₆alkylamino)C₀-C₄alkyl, (C₃-C₆cycloalkyl)C₀-C₄alkyl, mono- and di-Ci-C₆alkylcarboxamide, d- C₆alkylester, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy.

LCAT INHIBITORS AND ACTIVATORS [0103] Certain compounds of Formula I, II, and III may be classified as activators and inhibitors according to the substituents present at the R, R₀, Ri, and R₂ positions, or in Formula III according to the substituents present at R. R₀ Rio, Rn, and R₂.

[0104] For example the disclosure provides LCAT activators and inhibitors having the following characteristics substituents.

[ ] T s scosure ncu es compoun s an sat o Formua I, II, or III w c act as LCAT activators. [0106] For example the disclosure includes LCAT activators of Formula I in which the following conditions are met.

[0107] (i) A compound or salt of Formula I in which

R is chosen from hydrogen and Ci-C₄alkyl;

R₀ is hydrogen, Ci-C₄alkyl, or -ORx, where Rx is Ci-C₄alkyl, -C(0)CH₃, Ar_{1 ;} or - CH₂phenyl;

Ri is -Li-Ari, where Li is S(0)m, where m is 0 or 1 ;

Ari is independently chosen at each occurrence from phenyl, naphthyl, and 5- or 6-membered heteroaryl groups having from 1 to 3 heteroatoms independently chosen from N, O, and S, each of which Ari is unsubstituted or substituted with 1 or more substituents independently chosen from halogen, cyano, nitro, -SH, Ci-C₈alkyl, C₂-C₈alkenyl, C₂-C₆alkanoyl, (Ci-C₆alkoxy)C₀-C₄alkyl, (Q- C₆alkylthio)C₀-C alkyl, (mono- or di-Ci-C₆alkylamino)C₀-C alkyl, (C₃-C₆cycloalkyl)C₀-C alkyl, C_\- C₂haloalkyl, and Ci-C₂haloalkoxy;

R₂ is SRy, where Ry is Ci-Cealkyl; or

R₂ is -L₂-Ar₂; where

L₂ is -S- and Ar₂ is phenyl, naphthyl, or a 5- or 6-membered heteroaryl group having from 1 to 3 heteroatoms independently chosen from N, O, and S, each of which Ar₂ is unsubstituted or substituted with 1 or more substituents independently chosen from halogen, hydroxyl, amino, cyano, nitro, -CHO, -COOH, -SH, d-C₈alkyl, C₂-C₈alkenyl, C₂-C₆alkanoyl, (C₁-C₆alkoxy)C₀-C₄alkyl, (Q- C₆alkylthio)C₀-C alkyl, (mono- or di-Ci-C₆alkylamino)C₀-C alkyl, (C₃-C₆cycloalkyl)C₀-C alkyl, mono- and di-Ci-Cealkylcarboxamide, Ci-Cealkylester, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy.

[0108] (ii) R₂ is SRy, where Ry is Ci-C₆alkyl.

[0109] (iii) Ri is -S-Ar_1; where

Ar_! is phenyl, naphthyl, and 5- or 6-membered heteroaryl groups having from 1 to 3 heteroatoms independently chosen from N, O, and S, each of which Ar_! is unsubstituted or substituted with 1 or more substituents independently chosen from halogen, cyano, nitro, -SH, Ci-C₈alkyl, C₂- C₈alkenyl, C₂-C₆alkanoyl, (Ci-C₆alkoxy)C₀-C₄alkyl, (Ci-C₆alkylthio)C₀-C₄alkyl, (mono- or di- V C₆alkylamino)C₀-C₄alkyl, (C₃-C₆cycloalkyl)C₀-C₄alkyl, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy; and optionally

R₂ is SRy, where Ry is Ci-C₆alkyl.

[0110] (iv) Ri is Ι^Α and Ar_! is phenyl or thienyl, each of which Aii is unsubstituted or substituted with 1 or more substituents independently chosen from fluoro, chloro, and Ci-C₈alkyl; and optionally

R₂ is SRy, where Ry is Ci-Cealkyl.

[0111] The disclosure includes LCAT activators of Formula II, in which the following conditions are met.

[0112] Ri is LiAri; where Li is -S-; and Ar_! is independently chosen at each occurrence from phenyl, naphthyl, and 5- or 6-membered heteroaryl groups having from 1 to 3 heteroatoms independently chosen from N, O, and S, each of which Ar_! is unsubstituted or substituted with 1 or more substituents independently chosen from halogen, hydroxyl, amino, cyano, -CHO, -COOH, -SH, Ci-C₈alkyl, C₂-C₈alkenyl, C₂-C₆alkanoyl, (Ci-C₆alkoxy)C₀-C₄alkyl, (Ci-C₆alkylthio)C₀-C₄alkyl, (mono- or di-Ci-C₆alkylamino)Co-C₄alkyl, (C₃- C₆cycloalkyl)C₀-C₄alkyl, mono- or di-Ci-Cealkylcarboxamide, Ci-Cealkylester, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy.

[0113] The disclosure includes LCAT activators of Formula III, in which the following conditions are met.

[0114] (i) R₂ is SRy, where Ry is Ci-Cealkyl or R₂ is -L₂Ar₂; where L₂ is -S-; and

Ar₂ is phenyl, naphthyl, or a 5- or 6-membered heteroaryl group having from 1 to 3 heteroatoms independently chosen from N, O, and S, each of which Ar₂ is unsubstituted or substituted with 1 or more substituents independently chosen from halogen, hydroxyl, amino, cyano, nitro, -CHO, -COOH, -SH, d-Cgalkyl, C₂-C₈alkenyl, C₂-C₆alkanoyl, (C₁-C₆alkoxy)C₀-C₄alkyl, (Q- C₆alkylthio)C₀-C₄alkyl, (mono- or di-Ci-C₆alkylamino)C₀-C₄alkyl, (C₃-C₆cycloalkyl)C₀-C₄alkyl, mono- and di-Ci-C₆alkylcarboxamide, Ci-C₆alkylester, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy.

[0115] (ii) R₂ is SRy, where Ry is Ci-C₆alkyl.

[0116] The disclosure also includes LCAT inhibitors of Formula I in which L₂ is - C(0)NR₃(CR₄R₅)n- or -C(0)0(CR₄R₅)n-, where n is 0, 1 , or 2.

[0117] The disclosure includes LCAT inhibitors of Formula II in which any of the following conditions are met.

[0118] (i) Ri is LiAri; Li is -S-; and

Ari is independently chosen at each occurrence from phenyl, naphthyl, and 5- or 6-membered heteroaryl groups having from 1 to 3 heteroatoms independently chosen from N, O, and S, each of which Ar_! is substituted with at least on nitro group and substituted with 1 or more substituents independently chosen from halogen, hydroxyl, amino, cyano, -CHO, -COOH, -SH, Ci-C₈alkyl, C₂- C₈alkenyl, C₂-C₆alkanoyl, (Ci-C₆alkoxy)C₀-C₄alkyl, (Ci-C₆alkylthio)C₀-C₄alkyl, (mono- or di-Ci- C₆alkylamino)C₀-C₄alkyl, (C₃-C₆cycloalkyl)C₀-C₄alkyl, mono- or di-Ci-C₆alkylcarboxamide, d- C₆alkylester, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy.

[0119] (ii) Ri is L^r^ hi is -S-; and Ar_! is phenyl substituted with nitro.

[0120] The disclosure includes LCAT inhibitors of Formula III in which R₂ is -L₂Ar₂ and L₂ is -C(0)NR₃(CR₄R₅)n- or -C(0)0(CR₄R₅)n-, where n is 0, 1 , or 2.

