Quinolines and quinoxalines for the treatment of darier's disease

Abstract

Provided herein is a method of treating Darier's disease comprising administering to the subject a therapeutically effective amount of a compound represented by Formula (I).

Description

Docket No. 135304-00420QUINOLINES AND QUINOXALINES FOR THE TREATMENT OF DARIER’S DISEASERELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 753,012, filed on February 3, 2025, the entire teachings of which are incorporated herein by reference.FIELD OF THE INVENTION

[0002] Provided herein are methods for treating Darier’s disease. Darier’s disease affects the assembly of desmosomes, which are junctions by which adjacent cells, namely keratinocytes, are attached. The methods herein utilize compounds that, when administered to diseased keratinocytes, significantly increase the adhesion components within the cell for the treatment of Darier’s disease.BACKGROUND OF THE INVENTION

[0003] Darier-White disease (DD), also known as keratosis follicularis is a dominantly inherited skin disorder characterized by warty papules and plagues in seborrheic areas (i.e. central trunk, flexures, scalp, and forehead), palmo-plantar pits, and distinctive nail abnormalities. Burge, S. & Wilkinson, D.J. J. Am. Acad. Dermatol., 1992, 27, 40-50. The prevalence of the disease has been estimated at 1 in 55,000. Further, in some instances, individuals with Darier’s disease have been shown to have elevated frequencies of neuropsychiatric conditions. Gordon-Smith, K. et al. J. Dermatol. 2010, 163, 515-522.

[0004] The severity of the symptoms can vary markedly between individuals. In the most severe cases, the resulting lesions can cause considerable distress to the affected individual. However, typical histological features include focal areas of separation between suprabasal epidermal cells (acantholysis), suprabasal clefting and unusual dyskeratosis (abnormal keratinization) with round dyskeratotic keratinocytes. Electron microscopy of diseased areas reveals loss of desmosomal attachments, perinuclear aggregations of keratin filaments, and cytoplasmic vacuolization. Sakuntabhai, A. et al., 7 . Genet. 1999, 21, 271-277. These observations suggest that the adhesion components between keratinocytes, such as the desmosomal cadherins (desmogleins and desmocollins) and desmosomal plaque proteins (desmoplakin, plakoglobin), or intermediate filament proteins might be involved in the loss of cell-cell adhesion in the epidermis. Burge, S. and Garrod, D.R. Br. J. Dermatol., 1991, 124, 242-251.Docket No. 135304-00420

[0005] There are currently no validated treatments for Darier’s disease. Current practices focus on symptom management and behavioral modifications to avoid triggers that exacerbate the symptoms. In mild cases of the disease, symptoms are largely attenuated by using moisturizers. However, in more severe cases, treatments range from the use topical and oral retinoids, photodynamic therapy, and surgical excision. These treatments have not been shown to be generally effective. Thus, there is a need for novel therapeutic methods and therapeutic agents capable of treating Darier’s disease.SUMMARY OF THE INVENTION

[0006] Compounds disclosed herein demonstrate significant increases in adhesion components in keratinocytes derived from Darier disease patients (See Table 2). Based in part on this finding, disclosed are methods for treating or ameliorating one or more of the symptoms of Darier’s disease in a subject in need thereof.

[0007] One embodiment of the invention is a method of treating a subject with Darier’s disease comprising administering to the subject a therapeutically effective amount comprising administering to the subject a therapeutically effective amount of a compound represented by Formula (I):or a pharmaceutically acceptable salt thereof, wherein:X is =0 or is absent;Yis CH orN;Ar is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl wherein said 6- to 10-membered aryl or 5- to 10-membered heteroaryl are optionally substituted with one or more R2;R1is selected from the group consisting of H, Ci-ealkyl and Ci-ehaloalkyl;each R2is independently selected from the group consisting of halogen, -CN, -NO2, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, andNR2aR2b; andR2aand R2bare each independently hydrogen or Ci-ealkyl.

[0008] Another embodiment of the invention is a compound disclosed herein for use in treating Darier’s disease.Docket No. 135304-00420

[0009] In yet another embodiment, the invention is a compound disclosed herein for use in the manufacture of a medicament for the treatment of Darier’s disease.

