WO2011028651A1 - Inhibitors of human 15-lipoxygenase-1 - Google Patents

Abstract

Disclosed are inhibitors of human 15 lipoxygenase 1, for example, of formula (I), wherein R¹, R², R³, R⁴, X, Y, and Z are as defined herein, that are useful in treating a 15-lipoxygenase mediated disease or disorder, e.g., prostate cancer. Also disclosed is a composition comprising a pharmaceutically suitable carrier and at least one compound of the invention, and a method of treating prostate cancer in a mammal.

Description

INHIBITORS OF HUMAN 15-LIPOXYGENASE- 1

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001 ] This patent application claims the benefit of U.S . Provisional Patent Application No. 61/238,972, filed September 1, 2009, and U.S. Provisional Patent Application No.

61/315,788, filed March 19, 2010, the disclosures of which are incorporated by reference.

BACKGROUND OF THE INVENTION

[0002] Lipoxygenases are a class of non-heme iron-containing enzymes found in plants and animals which catalyze the oxidation of polyunsaturated fatty acids, including those found in lipoproteins, to hydroperoxy derivatives. In humans, there are genes coded for the following lipoxygenases: e-LOX-3 (epidermis-type lipoxygenase 3), 5-LO (5-lipoxygenase), 12-LO (12-lipoxygenase), 12(R)-LOX (12(R)-lipoxygenase), 15-LO-l (reticulocyte type- 15-lipoxygenase- 1), and 15-LO-2 (15-lipoxygenase-2). The lipoxygenases are named according to the specificity of the position of oxidation on arachidonic acid. 12-LO and 15- LO respectively convert arachidonic acid to 12(S)-hydroxyperoxy- 5,8,10,14(Z,Z,E,Z)eicosatetraenoic acid (12(S)-HPETE) and 15(S)-hydroxyperoxy- 5,8,10,14(Z_tZ,E,Z)eicosatetraenoic acid (15(S)-HPETE). Biochemical reduction of 12(S)- HPETE and 15(S)-HPETE respectively leads to the formation of 12(S)-HETE (12-(S)- hydroxy-eicosatetraenoic acid) and 15(S)-HETE (15-(S)-hydroxy-eicosatetraenoic acid) which is the precursor of a class of compounds known as lipoxins. While arachidonic acid is the sole substrate of 15-LO-2, 15-LO-l also metabolizes, in a preferential manner, linoleic acid to 13(S)-hydroxyperoxy-9Z,l lE-octodecadienoic acid (13(S)-HODE).

[0003] Prostate cancer is the most commonly diagnosed malignancy among men in the USA and Europe. There are a number of mutated genes, as well as several genes that are up-or down-regulated in prostate cancer. 15-LO-l is also overexpressed in adenocarcinoma tissues, as well as in all prostate cancer cell lines. The oxidation products of arachidonic acid and linoleic acid produced by 15-LO-l, namely, 15(S)-HETE and 13(S)-HODE, are subject to a further cascade of transformations to a variety of biologically active products, which are thought to act as mediators between cancer cells within the prostate tissue and that tumor progression and/or metastasis depends, in part, on the synthesis and disposition of these classes of compounds. [0004] In addition, 15-lipoxygenase has been implicated in several pathologies including atherosclerosis, asthma, other cancers, glomerulonephritis, osteoporosis, and Alzheimer's disease.

[0005] In view of the foregoing, there is a desire to provide new inhibitors of 15- lipoxygenase, in particular, inhibitors of human 15 -lipoxygenase- 1.

BRIEF SUMMARY OF THE INVENTION

[0006] The invention provides compounds that are potent inhibitors of human

15 -lipoxygenase- 1. addition, the present invention provides compositions comprising these compounds and methods of using these compounds as therapeutic agents in the treatment of human 15 -lipoxygenase- 1 mediated diseases or disorders, in particular, in the treatment of prostate cancer or Alzheimer's disease.

[0007] The invention provides a compound of the formula (I):

(I)

wherein R is selected from the group consisting of a C₆-Cio aryl group and a heterocyclyl group, each optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the group consisting of halo, Ci-C₆ alkyl, 0₂-0₆ alkenyl, C₂-C₆ alkynyl, C₃-Cg cycloalkyl, C - Cg cycloalkenyl, Ce-Qo aryl, heteroaryl, -Ce haloalkyl, Q-Cg dihaloalkyl, Ci-C₆ trihaloalkyl, -N0₂, -OH, -OR⁵, -SH, -SR⁵, -SOR⁵, -S0₂R⁵, -COR⁵, -COOH, -COOR⁵, -CONHR⁵, and -CONR⁵R⁶,

X is O or S,

Y is S, NH, or O,

R² is selected from the group consisting of Ci-C₆ alkylene, C₂-C₆ alkenylene, C₂-C₆ alkynylene, C₆-Cio arylene, C₇-d₂ alkylarylene, C₇-C₁₂ dialkylarylene, each optionally substituted with 1, 2, 3, or 4 C]-C₆ alkyl substituents,

Z is S, NH, NR⁵, NHS0₂, or O,

R³ is a bond, CH₂, or C=0,

R⁴ is selected from the group consisting of C_\-Ce alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl, C₆-Cio aryl, heterocyclyl, each optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halo, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-Cg cycloalkyl, C₃-Cs cycioalkenyl, Ce-C o aryl, heteroaryl, Ci-C₆ haloalkyl, d-C₆ dihaloalkyl, Q-Q, trihaloalkyl, -N0₂, -OH, -OR⁵, -NH₂, -NHR⁵, -NR⁵R⁶, - SH, -SR⁵, -SOR⁵, -S0₂R⁵, -COR⁵, -COOH, -COOR⁵, -CONHR⁵, and -CONR⁵R⁶, and

R⁵ and R⁶ are selected from the group consisting of C Q alkyl, C₂-C6 alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, and C₃-C₈ cycioalkenyl,

or a pharmaceutically acceptable salt thereof.

[0008] The invention also provides a compound of the formula (II):

(Π)

wherein R⁷ is selected from the group consisting of a C₆-Ci₀ aryl group and a heterocyclyl group, each optionally substituted by 1 , 2, 3, 4, or 5 substituents selected from the group consisting of halo, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-Cg cycloalkyl, C₃- C₈ cycioalkenyl, C₆-Cio aryl, heteroaryl, Cj-Ce haloalkyl, Q-C6 dihaloalkyl, C Cg trihaloalkyl, -N0₂, -OH, -OR⁵, -SH, -SR⁵, -SOR⁵, -S0₂R⁵, -COR⁵, -COOH, -COOR⁵, -CO HR⁵, and -C0NR⁵R⁶,

X is O or S,

Y is S, NH, or O,

R⁸ is selected from the group consisting of Ci-Ce alkylene, C₂-C₆ alkenylene, C₂-C₆ alkynylene, C₆-Cio arylene, C₇-C₁₂ alkylarylene, and C₇-C₁₂ dialkylarylene, each optionally substituted with 1 , 2, 3, or 4 Ci-C₆ alkyl substituents,

R⁹ is CH₂ or C=0,

R¹⁰ is selected from the group consisting of C C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₃-Cg cycioalkenyl, C₆-Cio aryl, heterocyclyl, each optionally substituted with 1 , 2, 3, or 4 substituents selected from the group consisting of halo, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ cycioalkenyl, C₆-C₁₀ aryl, heteroaryl, Ci-C₆ haloalkyl, C, -C₆ dihaloalkyl, Ci-C₆ trihaloalkyl, -N0₂, -OH, -OR⁵, -NH₂, -NHR⁵, -NR⁵R⁶, - SH, -SR⁵, -SOR⁵, -S0₂R⁵, -COR⁵, -COOH, -COOR⁵, -CONHR⁵, and -~CONR⁵R⁶, and R⁵ and R⁶ are independently selected from the group consisting of Ci -Ce alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, and C₃-C₈ cycioalkenyl, or a pharmaceutically acceptable salt thereof. [0009] The invention also provides a pharmaceutical composition comprising a compound or salt of the invention and a pharmaceutically acceptable carrier.

[0010] The invention further provides a method for treating a 15 -lipoxygenase mediated disorder, for example, cancer or Alzheimer's disease, comprising administering an effective amount of the compound on the invention to a mammal afflicted therewith.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S)

[0011] Figure 1 illustrates a synthetic scheme to prepare oxadiazole-2-thio compounds in accordance with an embodiment of the invention.

[0012] Figure 2 illustrates a synthetic scheme to prepare thiadiazole-2-thio compounds in accordance with another embodiment of the invention.

[0013] Figure 3 illustrates a synthetic scheme to prepare oxadiazole-2-amino compounds in accordance with a further embodiment of the invention,

[0014] Figure 4 illustrates a synthetic scheme to prepare an oxadiazole-2-thio compound in accordance with a further embodiment of the invention.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with an embodiment, the invention provides a compound of the

(I)

wherein R is selected from the group consisting of a C₆-Cio aryl group and a heterocyclyl group, each optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the group consisting of halo, C]-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₃- Cs cycloalkenyl, C₆-Cio aryl, heteroaryl, Ci-C₆ haloalkyl, Ci-C₆ dihaloalkyl, Q-Ce trihaloalkyl, -N0₂, -OH, -OR⁵, -SH, -SR⁵, -SOR⁵, -S0₂R⁵, -COR⁵, -COOH, -COOR⁵, -CONHR⁵, and -CONR⁵R⁶,

X is O or S,

Y is S, NH, or O,

R² is selected from the group consisting of Ci-C₆ alkylene, C₂-C₆ alkenylene, C₂-C₆ alkynylene, C₆-Ci₀ arylene, C₇-Ci₂ alkylarylene, and C₇-Cn dialkylarylene, each optionally substituted with 1, 2, 3, or 4 CrC₆ alkyl substituents, Z is S_} NH, NR⁵, NHS0₂, or O,

R³ is a bond, CH₂, or C=0,

R⁴ is selected from the group consisting of Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C -C₈ cycloalkyl, C₃-C₈ cycloalkenyl, C₆-Ci₀ aryl, heterocyclyl, each optionally substituted with 1 , 2, 3, or 4 substituents selected from the group consisting of halo, Ci-C₆ alkyl, C₂-C₆ alkenyl, C2-C₆ alkynyl, C₃-Cg cycloalkyl, C₃-C₈ cycloalkenyl, C₆-Cio aryl, heteroaryl, Ci-C₆ haloalkyl, Ci-C₆ dihaloalkyl, Ci-C₆ trihaloalkyl, -N0₂, -OH, -OR⁵, - H₂, -NHR⁵, -NR⁵R⁶, - SH, -SR⁵, -SOR⁵, -S0₂R⁵, -COR⁵, -COOH, -COOR⁵, -CONHR⁵, and -CONR⁵R⁶, and

R⁵ and R⁶ are independently selected from the group consisting of Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, and C₃-C₈ cycloalkenyl,

or a pharmaceutically acceptable salt thereof.

[0016] In accordance with an embodiment, the invention provides a compound of the formula (II):

N-N

R⁷^_X^Y__R8._R9._R10

(Π)

wherein R⁷ is selected from the group consisting of a C₆-Cio aryl group and a heterocyclyl group, each optionally substituted by 1 , 2, 3, 4, or 5 substituents selected from the group consisting of halo, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₃- C₈ cycloalkenyl, C₆-Cio aryl, heteroaryl, Cj-Ce haloalkyl, Ci-C₆ dihaloalkyl, Ci-C₆ trihaloalkyl, -N0₂, -OH, -OR⁵, -SH, -SR⁵, -SOR⁵, -S0₂R⁵, -COR⁵, -COOH, -COOR⁵, -CONHR⁵, and -CONR⁵R⁶,

X is O or S,

Y is S, NH, or O,

R⁸ is selected from the group consisting of Ci-C₆ alkylene, C₂-C₆ alkenylene, C₂-C₆ alkynylene, C - _\o arylene, C₇-Ci₂ alkylarylene, and C₇-Ci₂ dialkylarylene, each optionally substituted with 1, 2, 3, or 4 C]-C₆ alkyl substituents,

R⁹ is CH₂ or C=0,

R¹⁰ is selected from the group consisting of C C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₃-C_¾ cycloalkenyl, C₆-Cio aryl, heterocyclyl, each optionally substituted with 1 , 2, 3, or 4 substituents selected from the group consisting of halo, C C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₃-Cg cycloalkenyl, C₆-Cio aryl, heteroaryl, C C₆ haloalkyl, Q-C₆ dihaloalkyl, C C₆ trihaloalkyl, -N0₂, -OH, -OR⁵, -NH₂, -NHR⁵, -NR⁵R⁶, - SH, -SR⁵, -SOR⁵, -S0₂R⁵, -COR⁵, -COOH, -COOR⁵, -CONHR⁵, and -CONR⁵R⁶, and

R⁵ and R⁶ are independently selected from the group consisting of Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, and C₃-C₈ cycloalkenyl,

or a pharmaceutically acceptable salt thereof.

[0017] Referring now to terminology used generically herein, the term "alkyl" means a straight-chain or branched alkyl substituent containing from, for example, 1 to about 6 carbon atoms, preferably from 1 to about 4 carbon atoms, more preferably from 1 to 2 carbon atoms. Examples of such substituents include methyl, ethyl, propyl, isopropyl, /i-butyl, sec-butyl, isobutyl, teri-butyl, pentyl, isoamyl, hexyl, and the like.

[0018] The term "alkylene," as used herein, means a straight-chain or branched alkyl substituent containing from, for example, 1 to about 6 carbon atoms, preferably from 1 to about 4 carbon atoms, and is connected to two or more substituents at two or more different positions on the alkylene group.

[0019] The term "alkenyl," as used herein, means a linear alkenyl substituent containing at least one carbon-carbon double bond and from, for example, about 2 to about 6 carbon atoms (branched alkenyls are about 3 to about 6 carbons atoms), preferably from about 2 to about 5 carbon atoms (branched alkenyls are preferably from about 3 to about 5 carbon atoms), more preferably from about 3 to about 4 carbon atoms. Examples of such

substituents include vinyl, propenyl, isopropenyl, n-butenyl, _rec-butenyl, isobutenyl, tert- butenyl, pentenyl, isopentenyl, hexenyl, and the like.

[0020] The term "alkenylene," as used herein, means a straight-chain or branched alkenyl substituent containing from, for example, 2 to about 6 carbon atoms, preferably from 2 to about 4 carbon atoms, and is connected to two or more substituents at two or more different positions on the alkenylene group.

[0021] The term "alkynyl," as used herein, means a linear alkynyl substituent containing at least one carbon- carbon triple bond and from, for example, 2 to about 6 carbon atoms (branched alkynyls are about 3 to about 6 carbons atoms), preferably from 2 to about 5 carbon atoms (branched alkynyls are preferably from about 3 to about 5 carbon atoms), more preferably from about 3 to about 4 carbon atoms. Examples of such substituents include ethynyl, propynyl, isopropynyl, n-butynyl, sec-butynyl, isobutynyl, tert-butynyl, pentynyl, isopentynyl, hexynyl, and the like.

[0022] The term "alkynylene," as used herein, means a straight-chain or branched alkynyl substituent containing from, for example, 2 to about 6 carbon atoms, preferably from 2 to about 4 carbon atoms, and is connected to two or more substituents at two or more different positions on the alkynylene group.

[0023] The term "cycloalkyl," as used herein, means a cyclic alkyl substituent containing from, for example, about 3 to about 8 carbon atoms, preferably from about 4 to about 7 carbon atoms, and more preferably from about 4 to about 6 carbon atoms. Examples of such substituents include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. The term "cycloalkenyl," as used herein, means the same as the term "cycloalkyl," however one or more double bonds are present. Examples of such substituents include cyclopentenyl and cyclohexenyl. The cyclic alkyl groups may be unsubstituted or further substituted with alkyl groups such as methyl groups, ethyl groups, and the like.