PHARMACEUTICAL COMPOSITIONS

[0121] Compounds disclosed herein can be administered as the neat chemical, but are preferably administered as a pharmaceutical composition. Accordingly, the disclosure provides pharmaceutical compositions comprising a compound or pharmaceutically acceptable salt of any of the active compounds described herein, together with at least one pharmaceutically acceptable carrier. The pharmaceutical composition/ combination may contain a compound or salt of any of the active compounds described herein as the only active agent, but in another embodiment may also contain at least one additional active agent. In certain embodiments the pharmaceutical composition is in a dosage form that contains from about 0.1 mg to about 2000 mg, from about lmg to about 1000 mg of a compound or salt of Formula I, II, or III in a unit dosage form. In certain embodiments the active compound is delivered in an oral dosage form such as a pill, tablet or capsule in an effective amount, which may in some embodiments be at least 1, 10, 25, 50, 100, 150, 200, 250, 300, 350 or 400 mg. The pharmaceutical composition may also include a molar ratio of a compound of Formula I, II, or III and an additional active agent. For example the pharmaceutical composition may contain a molar ratio of about 0.5: 1, about 1: 1, about 2: 1, about 3: 1 or from about 1.5: 1 to about 4: 1 of the compound or salt of Formula I, II, or Illand an additional active agent.

[0122] Compounds disclosed herein may be administered by any suitable means, including orally, topically, parenterally, by inhalation or spray, sublingually, transdermally, via buccal or transmucosal administration, rectally, as an ophthalmic solution, injection, or by other means, in dosage unit formulations containing conventional pharmaceutically acceptable carriers. The pharmaceutical composition may be formulated as any pharmaceutically useful form, e.g., as an aerosol, a cream, a gel, a pill, a capsule, a tablet, a syrup, a transdermal patch, or an ophthalmic solution. Some dosage forms, such as tablets and capsules, are subdivided into suitably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose.

[0123] Carriers include excipients and diluents and should be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated. The carrier can be inert or it can possess pharmaceutical benefits of its own. The amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound.

[0124] Classes of carriers include, but are not limited to binders, buffering agents, coloring agents, diluents, disintegrants, emulsifiers, flavorants, glidents, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents. Some carriers may be listed in more than one class, for example vegetable oil may be used as a lubricant in some formulations and a diluent in others. Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin; talc, and vegetable oils. Optional active agents may be included in a pharmaceutical composition, which do not substantially interfere with the activity of the compound of the present disclosure.

[0125] The pharmaceutical compositions/ combinations can be formulated for oral administration. These compositions contain between 0.1 and 99 weight % (wt. ) of a compound of Formula I, II, or Illand usually at least about 5 wt.% of a compound of formula. Some embodiments contain from about 25 wt. to about 50 wt. % or from about 5 wt. to about 75 wt. of the compound of Formula I, II, or III.

[0126] An effective amount of a pharmaceutical composition/ combination of the disclosure may be an amount sufficient, for example, to (a) inhibit the progression of an LCAT mediated disorder; (b) cause a regression of an LCAT mediated disorder; (c) cause a cure of a remission of an LCAT mediated disorder to the point that the patient no longer experiences symptoms of the disorder, and (d) increase the level of HDL in a patient' s blood or serum without significantly increasing the level of LDL in the patient's blood or serum.

[0127] The compound or pharmaceutically acceptable salt of Formula I, II, or III and at least one additional active agent may be: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by any other combination therapy regimen known in the art. When delivered in alternation therapy, the methods of the disclosure may comprise administering or delivering the compound or salt of any of the active compounds described herein, and an additional active agent sequentially, e.g., in separate solution, emulsion, suspension, tablets, pills or capsules, or by different injections in separate syringes. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e., serially, whereas in simultaneous therapy, effective dosages of two or more active ingredients are administered together. Various sequences of intermittent combination therapy may also be used.

[0128] Frequency of dosage may also vary depending on the compound used and the particular disease treated. However, for treatment of most infectious disorders, a dosage regimen of 4 times daily or less is preferred and a dosage regimen of 1 or 2 times daily is particularly preferred.

[0129] It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the patient undergoing therapy.

[0130] The pharmaceutical packaging may include an active compound or salt as described herein in a container together with instructions for using the compound to treat a patient suffering from an LCAT mediated disorder are included herein.

[0131] Packaged pharmaceutical compositions/ combinations are also included herein. Such packaged combinations include any of the active compounds described herein in a container together with instructions for using the combination to treat and LCAT mediated disorder, such as a FLD, FED, low HDL, atherosclerosis, or LAL deficiency disorders including Wolman's disease and CESD. METHODS OF TREATMENT

[0132] The disclosure includes methods of treatment. In an embodiment the disclosure includes a method or treating an LCAT mediated disorder by administering a therapeutically effective amount of a compound or salt of Formula I, II, or III to a patient in need of such treatment. LCAT mediated disorders include familial Lecithin:Cholesterol Acyltransferase deficiency, Fish Eye Disorder (FED), Familial Lipase Disorder (FLD), low HDL, artherosclerosis, acid lipase deficiency, Wolman's disease, Lysosomal Acid Lipase deficiency (LAL deficiency), and Cholesterol ester storage disorder (CESD).

[0133] The disclosure includes a method for inhibiting cholesterol ester formation in a patient with acid lipase deficiency by administering a therapeutically effective amount of a compound of Formula I, II, or III to the patient.

[0134] The disclosure includes a method treating atherosclerosis (therapeutically or prophylactically) in a patient comprising administering a therapeutically effective amount of a compound or salt of Formula I, II, or III to the patient.

[0135] LCAT activators are desired for treating certain conditions. LCAT activators increase the rate of cholesterol esterification in a cholesterol esterification rate assay, such as the assay of Example 10. In certain embodiments LCAT activators increase the rate of cholesterol esterification in a cholesterol esterification rate assay at least 50%, at least 100%, or at least 150% over control. In certain embodiments cholesterol activators increase the rate of cholesterol esterification in a cholesterol esterification rate assay and exhibit an EC₅₀ of less than 0.1 mM, O.OlmM, or O.OOlmM in the cholesterol esterification rate assay.

[0136] Disorders that may be treated with an LCAT activator include LCAT mediated disorders include familial Lecithin: Cholesterol Acyltransferase deficiency, Fish Eye Disorder (FED), Familial Lipase Disorder (FLD), low HDL, and atherosclerosis.

[0137] LCAT activators are useful for treating disorders in which the patient has a genetic defect in the gene encoding LCAT or has decreased LCAT activity due to liver failure (such as liver failure, cirrhosis, primary billiard cirrhosis, cholestatic liver disease, or AlagiUe syndrome) or chronic renal disease, by administering a therapeutically effective amount of a compound or salt of

Compounds I, II, or III to the patient.

[0138] It has recently been reported that LCAT activators are neuroprotective in situations in which high levels of 24(S)-hydroxycholesterol are formed in the CNS ( La Marca, al., J.

Neurochemistry, (2014) 130: 97-108). Thus, the disclosure includes a method of reducing the rate of neurodegeneration in a patient suffering from Alzheimer's dementia or multiple sclerosis comprising administering a therapeutically effective amount of a compound or salt of the disclosure to the patient. The disclosure also includes a method of reducing neurodeneration in a patient following a brain injury due to concussion, oxygen deprivation, or stroke comprising administering a therapeutically effective amount of a compound or salt of the disclosure to the patient following the brain injury, for example within 0 to 128, 0 to 96, 0 to 72, 0 to 48, 0 to 14, or 0 to 12 hours after the brain injury has occurred. [0139] LCAT inhibitors are desired for treating certain conditions. LCAT inhibitors decrease the rate of cholesterol esteriiication in a cholesterol esterification rate assay, such as the assay of Example 10. In certain embodiments LCAT inhibitors decrease the rate of cholesterol esterification in a cholesterol esterification rate assay at least 10%, at least 20%, 50%, or at least 90%, relative to control. In certain embodiments cholesterol inhibitors decrease the rate of cholesterol esterification in a cholesterol esterification rate assay and exhibit an EC₅₀ of less than 0.1 mM, O.OlmM, or O.OOlmM in the cholesterol esterification rate assay. The disclosure includes methods of treating Wolman's disease, Lysosomal Acid Lipase deficiency (LAL deficiency), and Cholesterol ester storage disorder (CESD) comprising administering a therapeutically effective amount of an LCAT inhibitor of the disclosure to the patient.