[0010] In another embodiment, the invention is a method for increasing cell adhesion components such as integrins, immunoglobulin (Ig) superfamily, cadherins, and / or selectins, within the cells of a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound recited herein, or a pharmaceutically acceptable salt thereof.DETAILED DESCRIPTION1. Methods of the Invention

[0011] Disclosed herein are methods for treating Darier’s disease comprising administering to a subject a therapeutically effective amount of a compound described herein. These compounds demonstrate efficacy in increasing cell adhesion components in isolated keratinocytes derived from patients with Darier’s disease by up to 100%. The methods of the invention are described below.

[0012] A first embodiment of the invention is a method of treating Darier’s Disease in a subject in thereof, comprising administering to the subject a therapeutically effective amount of a compound represented by structural Formula (I), or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for structure Formula (I).

[0013] A second embodiment of the invention is a method according to the first embodiment, wherein the compound is represented by structural Formula (II):"or a pharmaceutically acceptable salt thereof; and the remainder of the variables are as described in the first embodiment.

[0014] A third embodiment of the invention is a method according to the first or second embodiment, wherein the compound is represented by structural Formula (Ila) or (lib) :Docket No. 135304-00420or a pharmaceutically acceptable salt thereof; and the remainder of the variables are as described in the first embodiment.

[0015] A fourth embodiment of the invention is a method according to the first embodiment, wherein the compound is represented by structural Formula (III):or a pharmaceutically acceptable salt thereof; and the remainder of the variables are as described in the first embodiment.

[0016] A fifth embodiment of the invention is a method according to the first or fourth embodiments, wherein the compound is represented by the structural Formula (Illa) or (Illb):or a pharmaceutically acceptable salt thereof; and the remainder of the variables are as described in the first embodiment.

[0017] A sixth embodiment of the invention is a method according to any one of the first through fifth embodiments, wherein R1is selected from a group consisting of hydrogen, Ci-4alkyl, and Ci-4haloalkyl; and the remainder of the variables are as described in the first embodiment.

[0018] A seventh embodiment of the invention is a method according to any one of the first through fifth embodiments, wherein R1is selected from a group consisting of hydrogen and Ci-4alkyl; and the remainder of the variables are as described in the first embodiment.

[0019] An eighth embodiment of the invention is a method according to any one of the first through fifth embodiments, wherein R1is hydrogen or -CH3; and the remainder of the variables are as described in the first embodiment.

[0020] A ninth embodiment of the invention is a method according to any one of the first through eighth embodiments, wherein Ar is phenyl or a 5- to 9-membered heteroaryl, wherein said phenyl and 5- to 9-membered heteroaryl represented by Ar are optionally substituted by one or two R2; and the remainder of the variables are as described in any one of the first or sixth through eighth embodiments.Docket No. 135304-00420

[0021] A tenth embodiment of the invention is a method according to any one of the first through ninth embodiments, wherein Ar is selected from the group consisting of phenyl, thiophenyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, benzothiophenyl, indolyl, pyridyl, pyrimidyl, pyrazinyl, and benzofuranyl, wherein said phenyl, thiophenyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, benzothiophenyl, indolyl, pyridyl, pyrimidyl, pyrazinyl, and benzofuranyl represented by Ar are optionally substituted by one or two R2; and the remainder of the variables are as described in any one of the first or sixth through ninth embodiments.

[0022] A eleventh embodiment of the invention is a method according to any one of the first through tenth embodiments, wherein Ar is selected from the group consisting of phenyl, thiophenyl, benzothiophenyl, pyridyl, and benzofuranyl, wherein said phenyl, thiophenyl, benzothiophenyl, pyridyl, and benzofuranyl represented by Ar are optionally substituted by one or two R2; and the remainder of the variables are as described in any one of the first or sixth through ninth embodiments.

[0023] A twelfth embodiment of the invention is a method according to any one of the first through eleventh embodiments, wherein Ar is selected from the group consisting ofand the remainder of the variables are as described in any one of the first or sixth through ninth embodiments.

[0024] A thirteenth embodiment of the invention is a method according to any one of the first through twelfth embodiments, wherein each R2is independently selected from halogen, -CN, -NO2, Ci-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, andNR2aR2b; and the remainder of the variables are as described in any one of the first or sixth through twelfth embodiments.

[0025] A fourteenth embodiment of the invention is a method according to any one of the first through thirteenth embodiments, wherein each R2is independently selected from halogen,Docket No. 135304-00420Ci-4alkyl, Ci-4alkoxy, and NR2aR2b, wherein R2aand R2bare each independently hydrogen or Ci-4alkyl; and the remainder of the variables are as described in any one of the first or sixth through twelfth embodiments.