[0024] The term "heterocyclyl," as used herein, refers to a monocyclic or bicyclic 5- or 6-membered ring system containing one or more heteroatoms selected from the group consisting of O, N, S, and combinations thereof. The heterocyclyl group can be any suitable heterocyclyl group and can be an aliphatic heterocyclyl group, an aromatic heterocyclyl group, or a combination thereof. The heterocyclyl group can be a monocyclic heterocyclyl group or a bicyclic heterocyclyl group. Suitable bicyclic heterocyclyl groups include monocylic heterocyclyl rings fused to a C₆-Cio aryl ring. When the heterocyclyl group is a bicyclic heterocyclyl group, both ring systems can be aliphatic or aromatic, or one ring system can be aromatic and the other ring system can be aliphatic as in, for example, dihydrobenzofuran. Preferably, the heterocyclyl group is an aromatic heterocyclyl group. Non-limiting examples of suitable heterocyclyl groups include mranyl, thiopheneyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, benzothiopheneyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolinyl, benzothiazolinyl, and quinazolinyl. The heterocyclyl group is optionally substituted with 1, 2, 3, 4, or 5

substituents as recited herein, wherein the optional substituent can be present at any open position on the heterocyclyl group. [0025] Whenever a range of the number of atoms in a structure is indicated (e.g., a Ci-C,2, Ci-C₈, Ci-C₆, Ci-C₄, or C₂-Ci_2; C₂-C₈, C₂-C₆, C₂-C₄ alkyl, alkenyl, alkynyl, etc.), it is specifically contemplated that any sub-range or individual number of carbon atoms falling within the indicated range also can be used. Thus, for instance, the recitation of a range of 1- 8 carbon atoms (e.g., Ci-Cg), 1-6 carbon atoms (e.g., -Cg), 1-4 carbon atoms (e.g., Ci-C₄), 1-3 carbon atoms (e.g., C1 -C3), or 2-8 carbon atoms (e.g., C₂-C₈) as used with respect to any chemical group (e.g., alkyl, alkylamino, etc.) referenced herein encompasses and specifically describes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and/or 12 carbon atoms, as appropriate, as well as any sub-range thereof (e.g., 1-2 carbon atoms, 1-3 carbon atoms, 1-4 carbon atoms, 1-5 carbon atoms, 1-6 carbon atoms, 1-7 carbon atoms, 1-8 carbon atoms, 1-9 carbon atoms, 1-10 carbon atoms, 1-11 carbon atoms, 1-12 carbon atoms, 2-3 carbon atoms, 2-4 carbon atoms, 2-5 carbon atoms, 2-6 carbon atoms, 2-7 carbon atoms, 2-8 carbon atoms, 2-9 carbon atoms, 2-10 carbon atoms, 2-11 carbon atoms, 2-12 carbon atoms, 3-4 carbon atoms, 3-5 carbon atoms, 3- 6 carbon atoms, 3-7 carbon atoms, 3-8 carbon atoms, 3-9 carbon atoms, 3-10 carbon atoms, 3-11 carbon atoms, 3-12 carbon atoms, 4-5 carbon atoms, 4-6 carbon atoms, 4-7 carbon atoms, 4-8 carbon atoms, 4-9 carbon atoms, 4-10 carbon atoms, 4-11 carbon atoms, and/or 4- 12 carbon atoms, etc., as appropriate). Similarly, the recitation of a range of 6-10 carbon atoms (e.g., C₆-Cio) as used with respect to any chemical group (e.g., aryl) referenced herein encompasses and specifically describes 6, 7, 8, .9, and/or 10 carbon atoms, as appropriate, as well as any sub-range thereof (e.g., 6-10 carbon atoms, 6-9 carbon atoms, 6-8 carbon atoms, 6-7 carbon atoms, 7-10 carbon atoms, 7-9 carbon atoms, 7-8 carbon atoms, 8-10 carbon atoms, and/or 8-9 carbon atoms, etc., as appropriate).

[0026] The term "halo" or "halogen," as used herein, means a substituent selected from Group VIIA, such as, for example, fluorine, bromine, chlorine, and iodine.

[0027] The term "aryl" refers to an unsubstituted or substituted aromatic carbocyclic substituent, as commonly understood in the art, and the term "C₆-Cio aryl" includes phenyl and naphthyl. It is understood that the term aryl applies to cyclic substituents that are planar and comprise 4n+2 π electrons, according to Hiickel's Rule.

[0028] The term "arylene" refers to an unsubstituted or substituted aromatic carbocyclic substituent as defined herein, wherein the arylene substituent is connected to two or more substituents at two or more different positions on the arylene group. For example, 1,2- dichlorobenzene can be considered to be a phenylene (arylene) group substituted with two chlorine atoms.

[0029] In accordance with a preferred embodiment, X is O.

[0030] In accordance with an embodiment, Y is S.

[0031] In accordance with an embodiment, Z is O.

[0032] In accordance with an embodiment, R³ is C=0.

[0033] In accordance with a preferred embodiment, X is O, Y is S, and Z is O.

[0034] In certain embodiments, R² is C₂-C₆ alkynylene, particularly C₃-C alkynylene. In a preferred embodiment, R² is but-2-ynylene.

[0035] In certain embodiments R⁴ is a C₆-Cio aryl group. The C₆-C]o aryl group can be a phenyl group or a naphthyl group. When the C₆-Cio aryl group is a naphthyl group, the naphthyl group can be attached to the oxadiazole or thiadiazole at the 1 -position or the 2-position of the naphthyl group. In certain preferred embodiments, R⁴ is a phenyl group substituted with one or more substituents selected from the group consisting of halo, C]-C₆ alkyl, -OH, -OR⁵, -NH₂, -NHR⁵, and - R⁵R⁶, wherein R⁵ and R⁶ are as defined herein. In more preferred embodiments, R⁴ is a phenyl group substituted with chloro, bromo, fluoro, methoxy, or dimethylamino, or R⁴ is a naphthyl group The phenyl group or a naphthyl group can be substituted with any of the aforesaid substituents at any position that is not occupied by R³, particularly para to the point of attachment to R³.

[0036] In certain embodiments, R⁴ is a heterocyclyl group. The heterocyclyl group can be any suitable heterocyclyl group and can be an aliphatic heterocyclyl group or an aromatic heterocyclyl group. The heterocyclyl group can be a monocyclic heterocyclyl group or a bicyclic heterocyclyl group. Suitable bicyclic heterocyclyl groups include monocylic heterocyclyl rings fused to a C₆-Cio aryl ring. When the heterocyclyl group is a bicyclic heterocyclyl group, both ring systems can be aliphatic or aromatic, or one ring system can be aromatic and the other ring system can be aliphatic as in, for example, dihydrobenzofuran. Preferably, the heterocyclyl group is an aromatic heterocyclyl group. Non-limiting examples of suitable heterocyclyl groups include furanyl, thiopheneyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, benzothiopheneyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolinyl, benzothiazolinyl, quinazolinyl, l-oxa-2,4-diazol-3-yl, oxadiazol-2-yl, l-oxa-2,4-diazol-5-yl, and l-oxa-3,4-diazol-2-yl. The heterocyclyl group can be attached to R at any suitable position of the heterocyclyl group. For example, illustratively, the indolyl group can be attached at positions 2, 3, 4, 5, 6, or 7 of the indolyl group.

[0037] In any of the above embodiments, R¹ is a C₆-C₁₀ aryl group, unsubstituted or optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the group consisting of halo, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C -C₈ cycloalkenyl, C₆-Ci₀ aryl, heteroaryl, Ci-C₆ haloalkyl, C]-C₆ dihaloalkyl, d-C₆ trihaloalkyl, -N0₂, -OH, -OR⁵, - SH, -SR⁵, -SOR⁵, -S0₂R⁵, -COR⁵, -COOH, -COOR⁵, -CONHR⁵, and -CONR⁵R⁶. The C₆-Cio aryl group can be a phenyl group or a naphthyl group. When the C₆-Cio aryl group is a naphthyl group, the naphthyl group can be attached to the oxadiazole ring or thiadiazole ring at the 1 -position or the 2-position of the naphthyl group. In a preferred embodiment, the naphthyl group is attached to the oxadiazole ring or thiadiazole ring at the 1 -position.

[0038] In certain embodiments, R¹ is a heterocyclyl group, unsubstituted or optionally substituted by 1 , 2, 3, 4, or 5 substituents selected from the group consisting of halo, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl, C₆-Cio aryl, heteroaryl, Ci-C₆ haloalkyl, C,-C₆ dihaloalkyl, Ci-C₆ trihaloalkyl, -N0₂, -OH, -OR⁵, -SH, - SR⁵, -SOR⁵, -S0₂R⁵, -COR⁵, -COOH, -COOR⁵, -CONHR⁵, and -CONR⁵R⁶ The

heterocyclyl group can be any suitable heterocyclyl group as discussed herein in connection with R⁴. Non-limiting examples of suitable heterocyclyl groups include furanyl, thiopheneyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-rriazolyl, 1 ,2,4-triazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl,

benzothiopheneyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolinyl, benzothiazolinyl, and quinazolinyl. The heterocyclyl group can be attached to the

oxadiazolyl group or thiadiazolyl group at any suitable position of the heterocyclyl group. For example, the indolyl group can be attached at positions 2, 3, 4, 5, 6, or 7 of the indolyl group. In certain preferred embodiment, the heterocyclyl group is selected from the group consisting of indolyl, benzimidazolyl, benzoxazolinyl, benzothiazolinyl, quinolinyl, quinazolinyl, quinoxalinyl, furanyl, pyrrolyl, and thiopheneyl.

[0039] In certain preferred embodiments, the invention provides a compound selected from the group consisting of 4-(5-(naphthalene-l -yl)-l ,3,4-oxadiazol-2-ylthio)but-2-ynyl thiophene-2-carboxylate, 4-(5 -(naphthalene- l-yl)-l ,3 ,4-oxadiazol-2-ylthio)but-2-ynyl furan- 2-carboxylate, 4-(5-(naphthalene- 1 -yl)-l ,3,4-oxadiazol-2-ylthio)but-2-ynyl benzofuran-2- carboxylate, 4-(5 -(naphthalene- 1 -yl)-l ,3 ,4-oxadiazol-2-ylthio)but-2-ynyl indole-4- carboxylate, 4-(5-(Naphthalen-l-yl)-l,3,4-oxadiazol-2-ylthio)bxit-2-ynyl 4-chlorobenzoate, 4- (5-(Naphthalen- 1 -yl)- 1 ,3 ,4-oxadiazol-2-ylthio)but-2-ynyl 4-methoxybenzoate, 4-(5- (Naphthalen-1 -yl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl lH-indole-4-carboxylate, 4-(5-(Furan- 2-yl)- 1, 3, 4-oxadiazol-2-ylthio)but-2-ynyl 4-fluorobenzoate, 4-(5-(Thiophen-2-yl)-l,3,4- oxadiazol-2-ylthio)but-2-ynyl 4-fluorobenzoate, 4-(5-Phenyl- 1 ,3,4-oxadiazol-2-ylthio)but-2- ynyl 4-fluorobenzoate, 4-(5-(2-Fluorophenyl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl 4- fluorobenzoate, 4-(5-(2-Chlorophenyl)-l ,3,4-oxadiazol-2-ylthio)but-2-ynyl 4- fluorobenzoate, 4-(5-(2-Methoxyphenyl)- 1 ,3,4-oxadiazol-2-ylthio)but-2-ynyl 4- fluorobenzoate, 4-(5 -(3 -Fluorophenyl)- 1 ,3,4-oxadiazol-2-ylthio)but-2-ynyl 4-fluorobenzoate, 4-(5-(4-Fluorophenyl)-l ,3,4-oxadiazol-2-ylthio)but-2-ynyl 4-fluorobenzoate, 4-(5-(4- Chlorophenyl)-l ,3,4-oxadiazol-2-ylthio)but-2-ynyl 4-fluorobenzoate, 4-(5-(3- Hydroxynaphthalen-2-yl)-l ,3,4-oxadiazol-2-ylthio)but-2-ynyl 4-fluorobenzoate, 4-(5- (Quinolin-5-yl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl 4-fluorobenzoate, 4-(5-(lH-indol-2-yl)- 1 ,3,4-oxadiazol-2-ylthio)but-2-ynyl 4-fluorobenzoate, 4-(5-(Naphthalen-l-yl)-l ,3,4- oxadiazol-2-ylthio)but-2-ynyl thiophene-3-caboxylate, 4-(5-(naphthalen-l-yl)-l ,3,4- oxadiazol-2-ylthio)but-2-ynyl cyclopropanecarboxylate, 4-(5-(Naphthalen-l-yl)-l ,3,4- oxadiazol-2-ylthio)but-2-ynyl cyclobutanecarboxylate, 4-(5-(Naphthalen-l -yl)- 1 ,3,4- oxadiazol-2-ylthio)but-2-ynyl cyclop entanecarboxylate, 4-(5-(Naphthalen- 1 -yl)- 1 ,3,4- oxadiazol-2-ylthio)but-2-ynyl lH-imidazole-4-carboxylate, 4-(5-(Naphthalen-l-yl)-l,3,4- oxadiazol-2-ylthio)but-2-ynyl benzo[b]thiophene-2-carboxylate, 4-(5-(Naphthalen-l-yl)- 1 ,3,4-oxadiazol-2-ylthio)but-2-ynyl benzo[b]thiophene-3-carboxylate, 4-(5-(naphthalen- 1 - yl)- 1 ,3 ,4-oxadiazol-2-ylthio)but-2-ynyl benzoate, 4-(5-(Naphthalen- 1 -yl)-l ,3,4-oxadiazol-2- ylthio)but-2-ynyl 3-fluorobenzoate, 4-(5-(Naphthalen-l-yl)-l,3,4-oxadiazol-2-ylthio)but-2- ynyl 3,4-difluorobenzoate, 4-(5-(Naphthalen-l-yl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl 2- methoxybenzoate, 4-(5-(Naphthalen-l-yl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl 4- (dimethylamino)benzoate, 4-(5-(Naphthalen-l-yl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl 4- (methylsulfonyl) benzoate, 4-(5-(Naphthalen-l-yl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl 4- (trifluoromethoxy) benzoate, 4-(5-(naphthalen-l-yl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyI 4- (trifluoromethyl) benzoate, 4-(5-(naphthalen-2-yl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl 4- fluorobenzoate, (E)-4-(5-(naphthalen-l-yl)-l ,3,4-oxadiazol-2-ylthio)but-2-enyl 4- fluorobenzoate, 4-(5-(naphthalen-l-yl)-l,3,4-oxadiazol-2-ylthio)butyl 4-fluorobenzoate, and 4-((5-(naphthalen-l-yl)-l,3,4-oxadiazol-2-ylthio)methyl)benzyl 4-fluorobenzoate.

[0040] In certain preferred embodiments, the invention provides a compound selected from the group consisting of 4-(5-(naphthalene-l-yl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl thiophene-2-carboxylate, 4-(5-(naphthalene-l-yl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl furan- 2-carboxylate, 4-(5-(naphthalene-l-yl)-l ,3,4-oxadiazol-2-ylthio)but-2-ynyl imidazole-2- carboxylate, 4-(5-(naphthalene- 1 -yl)- 1 ,3,4-oxadiazol-2-ylthio)but-2-ynyl benzofuran-2- carboxylate, and 4-(5-(naphthalene-l-yl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl indole-4- carboxylate.