EXAMPLES

GENERAL METHODS

[0140] All air- or moisture-sensitive reactions were performed under argon or nitrogen atmosphere using glassware that was pre -dried in an oven at 120 °C overnight. Irradiation reactions were performed in Discover LabMate from CEM (Weddington, NC). The reactions were monitored by thin-layer chromatography (TLC) using EM Reagent plates with fluorescence indicator (SiO₂-60, F254) and layer thickness: 350-250 μιη; purchased from EMD Chemicals, Inc. (Gibbstown, NJ).

Unless otherwise noted, the compounds were detected under UV light (254 nm) and iodine vapors.

[0141] General methods of purification of compounds involved flash chromatography by gradient elution from silica gel columns (60 A, particle size 40-75μιη, Sorbent Technologies, Inc., Atlanta, GA), preparatory chromatography plates (silica G prep TLC plates with UV254, 20x20nm glass backed, ΙΟΟΟμιη thickness, Sorbent Technologies, Inc., Atlanta, GA) and/or recrystallization.

[0142] All compounds were characterized by H and ¹³C NMR spectra (25 °C) were obtained at 400 MHz for H NMR and 125 MHz for ¹³C NMR with a Bruker 400 spectrometer (Billerica, MA) in CDCI₃ or acetone -d₆. Chemical shifts are reported in ppm (δ) relative to the residual solvent peak in the corresponding spectra; chloroform d 7.26 and d 77.23 and acetone d 2.05 coupling constants (J) are reported in hertz (Hz) (where, s = singlet, br = broad singlet, d = doublet, dd = double doublet, bd = broad doublet, ddd = doublet doublet of doublet, t = triplet, dt - doublet of triplet, q = quartet, p = pentet, m = multiplet). In most cases, signals due to exchangeable protons have been omitted.

[0143] IR spectra were obtained as a thin film on NaCl plates and in solid form (KBr standard) on a Shimadzu FT-IR-8300 (Columbia, MD). Elemental analyses were performed by Atlantic Microlab, Inc., Norcross, GA.

[0144] Melting points were determined using a TA Instruments Q-2000 Differential Scanning Calorimeter (New Castle, DE) connected to a Refrigerated Cooling System. 3.0 mg ± 0.2 mg samples were placed in T-Zero aluminum pans with lids and were heated and cooled at a scan rate of 10 °C/min while purged with 50 mL/min N2. Many of the compounds did not recrystallize, so temperatures during the first heating scan were reported. The reported temperatures have an uncertainty of 2s = ±1.0 °C.

[0145] All anhydrous solvents, reagent grade solvents for chromatography and starting materials were purchased from Sigma-Aldrich (St. Louis, MO), Fisher Scientific (Pittsburgh, PA), Aldrich Chemical Co. (Milwaulkee, WI), Matrix Scientific (Columbia, SC) and Acros Organics (Geel, Belgium). Unless stated otherwise, solutions in organic solvents were dried with anhydrous magnesium sulfate, 370 and concentrated under vacuum conditions using rotator evaporation.

[0146] All compounds are >98 pure by elemental analysis.

ABBREVIATIONS DCM dichloromethane

DMF dimethylformamide

EtOAc ethyl acetate

Et₃N triethylamine

EXAMPLE 1. SYNTHESIS OF BETA LACTAM COMPOUNDS

[0147] The synthetic procedure was adopted from Claus, et al. {Justus Liebigs Annalen der Chemie (19 '4) 4: 539-560) and Wasserman {Tetrahedron (2000) 56: 5621-5629) and applied to the beta-lactam compounds of this disclosure. Beta-Lactams 2 - 25 were prepared from the commercially available beta-lactam 1 in the presence of NaHC0₃ in acetone/water. To a solution of 4-acetoxy-2- azetidinone 1 (1 g, 8 mmol) in 50 mL acetone/water (3:2) and 1.05 mol eq. of the corresponding substituents (thiophenols, phenol or benzeneselenol, respectively) was added. Sodium bicarbonate (4 mol eq.) was added and the mixture was stirred vigorously for 12 h in a closed round bottom flask. Sodium chloride was added to the solution and after formation of two layers the mixture was filtered out and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over MgS0₄ and concentrated under vacuum. The crude product was purified by prep HPLC analysis, flash chromatography and/or re-crystallized.

[0148] Beta-Lactams 26-49, were prepared from beta-lactams 2-25 using aryl isocyanates and Et₃N in methylene chloride at RT, or by using a CEM microwave apparatus at 300W, 30°C for 20-45 minutes. Carbamylation of the lactam nitrogen (lactams 26 - 49) with a variety of isocyanates was accomplished by adopting a procedure from Mulchande et al. or by a microwave -based method developed in our laboratory. Beta-Lactams 33-35, and 49 were prepared in methylene chloride (5 ml) with 1.2 molar equivalents of triethylamine using a CEM microwave apparatus (300W, 30 °C for 10- 45 minutes). Incubation time varied depending on the nature of isocyanate and the unsubstituted lactam.

[0149] The synthesis of compounds 2 and 26 is shown below.

EXAMPLE 2. SYNTHESIS OF DIASTEREOMERS OF N-SUBSTITUTED C4 ARYLTHIO-, AND ARYLSELENO- BETA-LACTAMS

[0150] All of the lactams can be prepared as pure diastereomers. Illustration is given by the synthesis of lactams a, b and c, d (Scheme 2). The syntheses of these compounds are shown in Scheme 4. The four lactam stereoisomers were obtained by using the commercially available chiral methylbenzylisocyanate by the previously described procedures (Mulchande, J., et al., J. Org. & Biomol. Chem. (2007) 5: 2617) or by developed by a microwave approach of this disclosure.

[0151] Scheme 2. a. β-Lactams a and b, can be obtained from β-lactams 4 using commercially available 5-methylbenzylisocyanate and Et₃N in acetonitrile at room temperature, or by the procedure of this disclosure utilizing a CEM microwave apparatus at 300W, 30°C for 20-45 minutes; yields 45% - 70% for both isomers, b. Beta-Lactams c and d, can be obtained from β- lactams using commercially available R-methylbenzylisocyanate and Et₃N in acetonitrile at room temperature, or by the above CEM microwave procedure; yields 45%-70% for both isomers. The diastereomers were then separated by flash chromatography (Hexane:EtOAc 1: 1), and the absolute configuration was determined by X-ray crystallography. In Scheme 2 Ari may carry any of the definitions set forth herein for Ari and the substituent at Nl may be any -L₂-Ar₂ substituent that has a chiral center. EXAMPLE 3. ADDITIONAL BETA LACTAM COMPOUNDS

[0152] TABLE 1 provides additional compounds prepared by the method shown in Example

1.

[0153] In Tables 1, 2, and 3 an unsubstituted bond on a substituent indicates the point of

__s_/=\ attachment of the substituent to the β-lactam ring. For example, the R¹ substituent is tam ring as follows:

-(4-NITROPHENYL) BENZYLCARBAMOTHIOATE (Compound 57)

[0154] In a round bottom flask, the appropriate thiol (1.0 mol equiv), in this case 4-nitrothiol, benzyl isocyanate (1.2 mol equiv), and triethylamine (NEt₃, 1.2 mol equiv) were dissolved in methylene chloride and stirred at room temperature for 8 hours. The solution was then concentrated in vacuo and the crude reaction mixture was separated by flash chromatography using silica gel and eluted with hexane/EtOAc (1 : 1). The solvent was evaporated in vacuo and the product was obtained as a crystalline solid in 35-77% yield depending on the thiol used. ¾ NMR (400 MHz, CDC1₃): δΗ 4.44 (d, = 5.67, 2H); 7.13-7.36 (m, 6H); ¹³C NMR (125 MHz, CDC1₃): δ 44.83, 123.99, 127.58, 128.83, 128.86, 129.09, 134.95. Compound 57 is an LCAT activator under routine assay conditions. However it is an LCAT inhibitor in plasma.