[0026] A fifteenth embodiment of the invention is a method according to any one of the first through fourteenth embodiments, wherein each R2is independently selected fromthe remainder of the variables are as described in any one of the first or sixth through twelfth embodiments.

[0027] A sixteenth embodiment of the invention is a method according to any one of the first through fifteenth embodiments, wherein Ar is selected from the group consisting of:and the remainder of the variables are as described in any one of the first or sixth through fifteenth embodiments.

[0028] In another embodiment, the invention is a method according to any one of the previous embodiments, wherein the compound is represented by a compound in Table 1, or a pharmaceutically acceptable salt thereof.Docket No. 135304-00420Table 1. Compounds of the Invention< > <><> <Docket No. 135304-00420<2. Definitions

[0029] To facilitate understanding of the disclosure set forth herein, a number of terms are de fined below.

[0030] Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0031] The term “subject” refers to an animal, including, but not limited to, a primate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and “patient” are used interchangeably herein in reference, for example, to a mammalian subject. In one embodiment, the subject is a human.

[0032] The terms “treat,” “treating,” and “treatment” are meant to include alleviating or attenuating a disorder, disease, or condition, or one or more symptoms of the disorder, disease, or condition; or alleviating or attenuating the cause(s) of the disorder, disease, or condition itself.Docket No. 135304-00420

[0033] The term “therapeutically effective amount” is meant to include the amount of a compound that, when administered, is sufficient to alleviate, at least to some extent, one or more symptoms of the Darier’s disease. “A therapeutically effective amount” of the disclosed compounds or pharmaceutically acceptable salts thereof, is determined by the physician on the basis of the patientspecific parameters, such as age, weight, sex, severity of the disease, etc. The dosage is preferably between 0.0001 mg to 1000 mg / kg body weight.

[0034] Compounds of the present disclosure are generally administered as part of a pharmaceutical compositions, which comprises the compound and a pharmaceutically acceptable carrier or excipient. The term “pharmaceutically acceptable carrier,” “pharmaceutically acceptable excipient,” “physiologically acceptable carrier,” or “physiologically acceptable excipient” refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 7th Edition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2012; Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds., Gower Publishing Company: 2007; and Pharmaceutical Preformulation and Formulation, 2nd Edition, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2009. Exemplary routes of administration and suitable carriers and excipients are disclosed in U.S. Patent no. 11,730,729, the teachings of which are incorporated herein by reference.

[0035] The term “alkyl” refers to a linear or branched saturated monovalent hydrocarbon radical. The term “alkyl” encompasses both linear and branched alkyl. Unless otherwise specified, alkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 10 (Cnio), or 1 to 6 (Ci-6) carbon atoms, or a branched saturated monovalent hydrocarbon radical of 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms), n-propyl, isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl, sec-butyl, t-butyl, pentyl (including all isomeric forms), and hexyl (including all isomeric forms). Alternatively, Ci-6 alkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.Docket No. 135304-00420

[0036] As used herein, the term “alkoxy” refers to the group -OR, in which R is an alkyl, as that term is defined above. Non-limiting examples of alkoxy groups include: -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, or -OC(CH3)3.

[0037] The terms “haloalkyl” and “haloalkoxy” means alkyl or alkoxy, as the case may be, substituted with one or more halogen atoms. Examples of haloalkyl, include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl and the like. In certain aspects, the haloalkyl or haloalkoxy is represented by a fluoroalkyl or fluoroalkoxy. In other aspects, the haloalkyl or haloalkoxy is represented by a perfluoroalkyl or perfluoroalkoxy.

[0038] The term “aryl” refers to a monocyclic aromatic group and / or multi cyclic monovalent aromatic group that contain at least one aromatic hydrocarbon ring. In certain embodiments, the aryl has from 6 to 10 (Ce-io) ring atoms. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. In certain embodiments, the aryl is optionally substituted with one or more substituents R2as described herein.

[0039] The term “heteroaryl” refers to a monovalent monocyclic aromatic group or monovalent polycyclic aromatic group that contain one or two aromatic rings, wherein at least one aromatic ring contains one or more heteroatoms, each of which is independently selected from O, S, and N, in the ring. A heteroaryl group is bonded to the rest of a molecule through either ring. Each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms and / or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. In certain embodiments, the heteroaryl has from 5 to 10 ring atoms. Examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, thiazolyl, and thienyl. Examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothienyl, benzoxazolyl, indolyl, isoquinolinyl, naphthyridinyl, quinolinyl, quinoxalinyl, and quinazolinyl. In certain embodiments, the heteroaryl is optionally substituted with one or more substituents groups represented by R2, as described herein.