[0041] In certain embodiments, R³ is a bond or CH₂. In preferred embodiments, R³ is a bond or CH₂ and R⁴ is a C₆-Cio aryl group. In more preferred embodiments, R³ is a bond or CH₂, R⁴ is a C₆-Cio aryl group, and Z is O or N. In these embodiments, R¹ and R⁴ can be as recited herein.

[0042] The phrase "pharmaceutically acceptable salt" is intended to include nontoxic salts synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington 's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, 1990, p. 1445, and Journal of Pharmaceutical Science, 66, 2-19 (1977).

[0043] Suitable bases include inorganic bases such as alkali and alkaline earth metal bases, e.g., those containing metallic cations such as sodium, potassium, magnesium, calcium and the like. Non-limiting examples of suitable bases include sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate. Suitable acids include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, benzenesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, maleic acid, tartaric acid, fatty acids, long chain fatty acids, and the like. Preferred pharmaceutically acceptable salts of inventive compounds having an acidic moiety include sodium and potassium salts. Preferred pharmaceutically acceptable salts of inventive compounds having a basic moiety (e.g., a dimethylaminoalkyl group) include hydrochloride and hydrobromide salts. The compounds of the present invention containing an acidic or basic moiety are useful in the form of the free base or acid or in the form of a pharmaceutically acceptable salt thereof.

[0044] It should be recognized that the particular counterion forming a part of any salt of this invention is usually not of a critical nature, so long as the salt as a whole is

pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole.

[0045] It is further understood that the above compounds and salts may form solvates, or exist in a substantially uncomplexed form, such as the anhydrous form. As used herein, the term "solvate" refers to a molecular complex wherein the solvent molecule, such as the crystallizing solvent, is incorporated into the crystal lattice. When the solvent incorporated in the solvate is water, the molecular complex is called a hydrate. Pharmaceutically acceptable solvates include hydrates, alcoholates such as methanolates and ethanolates, acetonitrilates and the like. These compounds can also exist in polymorphic forms.

[0046] The compounds of the invention can be synthesized by any suitable method, for example, according to the procedures set forth in FIGS. 1-3, wherein R¹ and R⁴ are as defined herein.

[0047] FIG. 1 shows a method of preparation of compounds defined by Formula I, wherein X is O, Y is S, R is but-2-ynylene (i.e., C₄-alkynylene), Z is O, and R is C=0.

[0048] Reaction of acyl hydrazide V with carbon disulfide in the presence of a base such as potassium hydroxide and in a solvent such as ethanol at reflux gives oxadiazole-2-thiol 2 Alkylation of the sulfur atom of oxadiazole-2-thiol V_ with l-chloro-but-2-yn-4-ol 3^ in the presence of a base such as anhydrous potassium carbonate and in a solvent such as acetone or DMF gives S-alkylated compound 4\ Acylation of the hydroxyl group in compound ^ can be accomplished, for example, by reaction of the hydroxyl group of compound P with carboxylic acid 5 in the presence of, for example,

N-(3-dimethylaminopropyl)-3-ethylcarbodiimide ("EDC") in a suitable solvent such as dimethylformamide in the presence of a catalyst such as 4-dimethylaminopyridine ("DMAP") gives compound 6\

[0049] FIG. 2 shows a method of preparation of compounds defined by Formula I, wherein X is S, Y is S, R² is but-2-ynylene (i.e., C4-alkynylene), Z is O, and R³ is C=0.

[0050] Reaction of acyl hydrazide V_ with carbon disulfide in the presence of a base such as potassium hydroxide and in a solvent such as ethanol at room temperature gives an intermediate product which is isolated. Addition of the isolated intermediate product to concentrated sulfuric acid provides thiadiazole-2-thiol T_. Compound T_ is converted to product 8^ by the sequence of reactions illustrated in FIG. 1 for conversion of compound V_ to compound 6\

[0051] FIG. 3 shows a method of preparation of compounds defined by Formula I, wherein X is O, Y is N, R² is C₄-alkynylene, Z is O, and R³ is C=0.

[0052] Reaction of acyl hydrazide V_ with cyanogen bromide in a solvent such as ethanol at reflux gave 2-aminooxadiazole Ψ_. Compound Ψ_ is converted to product HP by the sequence of reactions illustrated in FIG. 1 for conversion of compound V_ to compound

[0053] The present invention is further directed to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound or salt described herein.

[0054] It is preferred that the pharmaceutically acceptable carrier be one that is chemically inert to the active compounds and one that has no detrimental side effects or toxicity under the conditions of use.

[0055] The choice of carrier will be determined in part by the particular compound of the present invention chosen, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the

pharmaceutical composition of the present invention. The following formulations for oral, aerosol, nasal, pulmonary, parenteral, subcutaneous, intravenous, intramuscular,

intraperitoneal, intrathecal, intratumoral, topical, rectal, and vaginal administration are merely exemplary and are in no way limiting.

[0056] The pharmaceutical composition can be administered parenterally, e.g., intravenously, subcutaneously, intradermally, or intramuscularly. Thus, the invention provides compositions for parenteral administration that comprise a solution or suspension of the inventive compound or salt dissolved or suspended in an acceptable carrier suitable for parenteral administration, including aqueous and non-aqueous isotonic sterile injection solutions.

[0057] Overall, the requirements for effective pharmaceutical carriers for parenteral compositions are well known to those of ordinary skill in the art. See, e.g., Banker and Chalmers, eds., Pharmaceutics and Pharmacy Practice, J. B. Lippincott Company,

Philadelphia, pp. 238-250 (1982), and Toissel, ASHP Handbook on Injectable Drugs, 4th ed., pp. 622-630 (1986). Such solutions can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. The compound or salt of the present invention may be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol, or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol, dimethylsulfoxide, glycerol ketals, such as 2,2-dimethyl-l_J3-dioxolane-4-methanol, ethers, such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose,

hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agents and other pharmaceutical adjuvants.

[0058] Oils useful in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils useful in such formulations include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.

[0059] Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts, and suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylenepolypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl-beta-aminopropionates, and 2-alkyl-imidazoline quaternary ammonium salts, and (e) mixtures thereof.

[0060] The parenteral formulations can contain preservatives and buffers. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations will typically range from about 5 to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol. The parenteral formulations can be presented in unit-dose or multi-dose sealed containers, such as ampules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.

[0061] Topical formulations, including those that are useful for transdermal drug release, are well-known to those of skill in the art and are suitable in the context of the invention for application to skin. Topically applied compositions are generally in the form of liquids, creams, pastes, lotions and gels. Topical administration includes application to the oral mucosa, which includes the oral cavity, oral epithelium, palate, gingival, and the nasal mucosa. In some embodiments, the composition contains at least one active component and a suitable vehicle or carrier. It may also contain other components, such as an anti-irritant. The carrier can be a liquid, solid or semi-solid. In embodiments, the composition is an aqueous solution. Alternatively, the composition can be a dispersion, emulsion, gel, lotion or cream vehicle for the various components. In one embodiment, the primary vehicle is water or a biocompatible solvent that is substantially neutral or that has been rendered substantially neutral. The liquid vehicle can include other materials, such as buffers, alcohols, glycerin, and mineral oils with various emulsifiers or dispersing agents as known in the art to obtain the desired pH, consistency and viscosity. It is possible that the compositions can be produced as solids, such as powders or granules. The solids can be applied directly or dissolved in water or a biocompatible solvent prior to use to form a solution that is substantially neutral or that has been rendered substantially neutral and that can then be applied to the target site, hi embodiments of the invention, the vehicle for topical application to the skin can include water, buffered solutions, various alcohols, glycols such as glycerin, lipid materials such as fatty acids, mineral oils, phosphoglycerides, collagen, gelatin and silicone based materials.

[0062] Formulations suitable for oral administration can consist of (a) liquid solutions, such as a therapeutically effective amount of the inventive compound dissolved in diluents, such as water, saline, or orange juice, (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient, as solids or granules, (c) powders, (d) suspensions in an appropriate liquid, and (e) suitable emulsions. Liquid formulations may include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a

pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent. Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and corn starch. Tablet forms can include one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible excipients. Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such excipients as are known in the art.

[0063] The compound or salt of the present invention, alone or in combination with other suitable components, can be made into aerosol formulations to be administered via inhalation. The compounds are preferably supplied in finely divided form along with a surfactant and propellant. Typical percentages of active compound are 0.01%-20% by weight, preferably 1%-10%. The surfactant must, of course, be nontoxic, and preferably soluble in the propellant. Representative of such surfactants are the esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as caproic, octanoic, lauric, palmitic, stearic, linoleic, linolenic, olesteric and oleic acids with an aliphatic polyhydric alcohol or its cyclic anhydride. Mixed esters, such as mixed or natural glycerides may be employed. The surfactant may constitute 0.1 %-20% by weight of the composition, preferably 0.25%-5%. The balance of the composition is ordinarily propellant. A carrier can also be included as desired, e.g., lecithin for intranasal delivery. These aerosol formulations can be placed into acceptable pressurized propellants, such as dichlorodifiuoromethane, propane, nitrogen, and the like. They also may be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer. Such spray formulations may be used to spray mucosa.

[0064] Additionally, the compound or salt of the present invention may be made into suppositories by mixing with a variety of bases, such as emulsifying bases or water-soluble bases. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.

[0065] It will be appreciated by one of ordinary skill in the art that, in addition to the aforedescribed pharmaceutical compositions, the compound or salt of the present invention may be formulated as inclusion complexes, such as cyclodextrin inclusion complexes, or liposomes. Liposomes serve to target the compounds to a particular tissue, such as lymphoid tissue or cancerous hepatic cells. Liposomes can also be used to increase the half-life of the inventive compound. Liposomes useful in the present invention include emulsions, foams, micelles, insoluble monolayers, liquid crystals, phospholipid dispersions, lamellar layers and the like. In these preparations, the active agent to be delivered is incorporated as part of a liposome, alone or in conjunction with a suitable chemo therapeutic agent. Thus, liposomes filled with a desired inventive compound or salt thereof, can be directed to the site of a specific tissue type, hepatic cells, for example, where the liposomes then deliver the selected compositions. Liposomes for use in the invention are formed from standard vesicle- forming lipids, which generally include neutral and negatively charged phospholipids and a sterol, such as cholesterol. The selection of lipids is generally guided by consideration of, for example, liposome size and stability of the liposomes in the blood stream. A variety of methods are available for preparing liposomes, as described in, for example, Szoka et al, Ann. Rev. Biophys. Bioeng., 9, 467 (1980), and U.S. Patents 4,235,871, 4,501,728, 4,837,028, and 5,019,369. For targeting to the cells of a particular tissue type, a ligand to be incorporated into the liposome can include, for example, antibodies or fragments thereof specific for cell surface determinants of the targeted tissue type. A liposome suspension containing a compound or salt of the present invention may be administered intravenously, locally, topically, etc. in a dose that varies according to the mode of administration, the agent being delivered, and the stage of disease being treated.

[0066] The invention further provides a method for treating or preventing a 15- lipoxygenase mediated disease or disorder. Preferably, the 15-lipoxygenase is human 15-lipoxygenase-l. The method comprises administering an effective amount of the compound of the invention to a mammal afflicted therewith. Preferably, the mammal is a human.

[0067] The term "mammal" includes, but is not limited to, the order Rodentia, such as mice, and the order Logomorpha, such as rabbits. It is preferred that the mammals are from the order Carnivora, including Felines (cats) and Canines (dogs). It is more preferred that the mammals are from the order Artiodactyla, including Bovines (cows) and Swines (pigs) or of the order Perssodactyla, including Equines (horses). It is most preferred that the mammals are of the order Primates, Ceboids, or Simioids (monkeys) or of the order Anthropoids (humans and apes). An especially preferred mammal is the human. Furthermore, the subject can be the unborn offspring of any of the forgoing hosts, especially mammals (e.g., humans), in which case any screening of the subject or cells of the subject, or administration of compounds to the subject or cells of the subject, can be performed in utero.

[0068] In accordance with an embodiment, the invention provides a method of treating or preventing cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by Formula I. The cancer can be any suitable cancer responsive to inhibition of human 15-lipoxygenase-l, for example, adenocarcinoma, in particular, prostate cancer.

[0069] In accordance with another embodiment, the invention provides a method of treating or preventing Alzheimer's disease.

[0070] In accordance with other embodiments, the invention provides a method of treating or preventing a 15-lipoxygenase mediated disease or disorder selected from the group consisting of inflammatory disorders, atherosclerosis, formation of atherosclerotic plaques, thrombosis, peripheral arterial disease, coagulation syndromes, intermittent claudication, diabetes, vascular restenosis, hypertension, asthma, rheumatoid arthritis, osteoarthritis, and inflammatory bowel disease.

[0071] "Treating" within the context of the present invention, means an alleviation of symptoms associated with a disorder or disease, or halt of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder. For example, within the context of treating patients with prostate cancer, successful treatment may include a reduction in the proliferation of capillaries feeding the diseased tissue, an alleviation of symptoms related to a cancerous growth or tumor, or a halting in the progression of a disease such as cancer or in the growth of cancerous cells. Treatment may also include administering the pharmaceutical formulations of the present invention in combination with other therapies. For example, the compounds and pharmaceutical formulations of the present invention may be administered before, during, or after surgical procedure and/or radiation therapy. The compounds of the invention can also be administered in conjunction with other anti-cancer drugs and drugs used in antisense and gene therapy. Appropriate combinations can be determined by those of skill in the oncological and medical arts.

[0072] "Preventing" within the context of the present invention, refers to a prophylactic treatment of an individual prone or subject to development of a condition, in particular, a disease or disorder responsive to inhibition of 15-lipoxygenase. For example, those of skill in the oncological and medical arts may be able to determine, based on clinical symptoms and patient history, a statistical predisposition of a particular individual to the development of the aforesaid disease or disorder. Accordingly, an individual predisposed to the development of a disease or disorder responsive to inhibition of 15-lipoxygenase may be treated with a compound or a composition of the present invention in order to prevent, inhibit, or slow the development of the disease or disorder.

[0073] One skilled in the art will appreciate that suitable methods of utilizing a compound and administering it to a human for the treatment or prevention of disease states, in particular, cancer (e.g., prostate cancer), Alzheimer's disease, inflammatory disorders, atherosclerosis, formation of atherosclerotic plaques, thrombosis, peripheral arterial disease, coagulation syndromes, intermittent claudication, diabetes, vascular restenosis, hypertension, asthma, rheumatoid arthritis, osteoarthritis, and inflammatory bowel disease which would be useful in the method of the present invention, are available. Although more than one route can be used to administer a particular compound, a particular route can provide a more immediate and more effective reaction than another route. Accordingly, the described methods are merely exemplary and are in no way limiting.

[0074] The dose administered to a mammal, particularly, a human, in accordance with the present invention should be sufficient to effect the desired response. Such responses include reversal or prevention of the bad effects of the disease for which treatment is desired or to elicit the desired benefit. One skilled in the art will recognize that dosage will depend upon a variety of factors, including the age, condition, and body weight of the human, as well as the source, particular type of the disease, and extent of the disease in the human. The size of the dose will also be determined by the route, timing and frequency of administration as well as the existence, nature, and extent of any adverse side-effects that might accompany the administration of a particular compound and the desired physiological effect. It will be appreciated by one of skill in the art that various conditions or disease states may require prolonged treatment involving multiple administrations.

[0075] Suitable doses and dosage regimens can be determined by conventional range- finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compound.

Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. The present inventive method typically will involve the administration of about 0.1 to about 300 mg of one or more of the compounds described above per kg body weight of the mammal.