EXAMPLE 5. ADDITIONAL CARBAMOTHIOATE COMPOUNDS

[0155] Carbamothioate compounds 58 -61 , shown in Table 2 are prepared by the method set forth in Example 4. The identity of the thiol was varied to produce the desired compound. LCAT modulators for Formula II are typically LCAT Activators unless Ri is -S-Ari where the aryl (Ari) group is substituted with a nitro group. Even so, there are exceptions as Compound 57, in which Ri is 4-nitro- phenyl-S-, is an activator under in vitro assay conditions but an LCAT inhibitor in plasma, and compound 58 and 59 which do not contain a nitro substituted Ari group and yet act as inhibitors.

TABLE 2

No. Ri R₂ Name Analytical Data

8.86, 2H).

¹³C NMR (125 MHz, CDC1₃): δ 8.63, 30.99, 45.70, 116.60, 123.52, 127.80, 128.70, 137.59, 162.39, 164.88, 165.95, 207.16

60 benzyl S-(3,5- ¾ NMR (400 MHz, CDC1₃): δΗ 4.38 (s, bis (trifluoromethyl)phe 2H); 4.52 (d, = 5.69, 2H); 5.9 (brs, 1H); nyl) 7.25-7.43 (m, 6H); 7.73 (dt, J= 4.89, =

CF₃ benzylcarbamothioate 2.25, 2H); 8.24 (dt, = 4.92, = 2.22,

2H). ¹³C NMR (125 MHz, CDC13): δ 30.99, 44.69, 45.83, 123.84, 127.45, CF₃ 127.94, 128.06, 128.72, 128.94, 134.83,

136.99, 137.13, 147.88, 158.07, 163.36, 207.17

61 benzyl S -vinyl 'Η NMR (400 MHz, CDC1₃): 3.55 (d, = benzylcarbamothioate 6.87, 1H); 4.37 (d, = 5.65, 1H); 5.08

(dd, J = x, J = 9.98, 1H), 5.23 (, dd, = 15.63, = 1.29, 1H); 5.81- 5.92 (m, 3H); 6.98 (brs, 1H), 7.23- 7.31 (m, 3H). ¹³C NMR (125 MHz, CDC1₃): δ 32.73, 45.06, 117.63, 127.80, 127.63, 128.83, 134.48, 138.38, 167.49

EXAMPLE 6. TETRABUTYLAMMONIUM 2-OXO-4-(THIOPHEN-2-YLTHIO)AZETIDINE-1 -SULFONATE

T Activity not predicted)

EXAMPLE 7. SYNTHESIS OF 1-METHYLSULFANYL-4-(4-TRIFLUOROMETHYL-PHENYLSULFANYL)- AZETIDIN-2-ONE (Compound 63)

[0156] Compound 63 is prepared from Compound 15, 4-((4-

(trifluoromethyl)phenyl)thio)azetidin-2-one, according to the following reaction scheme.

Ry = C_rC₄ alkyl

[0157] N-thiomethylated Compound 63 is prepared by deprotonation, followed by treatment with the S-alkylating reagent, l-((methyldisulfanyl)oxy)ethanone (CH₃0₂SSCH₃).

[0158] Oil. IR (neat) 1757 cm ¹ (C=0). *H NMR (400 MHz) δ 7.71 -7.64 (dd, 4H, J=8.28, 2.01), 5.51 (dd, 1H, J=7.89), 3.72-3.16 (dd, 2H, J=15.89, 7.89), 2.35 (s, 3H); ¹³C NMR (125 MHz) d 166.3, 137.7, 131.8, 130.1, 126.3, 123.8, 53.8, 46.0 IR (neat) _¾max (C=0) 1764 cm ¹. Compound 63 is an LCAT activator. -THIO ALKYLATED BETA-LACTAMS

F, CI, Br n = 0, 1-5

= C_rC₄ alkyl

[0159] N-thioalkylated β-lactams may be prepared from the corresponding acid chloride and the A/-(4-methoxyphenyl)imine of the corresponding aldehydes. N-Deprotection of l-(4- methoxyphenyl)azetidin-2-ones by chemical oxidation by Cerium Ammonium Nitrate (CAN) is an established method in β-lactam chemistry. Following deprotection N-thiomethylated lactams were prepared by deprotonation, followed by treatment with the appropriate S-alkylating reagent via established procedures. The compounds shown in Table 3 were prepared via this procedure. Compounds of Table 3 are LCAT Activators.

TABL £ 3.

No. R Ro Ri R₂ Name Analytical Data

70 -OCH₃ H -SMe 4-(2,5-difluorophenyl)-3- Colorless crystal; mp 57- methoxy-1- 60 °C. IR (neat) 1757

(methylthio)azetidin-2- cm ¹(C=0). H NMR (250

F one MHz) δ 7.09-7.00 (m,

3H), 5.19 (d, 1H, J=4.9 Hz), 4.85 (d, IH, J=5.0 Hz), 3.27 (s, 3H), 2.45 (s, 3H); ¹³C NMR (63 MHz) δ

(overlapping m), 59.0, 58.7, 21.8.

71 -OCH₃ H -SMe 4-(2,6-difluorophenyl)-3- Pale-yellow solid; mp 51- methoxy-1- 53 °C. IR (neat) 1762 cm ¹

(methylthio)azetidin-2- (C=0). ¾ NMR (250

F one MHz) δ 7.25 (m, IH), 6.93

(t, IH, J=8.8 Hz), 5.26 (d, IH, J=5.0 Hz), 4.87 (d, IH, J=5.0 Hz), 3.32 (s, 3H), 2.39 (s, 3H); ¹³C NMR (63 MHz) δ 170.5, 162.7 (dd, app J_c_F =251, 7 Hz), 131.2 (t, app Jc-F =11 Hz), 112.5 (d, app Jc-F =22 Hz), 110.1 (d, app Jc-F =14 Hz), 86.3, 59.3, 57.6, 22.1.

72 -OCH₃ H -SMe 4-(3,4-difluorophenyl)-3- Colorless crystal; mp 49- methoxy-1- 51 °C. IR (neat) 1757 cm ¹

(methylthio)azetidin-2- (C=0). ¾ NMR (250 one MHz) δ 7.25-7.14 (m,

3H), 4.80 (app s, 2H), 3.24 (s, 3H), 2.40 (s, 3H); ¹³C NMR (63 MHz) δ 170.0, 150.9 (m), 130.6, 125.0, 117.5 (m), 86.4, 65.0, 58.5, 22.1.

73 -OCH₃ H -SMe 4-(2,4,5-difluorophenyl)- Yellow solid; mp 56-59

3-methoxy-l- °C. IR (neat) 1767 cm ¹ (methylthio)azetidin-2- (C=0). ¾ NMR (250

F one MHz) d 7.17 (m, IH), 7.02

(td, IH, J=9.6, 6.5 Hz),

etidin-2-one EXAMPLE 9. PREPARATION OF 2-METHOXY-N-(4-METHOXYPHENYL)-3,3-BIS(METHYLTHIO)ACRYLAMIDE (Compound 81)

[0160] Compound 80 is prepared according to the above reaction scheme. Compound 81 is prepared from 80 by repeatedly passing compound 80 through a silicagel column for a prolonged period.

EXAMPLE 10. CHOLESTEROL ESTERIFICATION RATE ASSAY

[0161] The LCAT activity assay measures the rate of conversion of ³H labeled cholesterol to cholesterol ester. In the Cholesterol Esterification Rate (CER) assay a small amount of radiolabeled cholesterol is directly added to plasma or LDL-depleted plasma and the percent that is esterified over time is measured. The esterification of radiolabeled cholesterol is determined after separation from free cholesterol by thin layer chromatography. This assay is not only dependent upon the amount of LCAT present but also on the type of endogenous lipoprotein particles present in a sample because no exogenous HDL is added.