[0040] The term “halogen”, “halide” or “halo” refers to fluorine, chlorine, bromine, and / or iodine.

[0041] As used herein, many moieties (e.g., alkyl, aryl, or heteroaryl) are referred to as being either “substituted” or “optionally substituted.” When a moiety is modified by one of these terms, unless otherwise noted, it denotes that any portion of the moiety that is known to one skilled in the art as being available for substitution can be substituted, which includes one orDocket No. 135304-00420more substituents. Where if more than one substituent is present, then each substituent may be independently selected. Such means for substitution are well-known in the art and / or taught by the instant invention. The optional substituents can be any substituents that are suitable to attach to the moiety.

[0042] When a compound provided herein contains an acidic or basic moiety, it may also be provided as a pharmaceutically acceptable salt See, Berge et al., J. Pharm. Sci. 1977, 66, 1-19; and “Handbook of Pharmaceutical Salts, Properties, and Use,” Stahl and Wermuth, Ed.; Wiley-VCH and VHCA, Zurich, 2002).

[0043] Suitable acids for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(15)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-l,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, a-oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-l,5-disulfonic acid, 1 -hydroxy -2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, -toluenesulfonic acid, undecylenic acid, and valeric acid.

[0044] Suitable bases for use in the preparation of pharmaceutically acceptable salts, include, but are not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; and organic bases, such as primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including, but not limited to, L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine, U / -imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, l-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, secondary amines,Docket No. 135304-00420triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)- 1,3 -propanediol, and tromethamine.

[0045] The compounds provided herein can be prepared, isolated, or obtained by any methods known to one of skill in the art, and the following examples are only representative and do not exclude other related procedures.

[0046] “Cell adhesion”, as described herein, is the process by which cells interact and attach to neighboring cells through specialized molecules of the cell surface. This process can occur either through direct contact between cell surfaces such as cell junctions or indirect interaction, where cells attach to surrounding extracellular matrix, a gel-like structure containing molecules released by cells into spaces between them. Cells adhesion occurs from the interactions between cell adhesion components (COMs), transmembrane proteins located on the cell surface. COMs are classified into four major families: integrins, immunoglobulin (Ig) superfamily, cadherins, and selectins. Cadherins and IgSF are homophilic COMs, as they directly bind to the same type of COMs on another cell, while integrins and selectins are heterophilic COMs that bind to different types of CAMs. Each of these adhesion molecules has a different function and recognizes different ligands. Defects in cell adhesion are usually attributable to defects in expression of COMs.Docket No. 135304-00420EXEMPLIFICATION1. Definitions

[0047] The disclosure will be further understood by the following non-limiting examples.

[0048] As used herein, the symbols and conventions used in these processes, schemes and examples, regardless of whether a particular abbreviation is specifically defined, are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Specifically, but without limitation, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams); mL (milliliters); pL (microliters); M (molar); mM (millimolar); pM (micromolar); mol (moles); mmol (millimoles); hr or hrs (hour or hours); and min (minutes).

[0049] For all of the following examples, standard procedures and methods known to those skilled in the art can be utilized. Unless otherwise indicated, all temperatures are expressed in °C (degrees Centigrade). All procedures are conducted at room temperature unless otherwise noted.2. Biological AssaysAdhesion Components Assay

[0050] Isolated keratinocytes derived from Darier disease patients were maintained on media consisting of Dulbecco’s modified eagle medium (DMEM) with fetal bovine serum (FBS). The cells were transferred to glass bottomed 96-well plates and media was replaced with a low calcium, serum-free Ml 54 media containing growth factor cocktails. To initiate formation of intermolecular adhesion proteins and junction components, the CaCb concentration was increased from 0.05 mM to 1.2 mM and incubated in the high calcium solution for 1-4 hrs. At this time, 10 pM of test compound or vehicle was added. After fixation, cultures were immunostained for desmosomal adhesion markers using standard primary antibodies against adherens junction markers such as E-cadherin. Subsequently, image acquisition was achieved with a Zeiss apotome-equipped microscope enabling collection of multiple fields per condition at a range of z-planes to guarantee capture of nascent adhesions. To analyze and quantify accumulation of adhesion plaque components at cell junctions the published cell segmentation program, CellPose was utilized. This program identifies boundaries of cells and yields an adhesion stain index correlated to the fluorescenceDocket No. 135304-00420intensity. Untreated patient DD keratinocytes generally have a 40%-50 % reduction in adhesion components when compared to normal keratinocytes. The adhesion stain intensity of vehicle-treated DD cells was compared to that of cells treated with 10 pM of compound with the results summarized in Table 1. Regarding the increase in intercellular adhesions in Table 1, A represents an increase of 0%-25%, B represents an increase of 26%-50%, C represents an increase of 51%— 75%, and D represents an increase of 76%-100%.Table 2. Results of Adhesion Component Assay3. Synthesis of Compounds