[0076] The therapeutically effective amount of the compound or compounds

administered can vary depending upon the desired effects and the factors noted above.

Typically, dosages will be between 0.01 mg kg and 250 mg/kg of the subject's body weight, and more typically between about 0.05 mg/kg and 100 mg/kg, such as from about 0.2 to about 80 mg/kg, from about 5 to about 40 mg/kg or from about 10 to about 30 mg/kg of the subject's body weight. Thus, unit dosage forms can be formulated based upon the suitable ranges recited above and the subject's body weight. The term "unit dosage form" as used herein refers to a physically discrete unit of therapeutic agent appropriate for the subject to be treated. [0077] Alternatively, dosages are calculated based on body surface area and from about 1 mg m² to about 200 mg m², such as from about 5 mg/m² to about 100 mg/m² will be administered to the subject per day. In particular embodiments, administration of the therapeutically effective amount of the compound or compounds involves administering to the subject from about 5 mg/m to about 50 mg/m , such as from about 10 mg/m to about 40 mg/m² per day. It is currently believed that a single dosage of the compound or compounds is suitable, however a therapeutically effective dosage can be supplied over an extended period of time or in multiple doses per day. Thus, unit dosage forms also can be calculated using a subject's body surface area based on the suitable ranges recited above and the desired dosing schedule.

[0078] The invention further provides a use of a compound or salt of the invention in the manufacture of a medicament for treating or preventing a disease selected from the group consisting of adenocarcinoma, prostate cancer, Alzheimer's disease, inflammatory disorders, atherosclerosis, formation of atherosclerotic plaques, thrombosis, peripheral arterial disease, coagulation syndromes, intermittent claudication, diabetes, vascular restenosis, hypertension, asthma, rheumatoid arthritis, osteoarthritis, and inflammatory bowel disease. The

medicament typically is a pharmaceutical composition as described herein.

[0079] The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.

[0080] Unless otherwise stated, all reactions were carried out under an atmosphere of dry argon or nitrogen in dried glassware. Indicated reaction temperatures refer to those of the reaction bath, while room temperature (rt) is noted as 25° C. All solvents were of anhydrous quality purchased from Aldrich Chemical Co. and used as received. Commercially available starting materials and reagents were purchased from Aldrich and were used as received.

[0081] Analytical thin layer chromatography (TLC) was performed with Sigma Aldrich TLC plates (5 x 20 cm, 60 A, 250 μηι). Visualization was accomplished by irradiation under a 254 nm UV lamp. Chromatography on silica gel was performed using forced flow (liquid) of the indicated solvent system on Biotage KP-Sil pre-packed cartridges and using the Biotage SP-1 automated chromatography system. 1H- and ¹ C NMR spectra were recorded on a Varian Inova 400 MHz spectrometer. Chemical shifts are reported in ppm with the solvent resonance as the internal standard (CDC1₃ 7.26 ppm, 77.00 ppm, OMSO-de 2.49 ppm, 39.51 ppm for 1H, ¹³C respectively). Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constants, and number of protons. Low resolution mass spectra (electrospray ionization) were acquired on an Agilent Technologies 6130 quadrupole spectrometer coupled to the HPLC system. High resolution mass spectral data was collected in-house using an Agilent 6210 time-of- flight mass spectrometer, also coupled to an Agilent Technologies 1200 series HPLC system. If needed, products were purified via a Waters semi-preparative HPLC equipped with a Phenomenex Luna™ CI 8 reverse phase (5 micron, 30 x 75 mm) column having a flow rate of 45 mL/min. The mobile phase was a mixture of acetonitrile and H₂0 each containing 0.1% trifluoroacetic acid. The mobile phase was a mixture of acetonitrile (0.025% TFA) and H₂0 (0.05% TFA), and a temperature was maintained at 50° C.

[0082] Samples were analyzed for purity on an Agilent 1200 series LC MS equipped with a Luna™ CI 8 reverse phase (3 micron, 3 x 75 mm) column having a flow rate of 0.8-1.0 mL/min over a 7-minute gradient and a 8.5 minute run time. Purity of final compounds was determined to be >95%, using a 3 μL injection with quantitation by AUC at 220 and 254 nm (Agilent Diode Array Detector).

EXAMPLE 1

[0083] This example demonstrates a procedure for preparing an intermediate leading to compounds in accordance with an embodiment, specifically, the preparation of

5 - (naphthalene- 1 -yl)- 1 ,3 , 4-oxadiazole-2-thiol 2.

[0084] To a solution of KOH (3.01 g, 53.7 mmol) in ethanol (130 mL) was added naphthalene- 1 -carbohydrazide (5 g, 26.9 mmol); this was stirred at RT for 10 minutes.

Carbon disulfide (4 mL, 67.1 mmol) was then added dropwise and the reaction mixture was stirred at reflux for 10 h. Solvent was evaporated under diminished pressure and the residue was neutralized with 10% aq. HC1. The solid product was collected by filtration and recrystallized from ethanol to give pure white crystals of compound 2. ^!H NMR ( DMSO--4)

6 7.63 - 7.77 (m, 3 H), 8.06 - 8.16 (m, 2 H), 8.22 (d, J= 8.2 Hz, 1H) and 8.83 (dd, J= 8.5, 1.1 Hz, 1H); ¹³C NMR (DMSO- ) 6 118.51, 124.81, 125.32, 126.87, 128.35, 128.51, 128.62 , 129.01, 132.96, 133.34, 160.30 and 176.90; HRMS (m/z): [M + H]⁺ calcd. for Ci₂¾N₂OS, 229.0430; found, 229.0432. EXAMPLE 2

[0085] This example demonstrates a procedure for the preparation of

4-(5-naphthalen-l -yl)-l ,3 ,4-oxadiazol-2-ylthio)but-2-yn- 1 -ol 4.

[0086] A solution of 5-(naphthalen- 1 -yl)-l ,3,4-oxadiazole-2-thiol (6.1 g, 26.7 mmol), 4- chlorobut-2-yn-l-ol (2.76 mL, 32.1 mmol) and potassium carbonate (18.4 g, 134 mmol) in acetone (100 mL) was stirred at 40 °C for 1 h. The reaction mixture was filtered through celite, washed with ethyl acetate. The filtrate was concentrated and purified on a Biotage™ silica gel column. Elution with ethyl acetate (30%) in hexanes gave the product 4 as a white solid. 1H NMR ( DMSO-i ₆) δ 4.09 (dd, J= 5.6 and 2.4 Hz, 2 H), 4.29 - 4.33 (m, 2H), 5.21 (td, J= 5.8 and 2.4 Hz, 1 H), 7.63 - 7.78 (m, 3 H), 8.09 (d, J= 8.0 Hz, 1 H), 8.18 - 8.24 (m, 2 H), and 9.03 (d, J= 8.6 Hz, 1 H); ¹³C NMR (DMSO-rf₆) δ 21.18, 48.99, 78.61, 84.04, 119.27, 125.29, 125.36, 126.84, 128.28, 128.68, 128.90, 128.98, 132.72, 133.39, 162.48 and 165.37; HRMS (m/z): [M + H]⁺ calcd. for Ci₆H,₃N₂0₂S._; 297.0692; found, 297.0691.

EXAMPLE 3

[0087] This example demonstrates a procedure for the preparation of 4-(5-(naphthaIen-l- yl)-l _?3,4-oxadiazol-2-ylthio)but-2-ynyl 4-fluorobenzoate (9).

[0088] A solution of 4-(5-(naphthalen-l-yl)-l,3,4-oxadiazol-2-ylthio)but-2-yn-l-ol (0.06 g, 0.2 mmol), 4-fluorobenzoic acid (0.034 g, 0.24 mmol), N, N-dimethylaminopyridine (0.012 g, 0.1 mmol) and EDC (0.078 g, 0.4 mmol) in DMF (1 mL) was stirred at room temperature for 4 h. The crude product was purified by reversed phase HPLC to give the title product. Ή NMR (CDC1₃) δ 4.18 (t, J -2.2 Hz, 2H, S-CH₂), 4.93 (t, J =2.0 Hz, 2H, 0-CH₂), 7.05 (t, J= 8.6 Hz, 2H, Ar-H), 7.51-7.60 (m, 2H, Ar-H), 7.65-7.69 (m, 2H, Ar-H), 7.92 (d, J - 8.0 Hz, 1H, Ar-H), 8.0-8.04 (m, 3H, Ar-H), 8.12 (dd, J= 3.2 and 1.2 Hz, 1H, Ar-H) and 9.19 (d, J = 8.4 Hz, 1H, Ar-H); ¹³C-NMR (CDC1₃) δ 21.4, 52.8, 78.6, 80.6, 115.4, 115.6, 119.9, 124.8, 125.5 (d, J= 12 Hz), 126.1, 126.7, 128.2, 128.3, 128.6, 129.8, 132.3 (d, J = 38.8 Hz), 132.7, 133.8, 162.3, 164.6, 164.7, 166.2 and 167.1.

EXAMPLE 4

[0089] The following compounds were prepared in accordance with the methods described in Examples 2 and 3, except that the appropriate 5-(phenyl-l-yl)-l,3,4-oxadiazole- 2-thiol or 5-(heterocyclyl-l-yl)-l,3,4-oxadiazole-2-thiol were used in place of 5-(naphthalen- 1 -yl)- 1 ,3,4-oxadiazole-2-thiol. [0090] 4-(5-(Naphthalen- 1 -yl)-l ,3,4-oxadiazol-2-ylthio)but-2-ynyl 4-chlorobenzoate Q0): 1H NMR (CDCI₃) δ 4.18 (t, J= 2.1 Hz, 2 H), 4.94 (t, J= 2.2 Hz, 2 H), 7.35 (m, 2 H), 7.58 (m, 2 H), 7.68 (ddd, J= 8.6, 6.9 and 1.6 Hz, 1 H), 7.93 (m, 3 H), 8.03 (d, J= 8.2 Hz, 1 H), 8.13 (dd, J= 7.3 and 1.3 Hz, 1 H), 9.19 (dd, J= 8.6 and 1.0 Hz, 1 H); C NMR (CDC1₃); 5 21.47, 52.88, 78.58, 80.70, 1 19.94, 124.82, 126.11, 126.78, 127.76, 128.22, 128.31, 128.68, 128.75, 129.81, 131.13, 132.73, 133.80, 139.79, 162.32, 164.91 and 166.24.

[0091] 4-(5-(Naphthalen-l-yl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl 4-methoxybenzoate (12): 'H NMR (CDC1₃) 5 3.84 (s, 3 H), 4.18 (t, J= 2.1 Hz, 2 H), 4.92 (t, J= 2.1 Hz, 2 H), 6.87 (m, 2 H), 7.58 (m, 2 H), 7.68 (ddd, J = 8.6, 6.9 and 1.6 Hz, 1 H), 7.97 (m, 4 H), 8.14 (dd, J= 7.2 and 1.2 Hz, 1 H), 9.20 (d, J= 8.6 Hz, 1 H); ¹³C NMR (CDC1₃) 5 21.54, 52.40, 55.42, 79.12, 80.20, 105.02, 113.64, 119.99, 121.72, 124.85, 126.15, 126.75, 128.19, 128.33, 128.65, 129.84, 131.85, 132.69, 133.80, 162.42, 165.50 and 166.19.

[0092] 4-(5-(Naphthalen-l-yl)-l ,3,4-oxadiazol-2-ylthio)but-2-ynyl lH-indole-4- carboxylate (16): ^lH NMR (CDCI3) 5 4.20 (t, J = 2.1 Hz, 2 H), 5.03 (t, J = 2.1 Hz, 2 H), 7.17 - 7.23 (m, 2 H), 7.31 - 7.36 (m, 1 H), 7.50 - 7.61 (m, 3 H), 7.67 (ddd, J= 8.5, 6.9 and 1.4 Hz, 1 H), 7.92 (dd, J= 7.6 and 1.0 Hz, 2 H), 8.01 (d, J= 8.2 Hz, 1 H), 8.13 (dd, J= 7.3 and 1.3 Hz, 1 H), 8.43 (brs., 1 H), 9.19 (dd, J= 8.5 and 0.9 Hz, 1 H); ^I3C NMR (CDCI₃) δ 21.56, 52.30, 79.31, 80.07, 103.94, 116.31, 119.96, 120.63, 121.11, 123.77, 124.84, 126.12, 126.47, 126.72, 127.51, 128.16, 128.33, 128.63, 129.81, 132.64, 133.77, 136.53, 162.51, 166.17 and 166.65.

[0093] 4-(5-(Naphthalen- 1 -yl)- 1 ,3,4-oxadiazol-2-ylthio)but-2-ynyl benzofuran-2- carboxylate (15): 1H NMR (DMSO-d₆) δ 4.40 (t, J= 2.1 Hz, 2 H), 5.06 (t, J= 2.0 Hz, 2 H), 7.31 - 7.40 (m, 1 H), 7.51 (ddd, J= 8.4, 7.1 and 1.3 Hz, 1 H), 7.61 - 7.69 (m, 4 H), 7.69 - 7.77 (m, 2 H), 8.06 (d, J= 8.0 Hz, 1 H), 8.13 - 8.23 (m, 2 H), 9.03 (dd, J = 8.7 and 0.9 Hz, 1 H); ¹³C NMR (DMSO-d₆) δ 20.95, 52.73, 52.97, 77.85, 82.44, 112.10, 114.81, 1 19.22, 123.26, 124.04, 125.26, 125.29, 126.41, 126.80, 128.14, 128.24, 128.59, 128.87, 128.94, 132.68, 144.10, 155.05, 157.79, 162.26, and 165.44.

[0094] 4-(5-(Furan-2-yl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl 4-fhiorobenzoate (21): Ή NMR (DMSO-d₆) δ 4.29 (s, 2 H), 4.97 (s, 2 H), 6.77 (dd, J= 3.4 and 1.7 Hz, 1 H), 7.28 - 7.40 (m, 3 H), 7.92 - 8.00 (m, 2 H), 8.03 (s, 1 H); ¹³C NMR (DMSO-d₆) 21.19, 52.74, 78.36, 81.77, 112.60, 114.76, 115.85, 116.07, 125.48, 132.08, 132.18, 138.08, 147.06, 158.35, 161.67, 163.96 and 166.49.

[0095] 4-(5-(Thiophen-2-yl)-l ,3,4-oxadiazol-2-ylthio)but-2-ynyl 4-fluorobenzoate (22): Ή NMR (CDC1₃) δ 4.10 (t, J= 1.8 Hz, 2H), 4.91 (t, J= 2.2 Hz, 2H), 7.07-7.15 (m_; 3H), 7.53 (dd, J= 4.8 Hz and 1.2 Hz, 1H), 7.70 (dd, J= 3.6 Hz and 1.2 Hz, 1H) and 8.03-8.06 (m, 2H); ¹³C NMR (CDC1₃); 6 21.5, 52.7, 76.7, 77.0, 77.3, 78.7, 80.4, 115.5, 115.7, 124.6, 125.5, 125.6, 128.1, 129.8, 130.2, 132.3, 132.4, 161.9, 162.4, 164.6, 164.7 and 167.2.

[0096] 4-(5-Phenyl-l,3,4-oxadiazol-2-ylihio)but-2-ynyl 4-fluorobenzoate (23): 1H NMR (CDCI₃) δ 4.12 (t, J= 2.1 Hz, 2 H), 4.92 (t, J= 2.1 Hz, 2 H), 7.03 - 7.12 (m, 2 H), 7.43 - 7.55 (m, 3 H), 7.94 - 8.07 (m, 4 H); ¹³C NMR (CDC1₃) δ 21.46, 52.74, 78.62, 80.51, 115.46, 1 15.67, 123.41, 125.56, 125.59, 126.68, 129.02, 131.77, 132.30, 132.40, 162.50, 164.64, 164.74, 166.18 and 167.17.