[0162] Lipoproteins are precipitated from plasma by phosphotungstic acid and MgCl₂.

[0163] To the supernatant, which contains plasma with HDL only, is added a filter paper disk containing a trace of ³H cholesterol.

[0164] After an overnight incubation at 4°C, the disk is removed and the plasma with labeled HDL is heated to 37°C and incubated for 30 min (the esterification reaction is always linear over this time period). Test compounds are dissolved in DMSO at 10 mM and prior to incubation with labeled HDL are added directly to the plasma so that the final test compound concentration was 10 micromolar. After the incubation, lipids are extracted by ethanol, the ethanol is evaporated, and internal standards of cholesterol and cholesterol oleate are added, and the labeled cholesterol and cholesterol ester are separated by TLC. Spots of cholesterol and cholesterol ester are visualized by iodine, spots cut from TLC plates, and transferred to scintillation vials. The radioactivity is estimated by liquid scintillation counting. Samples enriched in pre-beta HDL, show increased cholesterol esterification with this assay, because pre-beta HDL is a better substrate for LCAT. LCAT activity is determined by measuring the conversion of ³H radiolabeled cholesterol to cholesterol ester and expressed in nmol CE/ ml per hour. [0165] Compounds 2, 6, 34, 38, 39, and 57 were tested in this assay and found to be LCAT activators. Compounds 26, 49, 58, and 59 were tested in this assay and found to be LCAT inhibitors. Table 4 provides Emax % activation and EC50 (mM) for particular LCAT activators in this assay. Compound D2 is l,2-bis(4-(trifluoromethyl)phenyl)disulfane. Compound A was previously disclosed in the structure

Claims

What is claimed is:

pound of the Formula

or a pharmaceutically acceptable salt thereof, wherein

R is chosen from hydrogen and Ci-C₄alkyl;

R₀ is hydrogen, Ci-C₄alkyl, or -ORx, where Rx is Ci-C₄alkyl, -C(0)CH₃, Ari, or -CH₂phenyl;

Ri is -I^-Ar^ where

Li is NH, O, Se, or S(0)m, where m is 0, 1, or 2;

Ari is independently chosen at each occurrence from phenyl, naphthyl, and 5- or 6-membered heteroaryl groups having from 1 to 3 heteroatoms independently chosen from N, O, and S, each of which Ari is unsubstituted or substituted with 1 or more substituents independently chosen from halogen, hydroxyl, amino, cyano, nitro, -CHO, -COOH, -SH, Ci-C₈alkyl, C₂-C₈alkenyl, C₂- C₆alkanoyl, (Ci-C₆alkoxy)Co-C₄alkyl, (Ci-C₆alkylthio)C₀-C alkyl, (mono- or di-Ci- C₆alkylamino)Co-C alkyl, (C3-C₆cycloalkyl)Co-C alkyl, mono- or di-Ci-C₆alkylcarboxamide, d- C₆alkylester, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy;

R₂ is hydrogen, Ci-C₆alkyl, SRy, where Ry is Ci-C₆alkyl, or S0₃H; or

R₂ is -L₂-Ar₂;

L₂ is -S-, -C(0)NR₃(CR₄R₅)n- or -C(0)0(CR₄R₅)n-, where n is 0, 1, or 2;

R₃ is hydrogen, Ci-C₄alkyl, or phenyl,

R^ and R₅ are independently chosen from hydrogen, halogen, Ci-C₄alkyl, or Ci-C₄alkoxy;

Ar₂ is phenyl, naphthyl, or a 5- or 6-membered heteroaryl group having from 1 to 3 heteroatoms

independently chosen from N, O, and S, each of which Ar₂ is unsubstituted or substituted with 1 or more substituents independently chosen from halogen, hydroxyl, amino, cyano, nitro, -CHO, - COOH, -SH, Ci-Cgalkyl, C₂-C₈alkenyl, C₂-C₆alkanoyl, (C₁-C₆alkoxy)C₀-C₄alkyl, (C

C₆alkylthio)C₀-C alkyl, (mono- or di-Ci-C₆alkylamino)Co-C alkyl, (C₃-C₆cycloalkyl)C₀-C alkyl, mono- and di-Ci-C₆alkylcarboxamide, Ci-C₆alkylester, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy. ompound of the Formula

or a pharmaceutically acceptable salt thereof, wherein

Ri is -L_!-Ar_! or -Lx-Qx where

Lx is NH, O, Se, or S(0)m, where m is 0, 1, or 2;

ATI is phenyl, naphthyl, or a 5- or 6-membered heteroaryl group having from 1 to 3 heteroatoms

independently chosen from N, O, and S, each of which Ari is unsubstituted or Ari is substituted with 1 or more substituents independently chosen from halogen, hydroxyl, amino, cyano, nitro, - CHO, -COOH, -SH, Ci-Cgalkyl, C₂-C₈alkenyl, C₂-C₆alkanoyl, (C₁-C₆alkoxy)C₀-C₄alkyl, (C C₆alkylthio)Co-C₄alkyl, (mono- and di-Ci-C₆alkylamino)Co-C₄alkyl, mono- and di-Cx- C₆alkylcarboxamide, Ci-C₆alkylester, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy;

Qi is C₂-C₆ alkenyl or alkynyl;

R₂ is- L₂-Ar₂;

Where L₂ is -S-, -(CR₄R₅)n-, or -C(0)0(CR₄R₅)n-, where n is 0, 1, or 2;

Rx and R₅ are independently chosen from hydrogen, halogen, Ci-C alkyl, or Ci-C alkoxy; and

Ar₂ is phenyl, naphthyl, or a 5- or 6-membered heteroaryl group having from 1 to 3 heteroatoms

independently chosen from N, O, and S, each of which Ar₂ is unsubstituted or substituted with 1 or more substituents independently chosen from halogen, hydroxyl, amino, cyano, nitro, -CHO, - COOH, d-Csalkyl, C₂-C₈alkenyl, C₂-C₆alkanoyl, (C₁-C₆alkoxy)C₀-C₄alkyl, (C₁-C₆alkylthio)C₀- C alkyl, (mono- and di-Ci-C₆alkylamino)Co-C alkyl, mono- and di-Ci-C₆alkylcarboxamide, d- C₆alkylester, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy.

A compound or salt of Claim 1 , wherein:

R₀ are each hydrogen or methyl.

4. A compound or salt of Claim 1 , wherein:

R and R₀ are both hydrogen.

5. A compound or salt of Claim 1 , wherein

R is hydrogen and R₀ is phenyl, which phenyl is unsubstituted or substituted with 1 or more substituents independently chosen from halogen, hydroxyl, amino, cyano, nitro, -CHO, -COOH, Ci-C₈alkyl, C₂-C₈alkenyl, C₂-C₆alkanoyl, (Ci-C₆alkoxy)Co-C₄alkyl, (Ci-C₆alkylthio)Co-C₄alkyl, (mono- or di-Ci-C₆alkylamino)Co-C₄alkyl, (C₃-C₆cycloalkyl)Co-C₄alkyl, mono- or di-Ci- C₆alkylcarboxamide, Ci-C₆alkylester, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy.

6. A compound or salt of Claim 1 , wherein R is hydrogen and R₀ is phenyl, which phenyl is

substituted with one or more substituents independently chosen halogen substituents.

7. A compound of salt of any one of Claims 1 to 6, wherein:

ATI is phenyl, thienyl, or naphthyl; each of which Ατι is unsubstituted or substituted with 1 or more

substituents independently chosen from halogen, hydroxyl, amino, cyano, nitro, -CHO, -COOH, -SH, d-Csalkyl, C₂-C₈alkenyl, C₂-C₆alkanoyl, (C₁-C₆alkoxy)C₀-C₄alkyl, (C₁-C₆alkylthio)C₀- C alkyl, (mono- and di-Ci-C₆alkylamino)Co-C alkyl, (C₃-C₆cycloalkyl)Co-C alkyl, mono- and di- Ci-C₆alkylcarboxamide, Ci-C₆alkylester, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy.