[0051] Compounds 1-16 disclosed herein have been previously reported in International Publication No. WO 2022 / 020261, U.S. Publication No. US 2021 / 269404, and U.S. Patent No. 10,730,843 Bl, each of which are incorporated herein by reference.

Claims

Docket No. 135304-00420CLAIMSWe claim:

1. A method of treating a subject with Darier’s disease comprising administering to the subject a therapeutically effective amount of a compound represented by Formula (I):or a pharmaceutically acceptable salt thereof, wherein:X is =0 or is absent;Y is CH orN;Ar is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl wherein said 6- to 10-membered aryl or 5- to 10-membered heteroaryl are optionally substituted with one or more R2;R1is selected from the group consisting of H, Ci-ealkyl and Ci-ehaloalkyl; each R2is independently selected from the group consisting of halogen, -CN, -NO2, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, and Cnehaloalkoxy, andNR2aR2b; andR2aand R2bare each independently hydrogen or Ci-ealkyl.

2. The method of claim 1, wherein the compound is represented by Formula (II):or a pharmaceutically acceptable salt thereof.

3. The method of claim 1 or claim 2, wherein the compound is represented by Formula (Ila) or (lib) :Docket No. 135304-004204. The method of claim 1, wherein the compound is represented by Formula (III):or a pharmaceutically acceptable salt thereof..

5. The method of claim 1 or claim 4, wherein the compound is represented by Formula (Illa) or (Rib):or a pharmaceutically acceptable salt thereof.

6. The method of any one of claims 1-5, wherein R1is selected from a group consisting of hydrogen, Ci-4alkyl, and Ci-4haloalkyl.

7. The method of any one of claims 1-6, wherein R1is selected from a group consisting of hydrogen and Ci-4alkyl.

8. The method of any one of claims 1-7, wherein R1is hydrogen or -CH3.

9. The method of any one of claims 1-8, wherein Ar is phenyl or a 5- to 9-membered heteroaryl, wherein said phenyl and 5- to 9-membered heteroaryl represented by Ar are optionally substituted by one or two R2.

10. The method of any one of claims 1-9, wherein Ar is selected from the group consisting of phenyl, thiophenyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, benzothiophenyl, indolyl, pyridyl, pyrimidyl, pyrazinyl, and benzofuranyl, wherein said phenyl, thiophenyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, benzothiophenyl, indolyl, pyridyl, pyrimidyl, pyrazinyl, and benzofuranyl represented by Ar are optionally substituted by one or two R2.Docket No. 135304-0042011. The method of any one of claims 1-10, wherein Ar is selected from the group consisting of phenyl, thiophenyl, benzothiophenyl, pyridyl, and benzofuranyl, wherein said phenyl, thiophenyl, benzothiophenyl, pyridyl, and benzofuranyl represented by Ar are optionally substituted by one or two R2.

12. The method of any one of claims 1-11, wherein Ar is selected from the group consisting of13. The method of any one of claims 1-12, wherein each R2is independently selected from the group consisting of halogen, -CN, -NO2, Ci-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, and NR2aR2b.

14. The method of any one of claims 1-13, wherein each R2is independently selected from the group consisting of halogen, Ci-4alkyl, Ci-4alkoxy, and NR2aR2b, wherein R2aand R2bare each independently hydrogen or Ci-4alkyl.

15. The method of any one of claims 1-14, wherein each R2is independently selectedfrom the group consisting of -Cl, -Br, -CH3, -OCH3, -N(CH3)2, -NHCH(CH3)2 and16. The method of any one of claims 1-15, wherein Ar is selected from the group consisting of:Docket No. 135304-0042017. The method of any one of claims 1-16, wherein the compound is represented by a compound in Table 1, or a pharmaceutically acceptable salt thereof.

18. A method for increasing cell adhesion components such as integrins, immunoglobulin (Ig) superfamily, cadherins, and / or selectins, within the cells of a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound recited in any one of claims 1-17, or a pharmaceutically acceptable salt thereof.

Images