[0097] 4-(5-(2-Fluorophenyl)-l ,3,4-oxadiazol-2-ylthio)but-2-ynyl 4-fluorobenzoate (24): 1H NMR (CDC1₃) δ 4.13 (t, J= 2.1 Hz, 2 H), 4.92 (t, J= 2.2 Hz, 2 H), 7.05 - 7.14 (m, 2 H), 7.17 - 7.25 (m, 1 H), 7.27 - 7.33 (m, 1 H), 7.49 - 7.57 (m, 1 H), 7.98 - 8.09 (m, 3 H); ¹³C NMR (CDCI₃) δ 21.48, 52.78, 78.69, 80.47, 111.93, 112.05, 115.49, 115.71, 116.15, 1 16.37, 116.88, 117.08, 124.63, 124.67, 124.99, 125.60, 125.63, 129.53, 132.34, 132.43, 133.24, 133.34, 133.55, 133.63, 158.55, 161.13, 162.94, 163.14, 164.68, 164.79, 165.43, 167.21 and 167.99.

[0098] 4-(5-(2-Chlorophenyl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl 4-fluorobenzoate (25): 1H Ή NMR (CDC1₃) δ 4.14 (t, J= 2.1 Hz, 2 H), 4.93 (t, J= 2.1 Hz, 2 H), 7.06 - 7.14 (m, 2 H), 7.36 - 7.42 (m, 1 H), 7.46 (td, J=7.6 and 1.8 Hz, 1 H), 7.51 - 7.56 (m, 1 H), 7.95 (dd, J= 7.8 and 1.8 Hz, 1 H), 8.01 - 8.10 (m, 2 H); ¹³C NMR (CDC1₃) δ 21.48, 52.78, 78.72, 80.46, 115.49, 115.72, 122.76, 127.07, 130.98, 131.26, 132.35, 132.44, 132.47, 133.07, 163.26, 164.54, 164.69 and 164.80.

[0099] 4-(5-(2-Methoxyphenyl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl 4-fluorobenzoate (26): Ή NMR (CDCI₃) δ 3.95 (s, 3 H), 4.12 (t, J= 2.2 Hz, 2 H), 4.92 (t, J= 2.2 Hz, 2 H), 7.01 - 7.13 (m, 4 H), 7.49 (ddd, J= 8.6, 7.3, and 1.8 Hz, 1 H), 7.87 (dd, J - 7.9 and 1.5 Hz, 1 H), 8.02 - 8.08 (m, 2 H); ¹³C NMR (CDC¾) δ 21.43, 52.81, 55.95, 78.51, 80.67, 11 1.91, 112.58, 115.48, 115.70, 120.72, 125.62, 125.65, 130.27, 132.34, 132.43, 133.18, 157.76, 162.19, 164.67, 164.80, 164.94 and 167.21. [0100] 4-(5-(3 -Fluorophenyl)- 1 ,3,4-oxadiazol-2-ylthio)but-2-ynyl 4-fluorobenzoate (27): 1H NMR (CDC1₃) δ 4.13 (ΐ, J= 2.1 Hz, 2 H), 4.92 (t, J= 2.1 Hz, 2 H), 7.06 - 7.13 (m, 2 H), 7.23 (td, J= 8.4 and 2.6 Hz, 1 H), 7.47 (td, J= 8.1 and 5.6 Hz, 1 H), 7.70 (dt, J= 9.2 and 2.1 Hz, 1 H), 7.80 (d, J= 7.8 Hz, 1 H), 8.01 - 8.08 (m, 2 H); ¹³C NMR (CDC1₃) δ 21.50, 52.74, 78.78, 80.39, 113.65, 113.89, 115.49, 115.72, 1 18.77, 118.98, 122.46, 122.49, 125.24, 125.32, 125.57, 125.60, 130.88, 130.97, 132.33, 132.42, 161.55, 163.05, 164.01, 164.69, 164.76, 165.17, 165.20 and 167.22.

[0101] 4-(5-(4-Fluorophenyl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl 4-fluorobenzoate (28): 'H NMR (CDCI₃) δ 4.12 (t, J= 2.1 Hz, 2 H), 4.92 (t, J= 2.1 Hz, 2 H), 7.06 - 7.13 (m, 2 H), 7.14 - 7.21 (m, 2 H), 7.97 - 8.09 (m, 4 H); ^,3C NMR (CDCI₃) δ 21.50, 52.75, 78.70, 80.45, 1 15.50, 115.73, 116.32, 116.54, 119.78, 119.81, 125.59, 125.62, 128.99, 129.07, 132.33, 132.43, 162.59, 163.53, 164.70, 164.77, 165.40, 166.05 and 167.23.

[0102] 4-(5-(4-Chlorophenyl)-l ,3,4-oxadiazol-2-ylthio)but-2-ynyl 4-fluorobenzoate (29): 1H NMR (CDCI₃) δ 4.13 (t, J= 2.1 Hz, 2 H), 4.92 (t, J= 2.1 Hz, 2 H), 7.06 - 7.14 (m, 2 H), 7.46 (m, 2 H), 7.94 (m, 2 H), 8.01 - 8.07 (m, 2 H); ^,3C NMR (CDCI3) δ 21.50, 52.73, 78.73, 80.41, 1 15.50, 115.72, 121.90, 125.56, 125.59, 127.97, 129.46, 132.33, 132.41, 138.10, 162.82, 164.69, 164.76, 165.39 and 167.23.

[0103] 4-(5-(3-Hydroxynaphthalen-2-yl)-l,3,4-oxadiazol-2-ylthio)but-2-yriyl 4- fluorobenzoate (30): 1H NMR (DMSO-d₆) δ 4.07 (s, 2 H), 4.19 (t, J=2.1 Hz, 2 H), 7.44 - 7.53 (m, 2 H), 7.64 - 7.77 (m, 2 H), 8.04 (d, J= 8.0 Hz, 1 H), 8.10 (s, 1 H), 8.19 - 8.23 (m, 1 H), 8.25 - 8.31 (m, 2 H), 8.79 (s, 1 H); ¹³C NMR (DMSO-d₆) δ 21.07, 48.97, 78.42, 84.04, 115.48, 116.05, 116.27, 121.87, 125.55, 125.58, 127.30, 127.42, 128.84, 129.16, 130.36, 130.61, 132.98, 133.08, 134.42, 144.24, 162.69, 162.83, 164.14, 164.30 and 166.82.

[0104] 4-(5-(Quinolin-5-yl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl 4-fluorobenzoate (3T): Ή NMR (DMSO-de) δ 4.38 (t, J= 2.1 Hz, 2 H), 4.98 (t, J= 2.0 Hz, 2 H), 7.14 - 7.23 (m, 2 H), 7.77 (dd, J= 8.7 and 4.2 Hz, 1 H), 7.81 - 7.88 (m, 2 H), 7.92 (dd, J= 8.5 and 7.3 Hz, 1 H), 8.23 - 8.31 (m, 2 H), 9.06 (dd, J= 4.2 and 1.7 Hz, 1 H), 9.41 - 9.48 (m, 1 H); ¹³C NMR (DMSO-d₆) 6 21.02, 52.72, 78.37, 81.96, 115.68, 115.90, 119.70, 123.12, 124.52, 128.74, 129.22, 131.90, 132.00, 133.13, 134.21, 147.21, 151.07, 162.55, 163.83, 164.58 and 166.34.

[0105] 4-(5-(lH-indol-2-yl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl 4-fluorobenzoate (32): Ή NMR (400 MHz, DMSO-<¾) δ 4.29 (t, J= 2.1 Hz, 2 H), 4.98 (t, J = 2.1 Hz, 2 H), 7.19 - 7.30 (m, 3 H), 7.53 (dd, J = 6.9 and 1.5 Hz, 1 H), 7.87 - 7.95 (m, 2 H), 8.02 - 8.09 (m, 1 H), 8.16 (d, J= 2.9 Hz, 1 H), 12.03 (br., 1 H); ^!3C NMR (DMSO-d₆) δ 21.13, 52.78, 78.19, 82.10, 99.02, 112.43, 115.74, 115.96, 120.10, 121.24, 122.87, 123.87, 128.40, 132.01, 132.10, 136.39, 159.20, 163.51 and 163.96.

[0106] 4-(5-(Naphthalen- 1 -yl)-l ,3,4-oxadiazol-2-ylthio)but-2-ynyl thiophene-3- carboxylate (33): LC-MS: rt (min) = 6.96; 1H NMR (CDC1₃) δ 4.19 (s, 2 H), 4.92 (s, 2 H), 7.28 - 7.30 (m, 1 H), 7.52 (d, J= 5.1 Hz, 1 H), 7.54 - 7.64 (m, 2 H), 7.69 (s, 1 H), 7.94 (d, J = 8.0 Hz, 1 H), 8.04 (d, J= 8.2 Hz, 1 H), 8.11 - 8.18 (m, 2 H) and 9.21 (d, J= 8.6 Hz, 1 H); HRMS (m/z): [M + H]⁺ calcd. for C₂₁Hi₅N₂0₃S₂, 407.0519; found, 407.0524.

[0107] 4-(5-(naphthalen- 1 -yl)- 1 ,3,4-oxadiazol-2-yIthio)but-2-ynyl furan-2-carboxylate (19): LC-MS: rt (min) = 6.58; 1H NMR (CDC1₃) δ 4.19 (s, 2 H), 4.94 (s, 2 H), 6.46 - 6.52 (m, 1 H), 7.22 (s, 1 H), 7.58 (s, 3 H), 7.66 - 7.73 (m, 1 H), 7.89 - 7.97 (m, 1 H), 8.04 (d, J= 8.2 Hz, 1 H), 8.15 (d, J= 7.24 Hz, 1 H) and 9.21 (d, J= 8.6 Hz, 1 H); HRMS (m/z): [M + H]⁺ calcd. for C_2!Hi₄N₂0₄S, 391.0758; found, 391.0754.

[0108] 4-(5-(naphthalen-l-yl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl

cyclopropanecarboxylate (34): LC-MS: rt (min) = 6.69; ^LH NMR (CDC1₃) δ 0.84 - 0.92 (m, 2 H), 0.99 - 1.06 (m, 2 H), 1.60 - 1.67 (m, 1 H), 4.18 (s, 2 H), 4.73 (s, 2 H), 7.55 - 7.64 (m, 2 H), 7.67 - 7.74 (m, 1 H), 7.92 - 7.97 (m, 1 H), 8.02 - 8.07 (m, 1 H), 8.16 (d, J= 8.0 Hz, 1 H) and 9.21 (d, J= 8.6 Hz, 1 H); HRMS (m/z): [M + H]⁺ calcd. for C₂oH,₇N₂0₃S, 365.0954; found, 365.0954.

[01 9] 4-(5-(Naphthalen- 1 -yl)- 1 ,3 ,4-oxadiazol-2-ylthio)but-2-ynyl

cyclobutanecarboxylate (35): LC-MS: rt (min) = 6.99; 1H NMR (CDC1₃) δ 1.91 (m, 2 H), 2.10 - 2.38 (m, 4 H), 3.07 - 3.22 (111, 1 H), 4.18 (s, 2 H), 4.71 (s, 2 H), 7.60 (d, J= 8.0 Hz, 2 H), 7.66 - 7.73 (m, 1 H), 7.91 - 7.97 (m, 1 H), 8.01 - 8.08 (m, 1 H), 8.12 - 8.19 (m, 1 H) and 9.21 (d, J= 8.6 Hz, 1 H); HRMS (m/z): [M + H]⁺ calcd. for C₂iHi₉N₂0₃S, 379.1122; found, 379.1119.

[0110] 4-(5-(Naphthalen- 1 -yl)- 1 ,3,4-oxadiazol-2-ylthio)but-2-ynyl

cyclopentanecarboxylate (36): LC-MS: rt (min) = 7.22; Ή NMR (CDC1₃) δ 1.57 - 1.95 (m, 8 H), 2.70 - 2.78 (m, 1 H), 4.18 (s, 2 H), 4.71 (s, 2 H), 7.55 - 7.65 (m, 2 H), 7.66 - 7.73 (m, 1 H), 7.91 - 7.97 (m, 1 H), 8.02 - 8.07 (m, 1 H), 8.13 - 8.19 (m, 1 H) and 9.21 (d, J= 8.6 Hz, 1 H); HRMS (m/z): [M + H]⁺ calcd. for C₂₂H₂₁N₂0₃S, 393.1279; found, 393.1279. [0111] 4-(5-(Naphthalen- 1 -yl)- 1 ,3,4~oxadiazol-2-ylthio)but-2-ynyl 1 H-imidazole-4- carboxylate (20): LC-MS: rt (min) = 4.63; Ή NMR (CDC1₃) δ 4.16 (s, 2 H), 4.93 (s, 2 H), 7.58 (dt, J= 14.87 and 7.43 Hz, 2 H), 7.68 (t, J= 7.5 Hz, 1 H), 7.79 (s, 1 H), 7.94 (d, J= 8.2 Hz, 1 H), 7.97 - 8.08 (m, 2 H), 8.13 (d, J= 7.2 Hz, 1 H) and 9.10 - 9.19 (m, 1 H); HRMS (m/z): [M + H]⁺ calcd. for C₂₀H₁₅N₄O₃S, 391.0859; found, 391.0863.

[0112] 4-(5-( aphthalen-l-yl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl benzo[b]thiophene-2- carboxylate (37): LC-MS: rt (min) = 7.36; 1H NMR (CDC1₃) δ 4.20 (s, 2 H), 4.98 (s, 2 H), 7.37 - 7.49 (m, 2 H), 7.52 - 7.63 (m, 2 H), 7.65 - 7.71 (m, 1 H), 7.81 - 7.87 (m, 2 H), 7.90 - 7.94 (m, 1 H), 8.02 (d, J= 8.22 Hz, 1 H), 8.07 (s, 1 H), 8.13 - 8.18 (m, 1 H) and 9.20 (d, J = 8.61 Hz, 1 H); HRMS (m/z): [M + H]⁺ calcd. for C25H17N2O3S2, 457.0687; found, 457.0689.

[0113] 4-(5-(Naphthalen-l-yl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl benzo[b]thiophene-3- carboxylate (38): LC-MS: rt (min) - 7.47; 1H NMR (CDCI3) δ 4.19 (s, 2 H), 4.99 (s, 2 H), 7.41 (d, J= 7.2 Hz, 1 H), 7.45 - 7.63 (m, 3 H), 7.64 - 7.73 (m, 1 H), 7.86 (d, J- 8.0 Hz, 1 H), 7.93 (d, J= 8.2 Hz, 1 H), 8.02 (d, J= 8.2 Hz, 1 H), 8.14 (d, J= 7.4 Hz, 1 H), 8.41 (s, 1 H), 8.57 (d, J= 8.0 Hz, 1 H) and 9.20 (d, J= 8.6 Hz, 1 H); HRMS {m/z): [M + H]⁺ calcd. for C₂₅H₁₇N₂0₃S2, 457.0675; found, 457.0676.

[0114] 4-(5-(naphthalen-l -yl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl benzoate (39): LC- MS: rt (min) = 7.07; 1H NMR (CDC1₃) δ 4.20 (s, 2 H), 4.97 (s, 2 H), 7.42 (t, J= 7.7 Hz, 2 H), 7.51 - 7.65 (m, 3 H), 7.68 (d, J= 7.4 Hz, 1 H), 7.94 (d, J= 8.2 Hz, 1 H), 8.04 (d, J= 8.2 Hz, 3 H), 8.15 (d, J= 7.2 Hz, 1 H) and 9.21 (d, J= 8.6 Hz, 1 H); HRMS (m/z): [M + H]⁺ calcd. for C₂₃H_!7N₂0₃S, 401.0954; found, 401.0954.