8. A compound or salt of Claim 7, wherein:

R and R₀ and both hydrogen;

is S; and

Aii is phenyl, thienyl, or naphthyl, each of which is unsubstituted.

9. A compound or salt of Claim 7, wherein:

R and R₀ and both hydrogen;

is S; and

Aii is phenyl, substituted at the ortho and/ or para positions with substituents independently chosen from halogen, cyano, nitro, -CHO, -COOH, -SH, Ci-C₃alkylthio, Ci-C₃alkoxy, C₂-C alkanoyl, d- C₂haloalkyl, and Ci-C₂haloalkoxy and optionally substituted with 1 or more substituents independently chosen from halogen, hydroxyl, amino, cyano, nitro, -CHO, -COOH, Ci-C₈alkyl, C₂-C₈alkenyl, C₂-C₆alkanoyl, (Ci-C₆alkoxy)C₀-C alkyl, (Ci-C₆alkylthio)C₀-C alkyl, (mono- and di-Ci-C₆alkylamirio)Co-C₄alkyl, (C3-C₆cycloalkyl)Co-C₄alkyl, mono- and di-Cr C₆alkylcarboxamide, Ci-C₆alkylester, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy.

10. A compound or salt of Claim 9, wherein:

ATI is phenyl substituted at one or more of the ortho or para positions with substituents independently chosen from fluoro, chloro, nitro, -SH, methylthio, trifluoromethyl, methoxy, and optionally substituted with one or more additional methyl or ethyl substituents.

11. A compound of salt of any one of Claims 1 or 3 to 10, wherein:

L₂ is -C(0)NHR₄R₅- where R₄ and R₅ are independently hydrogen or methyl.

12. A compound or salt any one of Claims 1 or 3 to 10, wherein L₂ is -CONH-.

13. A compound or salt of any one of Claims 2 to 10, wherein L₂ is -CR^-.

14. A compound or salt of Claim 13, wherein: R₄ and R₅ are independently hydrogen or methyl.

15. A compound or salt of any one of Claims 1 to 14, wherein:

Ar₂ is phenyl or naphthyl, each of which is unsubstituted.

16. A compound or salt of any one of Claims 1 to 14, wherein R₂ is hydrogen.

17. A compound of salt of any one of Claim 1 to 124 wherein:

Ar₂ is phenyl, naphthyl, thienyl, or pyridyl, each of which Ar₂ is unsubstituted or substituted with 1 to 3 substituents independently chosen from halogen, hydroxyl, amino, cyano, nitro, -CHO, -COOH, - SH, d-Cealkyl, C₂-C₆alkanoyl, (CrC₄alkoxy)Co-C₂alkyl, (CrC₄alkylthio)Co-C₂alkyl, (mono- and di-Ci-C alkylamino)C₀-C₂alkyl, (C3-C₆cycloalkyl)Co-C₂alkyl, mono- and di-Cr

C₆alkylcarboxamide, Ci-C₆alkylester, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy.

18. A compound or salt of Claim 1 , wherein any one of the following conditions is met:

Li is S, ATI is 2,4-difluorophenyl, and R₂ is H;

Li is S, ATI is 4-nitrophenyl, and R₂ is H;

Li is S, ATI is 2,4-difluorophenyl, R₂ is -L₂-Ar₂, L₂ is -CONHCH₂-, and Ar₂ is phenyl;

Li is S, AT_! is 2,4-difluorophenyl, R₂ is -L₂-Ar₂, L₂ is -CONHCH(CH₃)-, and Ar₂ is naphthyl; Li is S, ATI is 2,4-difluorophenyl, R₂ is -L₂-Ar₂, L₂ is -CONHCH₂-, and Ar₂ is 2-fluorophenyl; is S, Aii is 2,4-difluorophenyl, R₂ is -L₂-Ar₂, L₂ is -CONHCH₂-, and Ar₂ is 2-methoxyphenyl; is S, Aii i 2,4-difluorophenyl, R₂ is -L₂-Ar₂, L₂ is -CONH-, and Ar₂ is 2-fluorophenyl;

Li is S, Aii is 2-chloro-4-fluorophenyl, and R₂ is H;

Li is S, Aii is 4-trifluoromethylphenyl, R₂ is -L₂-Ar₂, L₂ is -CONHCH₂-, and Ar₂ is phenyl;

Li is S, Aii is 3-trifluoromethylphenyl, R₂ is -L₂-Ar₂, L₂ is -CONHCH₂-, and Ar₂ is phenyl;

Li is S, Aii is 2,4-dichlorophenyl, R₂ is -L₂-Ar₂, L₂ is -CONHCH₂-, and Ar₂ is phenyl; or

Li is S, Aii is 2-chloro-4-fluorophenyl, R₂ is -L₂-Ar₂, L₂ is -CONHCH(phenyl)-, and Ar₂ is phenyl.

19. A compound or salt of Claim 2, wherein any one of the following conditions is met:

Li is S, ATI is 4-nitrophenyl, L₂ is CH₂, and Ar₂ is phenyl; or

Li is S, ATI is phenyl, L₂ is CH₂, and Ar₂ is phenyl.

20. A compound or salt of Claim 1 , wherein the compound is

4-Phenylsulfanyl-azetidin-2-one;

4-(2-Fluoro-phenylsulfanyl)-azetidin-2-one;

4-(3-Fluoro-phenylsulfanyl)-azetidin-2-one;

4-(4-Fluoro-phenylsulfanyl)-azetidin-2-one;

4-(2,4-Difluoro-phenylsulfanyl)-azetidin-2-one;

4-(3,4-Difluoro-phenylsulfanyl)-azetidin-2-one;

4-Pentafluorophenylsulfanyl-azetidin-2-one;

4-(2-Chloro-4-fluoro-phenylsulfanyl)-azetidin-2-one;

4-(3-Chloro-4-fluoro-phenylsulfanyl)-azetidin-2-one;

4-(2,4-Dichloro-phenylsulfanyl)-azetidin-2-one;

4-(4-Nitro-phenylsulfanyl)-azetidin-2-one;

4-((2-(trifluoromethyl)phenyl)thio)azetidin-2-one;

4-((3-(trifluoromethyl)phenyl)thio)azetidin-2-one;

4-((4-(trifluoromethyl)phenyl)thio)azetidin-2-one;

4-((3,5-bis(trifluoromethyl)phenyl)thio)azetidin-2-one;

4-(2-Methoxy-phenylsulfanyl)-azetidin-2-one;

4-(3-Methoxy-phenylsulfanyl)-azetidin-2-one;

4-(4-Methoxy-phenylsulfanyl)-azetidin-2-one;

4-(2 ,5 -Dimethoxy-phenylsulf anyl)-azetidin-2-one ;

4-(3,4-Dimethoxy-phenylsulfanyl)-azetidin-2-one; 4-(Thiophen-2-ylsulfanyl)-azetidin-2-one ;

4-(4-Methylsulfanyl-phenylsulfanyl)-azetidin-2-one;

4-(Naphthalen-l-ylsulfanyl)-azetidin-2-one;

4-Phenylselanyl-azetidin-2-one;

2-Oxo-4-phenylsulfanyl-azetidine-l-carboxylic acid benzylamide;

2-(2-Fluoro-phenylsulfanyl)-4-oxo-azetidine-l-carboxylic acid benzylamide;

2-(3-Fluoro-phenylsulfanyl)-4-oxo-azetidine-l-carboxylic acid benzylamide;

2-(t-phenylsulfanyl)-4-oxo-azetidine-l-carboxylic acid benzylamide;

2-(2,4-Difluoro-phenylsulfanyl)-4-oxo-azetidine-l-carboxylic acid benzylamide;

N-benzyl-2-((3,4-difluorophenyl)thio)-4-oxoazetidine-l-carboxamide;

N-benzyl-2-oxo-4-((perfluorophenyl)thio)azetidine-l-carboxamide;

N-benzyl-2-((2-chloro-4-fluorophenyl)thio)-4-oxoazetidine-l-carboxamide;