[0115] 4-(5-(Naphthalen-l-yl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl 3-fiuorobenzoate (40): LC-MS: rt (min) = 7.12; 1H NMR (CDC1₃) δ 4.20 (s, 2 H), 4.97 (s, 2 H), 7.22 - 7.26 (m, 1 H), 7.38 (td, J= 7.9 and 5.8 Hz, 1 H), 7.52 - 7.64 (m, 2 H), 7.70 (dd, J= 14.7 and 7.8 Hz, 2 H), 7.82 (d, J= 7.6 Hz, 1 H), 7.94 (d, J= 8.2 Hz, 1 H), 7.99 - 8.08 (m, 1 H), 8.15 (d, J= 7.2 Hz, 1 H) and 9.20 (d, J= 8.6 Hz, 1 H); HRMS (m/z): [M + H]⁺ calcd. for C₂₃H₁₆FN₂0₃S, 419.0872; found, 419.0867.

[0116] 4-(5-(Naphthalen-l-yl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl 3,4-difluorobenzoate (41): LC-MS: rt (min) = 7.14; Ή NMR (CDCI₃) δ 4.19 (t, 2 H), 4.95 (t, J= 2.0 Hz, 2 H), 7.12 - 7.21 (m, 1 H), 7.52 - 7.65 (m, 2 H), 7.66 - 7.74 (m, 1 H), 7.76 - 7.89 (m, 2 H), 7.94 (d, J~ 8.0 Hz, 1 H), 8.04 (d, J= 8.2 Hz, 1 H), 8.14 (d, J= 7.2 Hz, 1 H) and 9.20 (d, J= 8.6 Hz, 1 H); HRMS (m/z): [M + H]⁺ calcd. for C₂3H₁₅F₂N₂0₃S, 437.0756; found, 437.0762.

[0117] 4-(5-(Naphthalen- 1 -yl)- 1 ,3,4-oxadiazol-2-ylthio)but-2-ynyl 2-methoxybenzoate (17): LC-MS: rt (min) = 6.85; 1H NMR (CDC1₃) δ 3.90 (s, 3 H), 4.20 (s, 2 H), 4.94 (s, 2 H), 6.93 - 7.01 (m, 2 H), 7.43 - 7.51 (m, 1 H), 7.58 (ddd, J= 17.7, 7.7 and 7.5 Hz, 2 H), 7.66 - 7.73 (m, 1 H), 7.80 - 7.86 (m, 1 H), 7.93 (d, J- 8.0 Hz, 1 H), 8.03 (d, J= 8.2 Hz, 1 H), 8.14 (d, J= 7.4 Hz, 1 H) and 9.20 (d, J = 8.6 Hz, 1 H); HRMS (m/z): [M + H]⁺ calcd. for

C₂4H₁₉N₂0₄S, 431.1071; found, 431.1067.

[0118] 4-(5-(Naphthalen-l-yl)-l ,3,4-oxadiazol-2-ylthio)but-2-ynyl 4- (dimethylamino)benzoate (13): LC-MS: rt (min) = 7.11 ; ^lH NMR (CDC1₃) δ 3.03 (s, 6 H),

4.19 (s, 2 H), 4.91 (s, 2 H), 6.57 - 6.63 (m, 2 H), 7.52 - 7.63 (m, 2 H), 7.65 - 7.73 (m, 1 H), 7.89 (d, J= 9.0 Hz, 3 H), 8.01 - 8.05 (m, 1 H), 8.13 - 8.18 (m, 1 H) and 9.21 (d, J= 8.6 Hz, 1 H); HRMS (m/z): [M + H]⁺ calcd. for C₂5H₂₂N₃0₃S, 445.1418; found, 445.1408.

[0119] 4-(5-(Naphthalen- 1 -yl)-l ,3,4-oxadiazol-2-ylthio)but-2-ynyl 4-(methylsulfonyl) benzoate (43): LC-MS: rt (min) = 6.30; Ή NMR (CDC1₃) δ 3.06 (s, 3 H), 4.12 - 4.24 (m, 2 H), 5.00 (s, 2 H), 7.58 (d, J= 8.0 Hz, 2 H), 7.70 (s, 1 H), 7.91 - 8.01 (m, 3 H), 8.02 - 8.07 (m, 1 H), 8.13 - 8.17 (m, 1 H), 8.17 - 8.22 (m, 2 H) and 9.20 (d, J= 8.6 Hz, 1 H); HRMS (m/z): [M + H]⁺ calcd. for C₂ H₁₉N₂0₅S₂, 479.0733; found, 479.0736.

[0120] 4-(5-( Iaphthalen-l-yl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl 4-(triiluoromethoxy) benzoate (44): LC-MS: rt (min) = 7.46; ^lH NMR (CDC1₃) δ 4.19 (s, 2 H), 4.95 (s, 2 H), 7.22 (d, J= 8.2 Hz, 2 H), 7.56 (s, 2 H), 7.65 - 7.73 (m, 1 H), 7.94 (d, J= 8.0 Hz, 1 H), 8.05 (t, J= 9.7 Hz, 3 H), 8.15 (d, J^~ 7.2 Hz, 1 H) and 9.20 (d, J= 8.6 Hz, 1 H); HRMS (m/z): [M + H]⁺ calcd. for C₂₄H₁₆F₃N₂0₄S, 485.0786; found, 485.0788.

[0121] 4-(5-(naphthalen-l -yl)-l ,3,4-oxadiazol-2-ylt io)but-2-ynyl 4-(trifluoromethyl) benzoate (45): LC-MS: rt (min) = 7.46; Ή NMR (CDC1₃) δ 4.24 (s, 2 H), 4.99 (s, 2 H), 7.53 - 7.72 (m, 5H), 7.94 (d, J= 8.2 Hz, 1 H), 8.03 (d, J= 8.2 Hz, 1 H), 8.10 - 8.18 (m, 3 H) and

9.20 (d, J= 8.6 Hz, 1 H); HRMS (m/z): [M + H]⁺ calcd. for C₂₄H₁₆F₃N₂0₃S, 469.0826;

found, 469.0824.

[0122] 4-(5-(naphthalen-2-yl)-l_J3,4-oxadiazol-2-ylthio)but-2-ynyl 4-fluorobenzoate (46): LC-MS: rt (min) = 7.07; 1H NMR (DMSO-J₆) δ 4.36 (s, 2 H), 4.98 (s, 2 H), 7.17 - 7.24 (m, 2 H), 7.61 - 7.71 (m, 2 H), 7.85 - 7.92 (m, 2 H), 7.99 - 8.05 (m, 2 H), 8.07 - 8.14 (m, 2 H) and 8.58 (s, 1 H); HRMS (m/z): [M + H]⁺ calcd. for C₂₃H₁₆FN₂0₃S, 419.0872; found, 419.0869.

[0123] (E)-4-(5-(naphthalen-l-yl)-l,3,4-oxadiazol-2-ylthio)but-2-enyl 4-fluorobenzoate (47): LC-MS: rt (min) - 7.27; 1H NMR (CDC1₃) δ 4.02 (d, J= 3.52 Hz, 2 H), 4.82 (d, J= 3.5 Hz, 2 H), 6.09 - 6.13 (m, 2 H), 7.04 (t, J= 8.7 Hz, 2 H), 7.53 - 7.64 (m, 2 H), 7.69 (s, 1 H), 7.93 (d, J= 8.0 Hz, 1 H), 7.98 - 8.05 (m, 3 H), 8.12 (s, 1 H) and 9.21 (d, J= 8.8 Hz, 1 H); HRMS (m/z) [M + H]⁺ calcd. for C₂₃Hi₈FN₂0₃S, 421.1028; found, 421.1025.

[0124] 6-(5-(Naphthalen- 1 -yl)- 1 ,3,4-oxadiazol-2-ylthio)- 1 -phenylhex-4-yn-l-one (48): LC-MS: rt (min) = 6.99; 1H MR (CDC1₃) 8 2.63 - 2.70 (m, 2 H), 3.14 - 3.30 (m, 2 H), 4.11 (s, 2 H), 7.40 - 7.46 (m, 2 H), 7.52 - 7.64 (m, 3 H), 7.66 - 7.72 (m, 1 H), 7.90 - 7.97 (m, 3 H), 8.04 (d, J= 8.2 Hz, 1 H), 8.15 (d, J= 7.2 Hz, 1 H) and 9.21 (d, J= 8.6 Hz, 1 H); HRMS . (m/z): [M + H]⁺ calcd. for C₂₄Hi₉N₂0₂S, 399.1173; found, 399.1171.

[0125] 4-(5-(naphthalen-l -yl)-l ,3,4-oxadiazol-2-ylthio)but-2-ynyl thiophene-2- carboxylate (18): 1H MR (CDC1₃) δ 4.15 - 4.22 (m, 2 H), 4.89 - 4.96 (m,- 2 H), 7.03 - 7.10 (m, 1 H), 7.51 - 7.64 (m, 3 H), 7.64 - 7.74 (m, 1 H), 7.77 - 7.84 (m, 1 H), 7.93 (d, J= 8.22 Hz, 1 H), 8.03 (d, J= 8.22 Hz, 1 H), 8.14 (dd, J= 7.34, 1.08 Hz, 1 H) and 9.18 (d, J=8.61 Hz, 1 H); ¹³C NMR (CDCI₃) 5 21.45, 52.69, 78.61, 80.55, 119.86, 124.81, 126.06, 126.73, 127.77, 128.18, 128.34, 128.64, 129.78, 132.61, 132.71, 132.99, 133.75, 134.08, 161.33, 162.44 and 166.17. HRMS (m/z): [M + H]⁺ calcd. for C_2iH₁₅N₂0₃S₂, 407.0519; found, 407.0517.

[0126] 4-(5-(naphthalen- 1 -yl)- 1 ,3 ,4-oxadiazol-2-ylthio)butyl 4-fluorobenzoate (53): 1H NMR (CDCI3) δ 1.92 - 2.18 (m, 4 H), 3.44 (td, J= 7.1 and 2.8 Hz, 2 H), 4.36 - 4.46 (m, 2 H), 7.04 - 7.14 (m, 2 H), 7.52 - 7.64 (m, 2 H), 7.66 - 7.74 (m, 1 H), 7.93 (d, J= 8.2 Hz, 1 H), 7.99 - 8.10 (m, 3 H), 8.10 - 8.18 (m, 1 H) and 9.21 (d, J= 8.6 Hz, 1 H); ¹³C NMR NMR (CDC1₃) 6 26.11, 27.74, 32.15, 64.25, 115.41, 115.64, 120.12, 124.83, 126.17, 126.38, 126.73, 128.14, 128.66, 129.83, 132.06, 132.15, 132.55, 133.82, 163.97, 164.49, 165.56 , 165.76 and 167.01; HRMS (m/z) [M + H]⁺ calcd. for C₂₃H₂oFN₂0₃S, 423.1178; found, 423.1176.

[0127] 4-((5-(naphthalen-l-yl)-l,3,4-oxadiazol-2-ylthio)methyl)benzyl 4-fluorobenzoate (54): Ή NMR (CDCI3) δ 4.59 (s, 2 H), 5.35 (s, 2 H), 7.06 - 7.14 (m, 2 H), 7.44 (d, J= 8.0 Hz, 2 H), 7.51 - 7.63 (m, 4 H), 7.65 - 7.72 (m, 1 H), 7.93 (d, J = 8.0 Hz, 1 H), 8.03 (d, J= 8.0 Hz, 1 H), 8.05 - 8.13 (m, 3 H) and 9.19 (d, J= 8.6 Hz, 1 H); ¹³C NMR NMR (CDC1₃) 636.41, 66.35, 115.44, 115.66, 120.08, 124.82, 126.16, 126.22, 126.25, 126.73, 128.14, 128.19, 128.64, 129.48, 129.82, 132.21, 132.30, 132.58, 133.81, 135.87, 135.93, 163.50, 164.57, 165.39, 165.89 and 167.10; HRMS ( /z): [M + H]⁺ calcd. for C2₇H₂oFN₂0₃S, 471.1178; found, 471.1175.

EXAMPLE 5

[0128] This example demonstrates a procedure for preparing an intermediate leading to compounds in accordance with an embodiment, specifically, the preparation of

2-(l -naphthyl)-5-amino- 1 ,3,4-oxadiazole (9).

[0129] A mixture of 1-naphthohydrazide (7) (2.0 g, 10.7 mmol) and cyanuric bromide (1.4 g, 13 mmol) in EtOH (107 mL) was heated at reflux for 1 h. The solvent was removed and the product was purified by recrystallization from ethanol to yield 1.9 g (84%) of pure product 9. 1H NMR ( OUSO-d₆) 5 7.36 (s, 2 H), 7.59 - 7. 1 (m, 3 H), 7.95 - 7.99 (m, 1 H), 8.03 (d, J= 8.0 Hz, 1 H), 8.08 (d, J= 8.2 Hz, 1 H) and 9.13 (d, J= 8.6 Hz, 1H); ^,3C NMR ( DMSO-i ) δ 120.62, 125.35, 125.80, 126.44, 126.57, 127.68, 128.69, 128.91, 130.96, 133.48, 157.28 and 163.52.

EXAMPLE 6

[0130] This example demonstrates a procedure for the preparation of 4-(5-(naphthalen-l - yl)-l,3,4-oxadiazol-2-ylamino)but-2-ynyl thiophene-2-carboxylate (49).

[0131] To a solution of 5-(naphthalen-l-yI)-l,3,4-oxadiazol-2-amine (0.256 g, 1.1 mmol) in DMF (3 mL) was added NaH (0.066 g, 2.2 mmol) at 0 °C. After 45 minutes, 4-chlorobut- 2-ynyl fniophene-2-carboxylate (0.26 g, 1.2 mmol) was added and allowed to stir for 5 h at room temperature. The crude product was purified by reversed phase HPLC. 1H NMR (CDC1₃) δ 4.15 - 4.22 (m, 2 H), 4.89 - 4.96 (m, 2 H), 7.03 - 7.10 (m, 1 H), 7.51 - 7.64 (m, 3 H), 7.64 - 7.74 (m, 1 H), 7.77 - 7.84 (m, 1 H), 7.93 (d, J - 8.22 Hz, 1 H), 8.03 (d, J= 8.22 Hz, 1 H), 8.14 (dd, J= 7.34, 1.08 Hz, 1 H) and 9.18 (d, J=8.61 Hz, 1 H); ¹³C NMR (CDC1₃) δ 21.45, 52.69, 78.61 , 80.55, 119.86, 124.81, 126.06, 126.73, 127.77, 128.18, 128.34, 128.64, 129.78, 132.61, 132.71, 132.99, 133.75, 134.08, 161.33, 162.44 and 166.17. HRMS (m/z): [M + H]⁺ calcd. for C₂iHi₅N₂0₃S₂, 407.0519; found, 407.0517.

EXAMPLE 7

[0132] This example demonstrates a procedure for the preparation of 7V-(4-(5- (naphthalen-1 -yl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl)thiophene -2-carboxamide (50). [0133] N-(4-chlorobut-2-ynyl)thiophene-2-carboxamide was prepared as follows. A mixture of thiophene-2-carboxylic acid (1.0 g, 7.8 mmol) and EDC (2.2 g, 11.7 mmol) in CH₂CI2 (40 mL) was stirred for 30 min and 4-chlorobut-2-yn-l-aminium chloride

hydrochloride (1.3 g, 8.6 mmol) was added and stirred at room temperature for 2 h. The reaction mixture was diluted with dichloromethane and washed with water. The organic layer was dried over sodium sulfate. The crude residue was purified on a Biotage® silica gel column. Elution with 20% ethyl acetate in hexanes gave the product. Yield: 1.32 g (79%) Ή NMR (DMSC δ 4.13 (dt, J= 5.6 and 2.1 Hz, 2 H), 4.46 (t, J= 2.0 Hz, 2 H), 7.15 (dd, J= 4.9 and 3.7 Hz, 1 H), 7.74 - 7.80 (m, 2 H) and 8.97 (t, J= 5.5 Hz, 1 H); ¹³C NMR (DMSO- ) δ 28.47, 31.07, 77.21, 83.81, 127.97, 128.45, 131.19, 139.14, and 160.84; HRMS ( /z): [M + Hf calcd. for C₉H₉C1N0S, 214.0088; found, 214.0090.

[0134] To a mixture of 2 (0.040 g, 0.18 mmol) and N-(4-chlorobut-2-ynyl)thiophene-2- carboxamide (0.041 g, 0.19 mmol) in DMF (1 mL) was added potassium carbonate (0.12 g, 0.88 mmol) and was stirred at 40 °C for 2 h. The resulting crude product was purified by preparative HPLC to give the title compound 50 (see General Methods for HPLC purification conditions). LC-MS: rt (min) = 6.15; 1H NMR (CDC1₃) δ 4.12 (t, J= 2.2 Hz, 2 H), 4.27 (dt, J= 5.3 and 2.2 Hz, 2 H), 6.30 - 6.39 (m, 1 H), 7.03 (dd, J= 4.9 and 3.7 Hz, 1 H), 7.46 (dd, J = 5.1 and 1.2 Hz, 1 H), 7.52 - 7.57 (m, 2 H), 7.57 - 7.64 (m, 1 H), 7.68 (ddd, J = 8.5, 6.9 and 1.4 Hz, 1 H), 7.90 - 7.95 (m, 1 H), 8.03 (d, J= 8.2 Hz, 1 H), 8.13 (dd, J= 7.3 and 1.3 Hz, 1 H) and 9.19 (dd, J- 8.6 and 0.8 Hz, 1 H); ^{, 3}C NMR (CDC1₃) δ 21.03, 21.56, 29.95, 80.44, 119.87, 124.84, 126.04, 126.75, 127.62, 128.19, 128.34, 128.49, 128.68, 129.78, 130.33, 132.74, 133.78, 138.01, 161.48, 162.50 and 166.23; HRMS (m/z): [M + H]⁺ calcd. for C₂₁Hi₆N₃0₃S, 406.0678; found, 406.0675.

EXAMPLE 8

[0135] This example demonstrates a procedure for preparing an intermediate leading to compounds in accordance with an embodiment, specifically the preparation of 2-(l- naphthyl)-5-mercapto- 1 ,3,4-thiadiazole (51).

[0136] 1-Naphthohydrazide (4.0 g, 21.5 mmol) and potassium hydroxide (1.2 g, 21.5 mmol) in ethanol (100 mL) was stirred for 30 min and then carbon disulfide (3.0 mL, 49.4 mmol) was added. The reaction mixture was stirred at room temperature for 4 h. The yellow precipitate was collected by filtration and the product was washed with ether. This product was slowly added to sulfuric acid (20 mL, 375 mmol) at 0 °C then stirred at rt for 2 h. The reaction mixture was poured into ice and the product was collected by filtration.

Recrystallization from ethanol gave pure yellow product 51 : (3.2 g, 61%). Ή NMR (DMSO- d₆) δ 7.60 - 7.74 (m, 3 H), 7.81 (d, J= 7.2 Hz, 1 H), 8.07 (d, J= 7.8 Hz, 1 H), 8.16 (d, J= 8.2 Hz, 1 H) and 8.60 (d, J= 8.2 Hz, 1 H); ¹³C NMR ( DMSO- ₆) δ 124.69, 124.98, 125.42, 126.87, 128.07, 128.78, 129.16, 129.55, 131.83, 133.46, 161.13 and 174.68; HRMS (m/z): [M + Hf calcd. for C₁₂H₉N₂S₂, 245.0202; found, 245.0204.

EXAMPLE 9

[0137] This example demonstrates a procedure for the preparation of 4-(5-(naphthalen-l- yl)- 1 ,3,4-thiadiazol-2-ylthio)but-2-ynyl thiophene-2-carboxylate (52).

[0138] To a solution of 51 (0.20 mmol) in DMF (1 mL) at 0 °C was added NaH (0.40 mmol) followed by 4-chlorobut-2-ynyl thiophene-2-carboxylate (0.22 mmol), the reaction mixture was stirred at 0 °C for 1 h then at room temperature for 5 h. The product was purified in a preparative HPLC (see general methods for details). LC-MS: rt (min) = 7.10; 1H NMR (CDC1₃) δ 4.23 (t, J= 2.2 Hz, 2 H), 4.89 - 4.96 (m, 2 H), 7.02 - 7.08 (m, 1 H), 7.50-7.65 (m, 4 H), 7.73 - 7.78 (m, 1 H), 7.80 - 7.84 (m, 1 H), 7.91 - 7.95 (m,l H), 8.00 (d, J= 8.2 Hz, 1 H) and 8.68 - 8.76 (m, 1 H); ^,3C NMR (CDC1₃) δ 22.55, 52.72, 78.49, 81.02, 93.24, 109.67, 124.89, 125.55, 126.66, 127.70, 127.77, 127.78, 128.39, 129.63, 129.68, 130.35 , 131.47, 132.87, 133.84, 133.98 , 161.27, 163.72 and 164.67; HRMS (m/z): [M + Na]⁺ calcd. for C₂₁H₁₅N₂0₂S₃, 445.0108; found, 445.0107.

[0139]

EXAMPLE 10

[0140] This example illustrates the functional bioactivity of inventive compounds of Formula III, in accordance with an embodiment of Formula I, using the human

15 -lipoxygenase- 1 inhibition ("15hLO-l") assay.

[0141] The enzyme activity of 15hLO-l was determined by a direct measurement of product formation by monitoring the absorbance at 234 nm in a 2 mL cuvette. IC50 values of inhibitors were obtained by measuring the enzymatic rate at a variety of concentrations.

[0142] For control experiments, 2 Ml of substrate buffer (7 μΜ arachidonic acid / 25 Mm HEPES / 0.01% (v/v) Triton X-100, Ph 7.5) was aliquoted in a cuvette with a magnetic stir bar. After equilibrium was ensured, an aliquot of inhibitor solvent was added (DM SO or MeOH), and equilibrium was once again assured. The reaction was started by adding enzyme (i.e., (50-200 Nm) to the cuvette and the reaction was followed until completed. The inhibition experiments were performed as above, except the actual inhibitory compound was added instead of vehicle. To achieve an IC50, typically 5 concentrations of the inhibitor were studied. If the inhibitor concentration was constant, then five different reaction volumes were used. All experiments were performed in duplicates twice.

[0143] Using Kinlab, the largest derivative of the rate at 234 nm is used for the data point in AU/s. Accordingly, the % inhibition is expressed as a ratio of the control to experimental rates (eq. 1):

[0144] percent inhibition = [1 - (experimental rate)/(control rate)]* 100% (eq. 1)

[0145] Each percent inhibition data point is plotted as a function of concentration. The plot is then fit to a hyperbolic curve using the equation 2:

[0146] ([I]*Imax)/([I] + IC₅o) (eq. 2)

[0147] where [I] is the inhibitor concentration, I_max is the maximum percent inhibition and IC50 is the concentration at 50% inhibition. I_max and the IC50 values are extracted from the hyperbolic curve fit. The results are set forth in Table 1.

Formula III

Table 1

Compound R⁴ ICso (nM)

9 4-fluorophenyl <10

10 4-chlorophenyl <10

11 4-bromophenyl <10

12 4-methoxyphenyl <10

13 4-dimethylaminophenyl 15

14 2-naphthyl 22

15 benzofuran-2-yl 15

16 indol-4-yl 76

17 2-methoxyphenyl 470

18 2-thiopheneyl 19

19 2-furanyl 170

20 imidazol-4-yl 1400

71 3 ,4, 5 -trichlorothiophen-2-yl <10

55 3-chlorothiophen-2-yl <10

33 thiophen-3-yl <10

34 cyclopropyl 270

35 cyclobutyl 85

36 cyclop entyl <10

56 2-fluoropyridine-2 -yl <10

37 benzothiophen-2-yl <10

38 benzothiophen-3-yl <10

58 3 -chlorobenzothiophen-2-yl 31

39 phenyl <10

59 2-fluorophenyl <10

40 3-fluorophenyl <10

60 2,4-difluorophenyl <10

41 3 ,4-di fluorophenyl <10

61 3,4,5 -trifluorophenyl 16 43 4-methylsulfonylphenyl 33

63 4-trifluoromethylthiophenyl <10

64 4-difluoromethoxyphenyl <10

44 4-trifluoromethoxyphenyl <10

65 3-trifluoromethylphenyl 27

45 4-trifluoromethylphenyl <10

66 3 -trifluoromethyl-4- 100

chlorophenyl

[0148] As is apparent from the results set forth in Table 1, the inventive compounds inhibited human 15-lipoxygenase-l with IC₅₀ values ranging from <10 nM to 1400 nM.

EXAMPLE 11

[0149] This example illustrates the functional bioactivity of inventive compounds of Formula IV, in accordance with an embodiment of Formula I, using the human

15-lipoxygenase-l inhibition ("15hLO-l") assay. The 15hLO-l assay was conducted as described in Example 10. The results are set forth in Table 2.

Formula IV

Table 2

[0150] As is apparent from the results set forth in Table 2, the inventive compounds inhibited human 15-Hpoxygenase-l with IC₅o values ranging from <10 nM to 1000 nM.

EXAMPLE 12

[0151] This example illustrates the functional bioactivity of inventive compounds of Formula V, in accordance with an embodiment of Formula I, using the human

15 -lipoxygenase- 1 inhibition ("15hLO-l") assay. The 15hLO-l assay was conducted as described in Example 10. The results are set forth in Table 3.

Formula V Table 3

[0152] As is apparent from the results set forth in Table 3, compounds 50 and 52 inhibited human 15-lipoxygenase-l. The IC₅o for compound 67 could not be determined due to low solubility of the compound.

EXAMPLE 13

[0153] This example illustrates the functional bioactivity of inventive compounds of Formula VI, in accordance with an embodiment of Formula I, using the human

15-lipoxygenase-l inhibition ("15hLO-l") assay. The 15hL01 assay was conducted as described in Example 10. The results are set forth in Table 4.

Formula V

Table 4

[0154] As is apparent from the results set forth in Table 4, compound 47 exhibited an IC₅₀ of 26 nM against 15hLO-l.

EXAMPLE 14

[0155] This example illustrates the lipoxygenase isozyme selectivity of certain compounds of the invention.

[0156] The initial one-point inhibition percentages were determined by following the formation of the conjugated diene product at 234 nm (ε = 25,000 M^cm^"1) with a Perkin- Elmer Lambda 40 UV Vis spectrophotometer at one inhibitor concentration. All reactions were 2 mL in volume and constantly stirred using a magnetic stir bar at room temperature (23° C) with approximately 40 nM for 12-hLO, 20 nM of 15-hLO-l (by iron content), 1 μΜ for 15-hLO-2. Reactions with with the crude, ammonium sulfate precipitated 5-hLO were carried out in 25 mM HEPES (pH 7.3), 0.3 mM CaCl₂, 0.1 mM EDTA, 0.2 mM ATP, 0.01% Triton X-100, 10 μΜ AA and with 12-hLO in 25 mM Hepes buffer (pH 8), 0.01 % Triton X- 100, 10 μΜ AA. Reactions with 15-hLO-l and 15-hLO-2 were carried out in 25 mM Hepes buffer (pH 7.5), 0.01% Triton X-100, 10 μΜ AA. The concentration of AA (for 5-hLO, 12- hLO and 15-hLO-2) and LA (for 15-hLO-l) were quantitatively determined by allowing the enzymatic reaction to go to completion. IC₅₀ values were estimated from three inhibitor concentrations and are reported in μΜ. The results are set forth in Table 5.

Table 5

[0157] As is apparent from the results set forth in Table 5, all of the compounds exhibited selectivity of greater than 10000 for 15-hLO-l over 15-hLO-2 and 12-hLO, and a selectivity of over 1500 for 15-hLO-l over 5-hLO.

EXAMPLE 15

[0158] This example illustrates the functional bioactivity of inventive compounds in accordance with certain embodiments of Formula II, using the human 15 -lipoxygenase- 1 inhibition ("15hLO-l ") assay. The 151iLO-l assay was conducted as described in Example 10. The results are set forth in Table 6.

Table 6

[0159] As is apparent from the results set forth in Table 6, the compounds inhibited 15-hLO-l with IC₅₀ values ranging from 8 μΜ to 78 μΜ.

[0160] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

[0161] The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to,") unless otherwise noted. Recitation of ranges of values herein 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. All methods described herein can be performed in any 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") provided herein, is intended merely to better illuminate the invention 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.

[0162] Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

CLAIM(S):

1. A compound of the formula (I):

(I)

wherein R¹ is selected from the group consisting of a C₆-C₁₀ aryl group and a heterocyclyl group, each optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the group consisting of halo, Ci-C alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C3-C8 cycloalkyl, C3- Cg cycloalkenyl, C₆-Cio aryl, heteroaryl, Ci-C₆ haloalkyl, C C₆ dihaloalkyl, Ci-C₆ trihaloalkyl, -N0₂, -OH, -OR⁵, -SH, -SR^S, -SOR⁵, -S0₂R⁵, -COR⁵, -COOH, -COOR⁵, -CONHR⁵, and -CONR⁵R⁶,

X is O or S,

Y is S, H, or O,

R² is selected from the group consisting of Ci-C₆ alkylene, C₂-C₆ alkenylene, C2-C6 alkynylene, C₆-Cjo arylene, C -C[₂ alkylarylene, and C₇-Ci₂ dialkylarylene, each optionally substituted with 1, 2, 3, or 4 C C₆ alkyl substituents,

Z is S, NH, NR⁵, NHS0₂, or O,

R³ is a bond, CH₂, or C=0,

R⁴ is selected from the group consisting of Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl, C6-C₁₀ aryl, heterocyclyl, each optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halo, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl, C₆-Cio aryl, heteroaryl, C]-C₆ haloalkyl, C C₆ dihaloalkyl, C_t-C₆ trihaloalkyl, -N0₂, -OH, -OR⁵, -NH₂, -NHR⁵, -NR⁵R⁶, - SH, -SR⁵, -SOR⁵, -S0₂R⁵, -COR⁵, -COOH, -COOR⁵, -CONHR⁵, and -CONR⁵R⁶, and

R⁵ and R⁶ are independently selected from the group consisting of Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, and C₃-Cg cycloalkenyl,

or a pharmaceutically acceptable salt thereof.