N-benzyl-2-((3-chloro-4-fluorophenyl)thio)-4-oxoazetidine-l-carboxamide;

N-benzyl-2-((2,4-dichloro)thio)-4-oxoazetidine-l-carboxamide;

A/-benzyl-2-((4-nitrophenyl)thio)-4-oxoazetidine-l-carboxamide;

N-benzyl-2-oxo-4-((2-(trifluoromethyl)phenyl)thio)azetidine-l-carboxamide;

N-benzyl-2-oxo-4-((3-(trifluoromethyl)phenyl)thio)azetidine-l-carboxamide;

N-benzyl-2-oxo-4-((4-(trifluoromethyl)phenyl)thio)azetidine-l-carboxamide;

N-benzyl-2-((3,5-bis(trifluoromethyl)phenyl)thio)-4-oxoazetidine-l-carboxamide;

A/-benzyl-2-((2-methoxyphenyl)thio)-4-oxoazetidine-l-carboxamide;

A/-benzyl-2-((3-methoxyphenyl)thio)-4-oxoazetidine-l-carboxamide;

A/-benzyl-2-((4-methoxyphenyl)thio)-4-oxoazetidine-l-carboxamide;

A/-benzyl-2-((2,5-dimethoxyphenyl)thio)-4-oxoazetidine-l-carboxamide;

A/-benzyl-2-((3,4-dimethoxyphenyl)thio)-4-oxoazetidine-l-carboxamide;

A/-benzyl-2-oxo-4-(thiophen-3-ylthio)azetidine-l-carboxamide;

A/-benzyl-2-((4-(methylthio)phenyl)thio)-4-oxoazetidine-l-carboxamide;

A/-benzyl-2-(naphthalen-l-ylthio)-4-oxoazetidine-l-carboxamide; N-benzyl-2-oxo-4-

(phenylselanyl)azetidine-l-carboxamide;

4-((4-methoxyphenyl)sulfinyl)azetidin-2-one;

4-((4-chlorophenyl)sulfinyl)azetidin-2-one;

4-(phenylsulfinyl)azetidin-2-one;

4-(2-Chloro-4-fluoro-benzenesulfinyl)-azetidin-2-one;

4-(2,4-Difluoro-benzenesulfinyl)-azetidin-2-one;

4-(4-Trifluoromethyl-benzenesulfinyl)-azetidin-2-one; 4-(4-Trifluoromethoxy-benzenesulfinyl)-azetidin-2-one;

(+/_)- (3S,4R)-4-(3,5-Difluorophenyl)-3-methoxy-l-(methylthio)azetidin-2-

(+/_)-(3S,4R)-4-(4-bromophenyl)-3-methoxy-l-(methylthio)azetidin-2-one;

(+/-)<3S,4R)-3-Methoxy-l-(methylthio)-4-(3,4,5-trifluorophenyl)azetidin-2

4-(2-fluorophenyl)-3-methoxy-l-(methylthio)azetidin-2-one;

4-(3 -fluorophenyl)-3 -methoxy- 1 -(methyl thio)azetidin-2-one;

4-(2,3-difluorophenyl)-3-methoxy-l-(methylthio)azetidin-2-one;

4-(2,5-difluorophenyl)-3-methoxy-l-(methylthio)azetidin-2-one;

4-(2,6-difluorophenyl)-3-methoxy-l-(methylthio)azetidin-2-one;

4-(3,4-difluorophenyl)-3-methoxy-l-(methylthio)azetidin-2-one;

4-(2,4,5-difluorophenyl)-3-methoxy-l-(methylthio)azetidin-2-one;

4-(2,3,5-trifluorophenyl)-3-methoxy-l-(methylthio)azetidin-2-one;

4-(2,3,6-trifluorophenyl)-3-methoxy-l-(methylthio)azetidin-2-one;

4-(2,3,4-trifluorophenyl)-3-methoxy-l-(methylthio)azetidin-2-one;

4-(2,3,4,5,6-pentafluorophenyl)-3-methoxy-l-(methylthio)azetidin-2-one;

l-Methylsulfanyl-4-(4-trifluoromethyl-phenylsulfanyl)-azetidin-2-one; or

4-(4-Trifluoromethoxy-benzenesulfinyl)-azetidin-2-one.

21. A compound or salt of Claim 2, wherein the c-(4-Trifluoromethoxy-benzenesulfinyl)-azetidin-2- one

pound is

S-(4-nitrophenyl) benzylcarbamothioate;

S-phenyl benzylcarbamothioate;

S -(4-fluorophenyl) benzylcarbamothioate ;

S-(3,5-bis(trifluoromethyl)phenyl) benzylcarbamothioate; or

S-vinyl benzylcarbamothioate.

A compound of the Formula

or a pharmaceutically acceptable salt thereof, wherein

R chosen from hydrogen and Ci-C₄alkyl;

R₀ is hydrogen, Ci-C₄alkyl, or -ORx, where Rx is Ci-C₄alkyl, -C(0)CH₃, Ari, or -CH₂phenyl; Rio and Rii are in dependently chosen from H and -L Rz, where

is N, O, Se, or S(0)m, where m is 0, 1, or 2;;

Rz is d-C₆alkyl;

R₂ is hydrogen, Ci-C₄alkyl, or SRy, where Ry is Ci-C₄alkyl; or

R₂ is -L₂-Ar₂;

L₂ is a bond, -S-, -C(0)NR₃(CR₄R₅)n- or -C(0)0(CR₄R₅)n-, where n is 0, 1, or 2;

R₃ is hydrogen, Ci-C alkyl, or phenyl,

R} and R₅ are independently chosen from hydrogen, halogen, Ci-C alkyl, or Ci-C alkoxy;

Ar₂ is phenyl, naphthyl, or a 5- or 6-membered heteroaryl group having from 1 to 3 heteroatoms

independently chosen from N, O, and S, each of which Ar₂ is unsubstituted or substituted with 1 or more substituents independently chosen from halogen, hydroxyl, amino, cyano, nitro, -CHO, -COOH, -SH, d-Csalkyl, C₂-C₈alkenyl, C₂-C₆alkanoyl, (C₁-C₆alkoxy)C₀-C₄alkyl, (C

C₆alkylthio)C₀-C alkyl, (mono- or di-Ci-C₆alkylamino)Co-C alkyl, (C3-C₆cycloalkyl)Co-C alkyl, mono- and di-Ci-C₆alkylcarboxamide, Ci-C₆alkylester, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy.

23. A compound or salt of Claim 22, wherin

R is hydrogen;

Ro is -ORx;

Rio and Rn are each -L Rz, wherein Li is S;

L₂ is a bond;

Ar₂ is phenyl which is unsubstituted or substituted with 1 or more substituents independently chosen from halogen, hydroxyl, amino, cyano, nitro, -CHO, -COOH, -SH, Ci-C₈alkyl, C₂-C₈alkenyl, C₂- C₆alkanoyl, (Ci-C₆alkoxy)C₀-C₄alkyl, (Ci-C₆alkylthio)C₀-C₄alkyl, (mono- or di-Ci- C₆alkylamino)C₀-C₄alkyl, (C₃-C₆cycloalkyl)C₀-C₄alkyl, mono- and di-Ci-C₆alkylcarboxamide, Ci-C₆alkylester, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy.

24. A compound or salt of Claim 22, wherein the compound is

25. A compound or salt of the Formula

26. A compound or salt of Claim 1 ,wherein

R is chosen from hydrogen and Ci-C₄alkyl;

R₀ is hydrogen, Ci-C₄alkyl, or -ORx, where Rx is Ci-C₄alkyl, -C(0)CH₃, Ari, or -CH₂phenyl;

Ri is -Li-Ari, where

Li is S(0)m, where m is 0 or 1 ;

Aii is independently chosen at each occurrence from phenyl, naphthyl, and 5- or 6-membered heteroaryl groups having from 1 to 3 heteroatoms independently chosen from N, O, and S, each of which Ari is unsubstituted or substituted with 1 or more substituents independently chosen from halogen, cyano, nitro, -SH, Ci-C₈alkyl, C₂-C₈alkenyl, C₂-C₆alkanoyl, (Ci-C₆alkoxy)Co-C₄alkyl, (Ci-C₆alkylthio)C₀-C alkyl, (mono- or di-Ci-C₆alkylamino)Co-C alkyl, (C₃-C₆cycloalkyl)Co- C alkyl, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy;

R₂ is SRy, where Ry is Ci-C₆alkyl; or

R₂ is -L₂-Ar₂;

L₂ is -S-

Ar₂ is phenyl, naphthyl, or a 5- or 6-membered heteroaryl group having from 1 to 3 heteroatoms

independently chosen from N, O, and S, each of which Ar₂ is unsubstituted or substituted with 1 or more substituents independently chosen from halogen, hydroxyl, amino, cyano, nitro, -CHO, - COOH, -SH, Ci-Cgalkyl, C₂-C₈alkenyl, C₂-C₆alkanoyl, (C₁-C₆alkoxy)C₀-C₄alkyl, (C

C₆alkylthio)C₀-C alkyl, (mono- or di-Ci-C₆alkylamino)Co-C alkyl, (C3-C₆cycloalkyl)Co-C alkyl, mono- and di-Ci-C₆alkylcarboxamide, Ci-C₆alkylester, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy.

27. A compound or salt of Claim 26, wherein R₂ is SRy, where Ry is Ci-C₆alkyl.

28. A compound or salt of Claim 26 or 27, wherein

Ri is -S-Ari, where

Aii is phenyl, naphthyl, and 5- or 6-membered heteroaryl groups having from 1 to 3 heteroatoms

independently chosen from N, O, and S, each of which Aii is unsubstituted or substituted with 1 or more substituents independently chosen from halogen, cyano, nitro, -SH, Ci-C₈alkyl, C₂- C₈alkenyl, C₂-C₆alkanoyl, (Ci-C₆alkoxy)C₀-C₄alkyl, (Ci-C₆alkylthio)C₀-C₄alkyl, (mono- or di- Ci-C₆alkylamino)Co-C₄alkyl, (C₃-C₆cycloalkyl)Co-C₄alkyl, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy.

29. A compound or salt of Claim 28, wherein

ATI is phenyl or thienyl, each of which Ατι is unsubstituted or substituted with 1 or more substituents independently chosen from fluoro, chloro, and Ci-C₈alkyl.

30. A compound or salt of Claim 1 , wherein

L₂ is -C(0)NR₃(CR₄R₅)n- or -C(0)0(CR₄R₅)n-, where n is 0, 1, or 2.

31. A compound or salt of Claim 2, wherein

Ri is LiAri;

is -S-; and

ATI is independently chosen at each occurrence from phenyl, naphthyl, and 5- or 6-membered heteroaryl groups having from 1 to 3 heteroatoms independently chosen from N, O, and S, each of which Ar_! is unsubstituted or substituted with 1 or more substituents independently chosen from halogen, hydroxyl, amino, cyano, -CHO, -COOH, -SH, Ci-C₈alkyl, C₂-C₈alkenyl, C₂-C₆alkanoyl, (Ci-C₆alkoxy)C₀-C alkyl, (Ci-C₆alkylthio)C₀-C alkyl, (mono- or di-Ci-C₆alkylamino)Co-C alkyl, (C3-C₆cycloalkyl)Co-C alkyl, mono- or di-Ci-C₆alkylcarboxamide, Ci-C₆alkylester, d- C₂haloalkyl, and Ci-C₂haloalkoxy.

32. A compound or salt of Claim 2, wherein

R_! is I^Ar^

is -S-; and

ATI is independently chosen at each occurrence from phenyl, naphthyl, and 5- or 6-membered heteroaryl groups having from 1 to 3 heteroatoms independently chosen from N, O, and S, each of which Ari is substituted with at least on nitro group and substituted with 1 or more substituents independently chosen from halogen, hydroxyl, amino, cyano, -CHO, -COOH, -SH, Ci-C₈alkyl, C₂-C₈alkenyl, C₂-C₆alkanoyl, (Ci-C₆alkoxy)C₀-C₄alkyl, (Ci-C₆alkylthio)C₀-C₄alkyl, (mono- or di-Ci-C₆alkylamino)C₀-C alkyl, (C3-C₆cycloalkyl)Co-C alkyl, mono- or di-Ci- C₆alkylcarboxamide, Ci-C₆alkylester, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy.

33. A compound or salt of Claim 32, wherein Ari is phenyl substituted with nitro.

34. A compound or salt of Claim 22, wherein

R₂ is SRy, where Ry is Ci-C₆alkyl or

R₂ is -L₂Ar₂;

L₂ is -S-;

Ar₂ is phenyl, naphthyl, or a 5- or 6-membered heteroaryl group having from 1 to 3 heteroatoms

independently chosen from N, O, and S, each of which Ar₂ is unsubstituted or substituted with 1 or more substituents independently chosen from halogen, hydroxyl, amino, cyano, nitro, -CHO, - COOH, -SH, Ci-Cgalkyl, C₂-C₈alkenyl, C₂-C₆alkanoyl, (C₁-C₆alkoxy)C₀-C₄alkyl, (Q- C₆alkylthio)C₀-C₄alkyl, (mono- or di-Ci-C₆alkylamino)C₀-C₄alkyl, (C₃-C₆cycloalkyl)Co-C₄alkyl, mono- and di-Ci-C₆alkylcarboxamide, Ci-C₆alkylester, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy.

35. A compound or salt of Claim 34, wherein R₂ is SRy, where Ry is Ci-C₆alkyl.

36. A compound or salt of Claim 22, wherein

R₂ is -L₂Ar₂; and

L₂ is -C(0)NR₃(CR₄R₅)n- or -C(0)0(CR₄R₅)n-, where n is 0, 1, or 2.

37. A pharmaceutical composition comprising a compound or salt of any one of Claims 1 to 36, together with a pharmaceutically acceptable carrier.

38. A method of treating familial LecithimCholesterol Acyltransferase deficiency in a patient

comprising administering a therapeutically effective amount of a compound or salt of any one of Claims 1 to 36 to the patient.

39. A method of raising HDL in a patient comprising administering a therapeutically effective

amount of a compound or salt of any one of Claims 1 to 36 to the patient.

40. A method of treating lysomal acid lipase deficiency, Wolman's disease, or Cholesterol ester storage disorder, in a patient comprising administering a therapeutically effective amount of a compound or salt of any one of Claims 1 to 36 to the patient.

41. A method inhibiting cholesterol ester formation in a patient with acid lipase deficiency by

administering a therapeutically effective amount of a compound of any one of Claims 1 to 36 to the patient.

42. A method of treating atherosclerosis in a patient or reducing the rate of arterial plague formation in a patient comprising administering a therapeutically effective amount of a compound or salt of any one of Claims 1 to 36 to the patient.

43 A method of reducing the rate of neurodegeneration in a patient suffering from Alzheimer's dementia or multiple sclerosis comprising administering a therapeutically effective amount of a compound or salt of any one Claims 1 to 36 to the patient.

44. A method of reducing neurodegeneration in a patient following a brain injury due to concussion, oxygen deprivation, or stroke comprising administering a therapeutically effective amount of a compound or salt of any one Claims 1 to 36 to the patient 0 to 72 hours after the brain injury has occurred.

45. A method of increasing LCAT activity in a patient in need thereof comprising administering a therapeutically effective amount of a compound or salt of any one Claims 1 to 36 to the patient.

46. The method of Claim 45 wherein the patient has a genetic defect in the gene encoding LCAT or has decreased LCAT activity due to liver failure or chronic renal disease.

47. The method of any one of Claims 38-39 and 42-46, wherein the compound or salt thereof is an LCAT activator.

48. The method of Claim 40 or 41, wherein the compound or salt thereof is an LCAT inhibitor.