2. The compound or salt of claim 1, wherein Z is S, NH, NR⁵, or 0.

3. The compound or salt of claim 1 or 2, wherein X is O.

4. The compound or salt of any of claims 1-3, wherein Y is S.

5. The compound or salt of any of claims 1-4, wherein Z is O.

6. The compound or salt of claim 5, wherein ³ is C=0.

7. The compound or salt of claim 6, wherein R² is C₂-C₆ alkynylene.

8. The compound or salt of claim 7, wherein R is but-2-ynylene.

9. The compound or salt of any of claims 6-8, wherein R⁴ is a C₆-Cio aryl group optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halo, C]-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-Cg cycloalkyl, C₃-C₈ cycloalkenyl, C₆-Cio aryl, heteroaryl, Ci-C₆ haloalkyl, Ci-C₆ dihaloalkyl, C]-C₆ trihaloalkyl, -N0₂, -OH, -OR⁵, -NH₂, -NHR⁵, -NR⁵R⁶, -SH, -SR⁵, -SOR⁵, -S0₂R⁵, -COR⁵, -COOH, -COOR⁵, -CONHR⁵, and -CONR⁵R⁶.

10. The compound or salt of claim 9, wherein R⁴ is a phenyl group or naphthyl group, each substituted with one or more substituents selected from the group consisting of halo, C C₆ alkyl, -OH, -OR⁵, -N¾, -NHR⁵, and -NR⁵R⁶.

11. The compound or salt of claim 10, wherein R⁴ is phenyl substituted with chloro, bromo, fluoro, methoxy, or dimethylamino, or R⁴ is a naphthyl group.

12. The compound or salt of any of claims 1-11, wherein R¹ is a C₆-Cio aryl group.

13. The compound or salt of claim 12, wherein R¹ is 1 -naphthyl.

14. The compound or salt of claim 13, wherein the compound is selected from the group consisting of 4-(5-(naphthalene-l-yl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl 4- fluorobenzoate, 4-(5-(naphthalene-l-yl)-l ,3,4-oxadiazol-2-ylthio)but-2-ynyl 4- chlorobenzoate, 4-(5-(naphthalene-l-yl)-l ,3,4-oxadiazol-2-ylthio)but-2-ynyl 4- bromobenzoate, 4-(5-(naphthalene- 1 -yl)- 1 ,3,4-oxadiazol-2-ylthio)but-2-ynyl 4- methoxybenzoate, 4-(5-(naphthalene-l-yl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl 4- dimethylaminobenzoate, and 4-(5-(naphthalene-l-yl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl 2- methoxybenzoate.

15. The compound or salt of claim 13, wherein the compound is 4-(5- (naphthalene- 1 -yl)- 1 ,3 ,4-oxadiazol-2-ylthio)but-2-ynyl 2-naphthalenecarboxylate.

16. The compound or salt of any of claims 6-8, wherein R⁴ is a heterocyclyl group.

17. The compound or salt of claim 16, wherein R⁴ furanyl, thiopheneyl, pyrrolyl, pyrazolyl, imidazolyl, ,2,3-triazolyl, 1,2,4-triazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl,

benzothiopheneyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazoiinyl, benzothiazolinyl, and quinazolinyl.

18. The compound or salt of claim 17, wherein R⁴ is selected from the group consisting of furanyl, thiopheneyl, pyrrolyl, indolyl, imidazolyl, benzofuranyl, benzodiazolyl, benzoxazolyl, benzthiazolyl, quinolinyl, isoquinolilyl, quinazolinyl, and quinoxalinyl.

19. The compound or salt of claim 18, wherein R⁴ is selected from the group consisting of furanyl, thiopheneyl, imidazolyl, indolyl, and benzofuranyl.

20. The compound or salt of any of claims 1-18, wherein the compound is selected from the group consisting of 4-(5-(naphthalene-l-yl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl thiophene-2-carboxylate, 4-(5 -(naphthalene- l-yl)-l ,3,4-oxadiazol-2-ylthio)but-2-ynyl furan- 2-carboxylate, 4-(5-(naphthalene-l-yl)-l ,3,4-oxadiazol-2-ylthio)but-2-ynyl benzofuran-2- carboxylate, 4-(5-(naphthalene- 1 -yl)- 1 ,3 ,4-oxadiazol-2-ylthio)but-2-ynyl indole-4- carboxylate, 4-(5-( aphthalen-l-yl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl 4-chlorobenzoate, 4- (5-(Naphthalen-l-yl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl 4-methoxybenzoate, 4-(5- (Naphthalen-1 -yl)- 1 ,3,4-oxadiazol-2-ylthio)but-2-ynyl lH-indole-4-carboxylate, 4-(5-(Furan- 2-yl)-l ,3,4-oxadiazol-2-ylthio)but-2-ynyl 4-fluorobenzoate, 4-(5-(Thiophen-2-yI)-l ,3,4- oxadiazol-2-ylthio)but-2-ynyl 4-fluorobenzoate, 4-(5-Phenyl- 1 ,3 ,4-oxadiazol-2-ylfhio)but-2- ynyl 4-fluorobenzoate, 4-(5-(2-Fluorophenyl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl 4- fluorobenzoate, 4-(5-(2-Chlorophenyl)- 1 ,3,4-oxadiazol-2-ylthio)but-2-ynyl 4- fluorobenzoate, 4-(5-(2-Methoxyphenyl)- 1 ,3,4-oxadiazol-2-ylthio)but-2-ynyl 4- fluorobenzo ate, 4-(5 -(3 -Fluorophenyl)- 1 , 3 ,4-oxadiazol-2-ylthio)but-2-ynyl 4- fluorobenzo ate, 4-(5-(4-Fluorophenyl)- 1 ,3,4-oxadiazol-2-ylfhio)but-2-ynyl 4-fluorobenzoate, 4-(5-(4- Chlorophenyl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl 4-fluorobenzoate, 4-(5-(3- Hydroxynaphthalen-2-yl)- 1 ,3,4-oxadiazol-2-ylthio)but-2-ynyl 4-fluorobenzoate, 4-(5- (Quinolin-5-yl)-l ,3,4-oxadiazol-2-ylthio)but-2-ynyl 4-fluorobenzoate, 4-(5-(lH-indol-2-yl)- l,3,4-oxadiazol-2-ylthio)but-2-ynyl 4-fluorobenzoate, 4-(5-(Naphihalen-l-yl)- 1,3,4- oxadiazol-2-ylthio)but-2-ynyl thiophene-3 -caboxylate, 4-(5-(naphthalen- 1 -yl)- 1 ,3,4- oxadiazol-2-ylthio)but-2-ynyl cyclopropanecarboxylate, 4-(5-(Naphthalen-l -yl)- 1 ,3,4- oxadiazol-2-ylthio)but-2-ynyl cyclobutanecarboxylate, 4-(5-(Naphthalen-l-yl)-l,3,4- oxadiazol-2-ylthio)but-2-ynyl cyclopentanecarboxylate, 4-(5-(Naphthalen-l-yl)-l,3,4- oxadiazol-2-ylthio)but-2-ynyl lH-imidazole-4-carboxylate, 4-(5-(Naphthalen-l-yl)-l,3,4- oxadiazol-2-ylthio)but-2-ynyl benzo[b]thiophene-2-carboxylate, 4-(5-(Naphthalen- 1 -yl)- 1 ,3,4-oxadiazol-2-ylthio)but-2-ynyl benzo[b]thiophene-3-carboxylate, 4-(5 -(naphthalen- 1 - yl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl benzoate, 4-(5-(Naphthalen-l-yl)-l,3,4-oxadiazol-2- yl thio)but-2 -ynyl 3 -fluorobenzoate, 4-(5 -(Naphthalen- 1 -yl) - 1 , 3 ,4- oxadi azol-2-ylthio)but-2- ynyl 3,4-difiuorobenzoate, 4-(5-(Naphthalen-l-yl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl 2- methoxybenzoate, 4-(5-(Naphthalen-l -yl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl 4- (dimethylamino)benzoate, 4-(5-(Naphthalen-l-yl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl 4- (methylsulfonyl) benzoate, 4-(5-(Naphthalen-l-yl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl 4- (trifluoromethoxy) benzoate, 4-(5-(naphthalen-l-yl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl 4- (trifluoromethyl) benzoate, 4-(5-(naphthalen-2-yl)-l,3,4-oxadiazol-2-ylthio)but-2-ynyl 4- fiuorobenzoate, (E)-4-(5-(naphthalen- 1 -yl)- 1 ,3,4-oxadiazol-2-ylthio)but-2-enyl 4- fluorobenzoate, 4-(5-(naphthalen-l-yl)-l,3,4-oxadiazol-2-ylthio)butyl 4-fluorobenzoate, and 4-((5 -(naphthalen- 1 -yl)-l ,3 ,4-oxadiazol-2-ylthio)methyl)benzyl 4-fluorobenzoate.

21. The compound or salt of any of claims 1 -4, wherein Z is Ή or NR⁵.

22. The compound or salt of claim 5 or 21, wherein R³ is a bond or CH₂.

23. The compound or salt of claim 22, wherein R⁴ is a C₆-Cio aryl group.

24. The compound or salt of claim 22, wherein R⁴ is a heterocyclyl group.

25. A compound o f the formula (II) :

(Π)

wherein R⁷ is selected from the group consisting of a C₆-Cso aryl group and a heterocyclyl group, each optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the group consisting of halo, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₃- C₈ cycloalkenyl, C6-C₁₀ aryl, heteroaryl, Ci-C₆ haloalkyl, Ci-C₆ dihaloalkyl, C C₆ trihaloalkyl, -N0₂, -OH, -OR⁵, -SH, -SR⁵, -SOR⁵, -S0₂R⁵, -COR⁵, -COOH, -COOR⁵, -CONHR⁵, and -C0NR⁵R⁶,

X is O or S,

Y is S, NH, or O, R is selected from the group consisting of C]-C₆ alkylene, C₂-C6 alkenylene, C₂-C₆ alkynylene, C₆-Cio arylene, G7-C12 alkylarylene, and C₇-C]₂ dialkylarylene, each optionally substituted with 1, 2, 3, or 4 Ci-C₆ alkyl substituents,

R⁹ is CH₂ or C=0,

R¹⁰ is selected from the group consisting of Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C3-C8 cycloalkyl, C₃-Cg cycloalkenyl, Ce-Qo aryl, heterocyclyl, each optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halo, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C3-C8 cycloalkenyl, C₆-Ci₀ aryl, heteroaryl, Ci-C₆ haloalkyl, C C₆ dihaloalkyl, C_rC₆ trihaloalkyl, -N0₂, -OH, -OR⁵, -NH₂, -NHR⁵, -NR⁵R⁶, - SH, -SR⁵, -SOR⁵, -S0₂R⁵, -COR⁵, -COOH, -COOR⁵, -CO HR⁵, and CONR⁵R⁶, and

R⁵ and R⁶ are independently selected from the group consisting of Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, and C₃-C₈ cycloalkenyl,

or a pharmaceutically acceptable salt thereof.

26. The compound or salt of claim 25, wherein X is O.

27. The compound or salt of claim 25 or 26, wherein Y is S.

28. The compound or salt of any of claims 25-27, wherein R⁹ is C=0.

29. The compound or salt of claim 28, wherein R⁸ is C₂-C₆ alkynylene.

30. The compound or salt of claim 29, wherein R⁸ is but-2-ynylene.

31. The compound or salt of any of claims 28-30, wherein R⁷ is a C₆-Cio aryl group.

32. The compound or salt of claim 31 , wherein R⁷ is 1-naphthyl.

33. The compound or salt of any of claims 28-32, wherein R¹⁰ is a C₆-Cio aryl group optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halo, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl, C₆-Cio aryl, heteroaryl, Ci-C₆ haloalkyl, Ci-C₆ dihaloalkyl, Ci-C₆ trihaloalkyl, -N0₂, -OH, - OR⁵, -NH₂, -NHR⁵, -NR⁵R⁶, -SH, -SR⁵, -SOR⁵, -S0₂R⁵, -COR⁵, -COOH, -COOR⁵,

-CONHR⁵, and -CONR⁵R⁶.

34. The compound or salt of claim 31, wherein R¹⁰ is a phenyl group or naphthyl group, each optionally substituted with one or more substituents selected from the group consisting of halo, d-C₆ alkyl, -OH, -OR⁵, -NH₂, -NHR⁵, and -NR⁵R⁶.

35. The compound or salt of claim 34, wherein the compound is 5 -(5 - (naphthalene- 1 -yl)- 1 , 3 ,4-oxadiaol-2-ylthio)- 1 -phenyl-pent-3 -yne- 1 -one .

36. The compound or salt of any of claims 25-27, wherein R⁹ is CH₂.

37. The compound or salt of claim 36, wherein R^s is C₂-C₆ alkynylene.

38. The compound or salt of claim 37, wherein R is but-2-ynylene.

39. The compound or salt of any of claims 36-38, wherein R⁷ is a C₆-Cio aryl group.

40. The compound or salt of claim 39, wherein R⁷ is 1-naphthyl.

41. The compound or salt of any of claims 36-40, wherein R¹⁰ is a heterocylyl group selected from the group consisting of furanyl, thiopheneyl, pyrrolyl, indolyl, imidazolyl, benzofuranyl, benzodiazolyl, benzoxazolyl, benzthiazolyl, quinolinyl, isoquinolilyl, quinazolinyl, quinoxalinyl, l-oxa-2,4-diazol-3-yl, oxadiazol-2-yl,

l-oxa-2,4-diazol-5-yl, and l-oxa-3,4-diazol-2-yl, wherein the heterocyclyl group is optionally substituted with one or more substituents selected from the group consisting of halo, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl, C₆-Ci₀ aryl, heteroaryl, C C₆ haloalkyl, Ci-C₆ dihaloalkyl, Ci-C₆ trihaloalkyl, -N0₃, -OH, -OR⁵, - H_2} -NHR⁵, -NR⁵R⁶, -SH, -SR⁵, -SOR⁵, -S0₂R⁵, -COR⁵, -COOH, -COOR⁵, -CONHR⁵, and - CONR⁵R⁶.

42. The compound or salt of claim 41 , wherein the compound is selected from the group consisting of Formulas A, B, C, D, E, F, G, and H:

43. A pharmaceutical composition comprising the compound or salt of any of claims 1-42 and a pharmaceutically acceptable carrier.

44. A method for treating or preventing a 15 -lipoxygenase mediated disease or disorder, comprising administering to a mammal in need of treatment a therapeutically effective amount of a compound or salt of any of claims 1-42.

45. The method of claim 44, wherein the 15 -lipoxygenase is human

15 -lipoxygenase- 1.

46. The method according to claims 44 or 45, wherein the 15-lipoxygenase mediated disease or disorder is selected from the group consisting of cancer, inflammatory disorders, atherosclerosis, formation of atherosclerotic plaques, thrombosis, peripheral arterial disease, coagulation syndromes, intermittent claudication, diabetes, vascular restenosis, hypertension, asthma, rheumatoid arthritis, osteoarthritis, and inflammatory bowel disease.

47. A method for treating or preventing cancer in a mammal comprising administering an effective amount of the compound or salt of any of claims 1-42 to a mammal afflicted therewith.

48. The method of claim 47, wherein the cancer is prostate cancer.

49. The method of claim 48, wherein the mammal is a human.

50. A method for treating or preventing Alzheimer's disease in a human comprising administering an effective amount of the compound or salt of any of claims 1-42 to a human afflicted therewith.

51. A compound or salt of any one of claims 1 -42 for treating or preventing cancer.

52. A compound or salt of any one of claims 1 -42 for treating or preventing Alzheimer's disease.

53. A compound or salt of any one of claims 1-42 for treating or preventing a disease or disorder selected from the group consisting of inflammatory disorder,

atherosclerosis, formation of atherosclerotic plaques, thrombosis, peripheral arterial disease, coagulation syndromes, intermittent claudication, diabetes, vascular restenosis, hypertension, asthma, rheumatoid arthritis, osteoarthritis, and inflammatory bowel disease.