WO2023287740A1 - Compounds and methods for treating autoimmune disorders by targeting hla-dq2 - Google Patents

Compounds and methods for treating autoimmune disorders by targeting hla-dq2 Download PDF

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WO2023287740A1
WO2023287740A1 PCT/US2022/036755 US2022036755W WO2023287740A1 WO 2023287740 A1 WO2023287740 A1 WO 2023287740A1 US 2022036755 W US2022036755 W US 2022036755W WO 2023287740 A1 WO2023287740 A1 WO 2023287740A1
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piperazinyl
acetyl
phenyl
propanone
butanone
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PCT/US2022/036755
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French (fr)
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Robert B. Perni
Ryan SCHUTTE
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Immunomolecular Therapeutics, Inc.
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Publication of WO2023287740A1 publication Critical patent/WO2023287740A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • TECHNICAL FIELD The invention relates to the use of small organic molecules in the prevention or treatment of autoimmune diseases, such as Celiac disease and Type 1 Diabetes.
  • BACKGROUND Autoimmune disorders are diseases caused by the body producing an inappropriate immune response against its’ own tissues, in which the immune system, T lymphocytes and autoantibodies, attack one’s own cells, tissues, and/or organs.
  • HLA human leukocyte antigen
  • the HLA complex is divided into three regions: class I, II, and III. Alleles of the class II genes, DQ and DR (and to a lesser extent DP), are the most important determinants for developing an autoimmune disease.
  • the HLA class II genes are polymorphic and encode major histocompatibility complex (MHC) II proteins. These MHC class II molecules are expressed on antigen presenting cells (e.g., B cells, dendritic cells, and macrophages) and function to present antigens to CD4 T-cells.
  • MHC major histocompatibility complex
  • Celiac disease is one of the most common autoimmune disorders, with a reported prevalence of 0.5–1% of the general population, with the exception of areas showing low frequency of celiac disease-predisposing genes and low gluten consumption (e.g., sub- Saharan Africa and Japan). Studies have shown that most celiac disease cases remain undetected in the absence of serological screening due to heterogeneous symptoms and/or poor disease awareness. Celiac disease prevalence is increasing in Western countries.
  • celiac disease prevalence increased 5-fold in the US, for reasons that are currently unknown.
  • the prevalence of celiac disease is higher in first- degree celiac disease relatives (10–15%) and in other at-risk groups, particularly patients with Down syndrome, type 1 diabetes, or IgA deficiency.
  • Celiac disease is diagnosed more frequently in women with a female-to-male ratio ranging from 2:1 to 3:1.
  • the disease can occur at any age from early childhood to the elderly, with two peaks of onset – one shortly after weaning with gluten in the first 2 years of life, and the other in the second or third decades of life.
  • the diagnosis of celiac disease can be challenging because symptoms can vary significantly from patient to patient.
  • Celiac disease is a unique autoimmune disease in that its key genetic elements (human leukocyte antigen (HLA)-DQ2 and HLA-DQ8), the auto-antigen involved (tissue transglutaminase (tTG)), and the environmental trigger (gluten) are all well-defined.
  • HLA human leukocyte antigen
  • tTG tissue transglutaminase
  • gluten environmental trigger
  • DQ2.5cis DQA1*05:01- DQB1*02:01
  • DQ2.5trans present with the genotype of DQA1*02:01-DQB1*02:02 + DQA1*05:05-DQB1*03:01
  • DQ2.2 DQA1*02:01-DQB1*02:02
  • DQ2.3 DQA1*03:01-DQB1*02:01
  • DQ8 DQA1*03:01-DQB1*03:02 is the other risk allele for celiac disease.
  • Gliadin one of the two principle protein components of gluten, contains a number of well-studied T cell epitopes. Deamidation of gliadin peptides by tissue transglutaminase (TTG) type 2 converts glutamine into glutamic acid, resulting in immunogenic T cell epitopes.
  • TTG tissue transglutaminase
  • a major drawback in celiac disease research has been the lack of a reliable and reproducible animal model, with the possible exception of the Irish setter dog, which may develop a gluten-related disease. Nevertheless, new technologies pertinent to human gut biology and immunology are opening unprecedented opportunities for major research breakthroughs.
  • celiac disease has a strong hereditary component as evidenced by its high familial recurrence (10–15%) and the high concordance of the disease among monozygotic twins (75–80%). Also common to other autoimmune diseases is the relevant role of HLA class II heterodimers, specifically DQ2 and DQ8, in the heritability of celiac disease. HLA-DQ2 homozygosis confers a much higher risk (25–30%) of developing early-onset celiac disease in infants with a first-degree family member affected by the disease.
  • Type 1 diabetes the immune mediated form of diabetes, is a chronic autoimmune disorder resulting in the destruction of insulin-producing beta cells within the pancreatic islets requiring lifelong daily insulin treatment.
  • Autoantibodies directed toward insulin (IAA) and beta cell-specific antigens, glutamic acid decarboxylase 65 (GAD65), insulinoma-associated antigen 2 (IA-2) and zinc transporter 8 (ZnT8) are considered diagnostic and predictive of T1D.
  • IAA insulin
  • GAD65 glutamic acid decarboxylase 65
  • IA-2 insulinoma-associated antigen 2
  • ZnT8 zinc transporter 8
  • the prevalence of CD ranges from 1% to 10% in patients with T1D, compared with 1% in the general population. In most subjects, the onset of T1D precedes the diagnosis of CD or the two diseases are diagnosed simultaneously.
  • Shared susceptibility genes in the HLA region contribute to the coexistence of T1D and CD with HLA-DR3-DQ2 and HLA-DR4-DQ8 haplotypes being the strongest genetic risk factors for T1D and CD.
  • the DR3-DQ2 haplotype is found in about 90% of CD and 55% of T1D patients.
  • the co-occurrence of T1D and CD is highly associated with the high-risk genotypes DR3-DQ2/DR3-DQ2 and DR3- DQ2/DR4-DQ8.
  • Stiff-person syndrome is a rare neurological disorder characterized by fluctuating muscle rigidity in the trunk and limbs and a heightened sensitivity to stimuli such as noise, touch, and emotional distress, which can set off muscle spasms. Abnormal postures, often hunched over and stiffened, are characteristic of the disorder, and people with SPS can be too disabled to walk or move. SPS affects twice as many women as men and is frequently associated with other autoimmune diseases such as diabetes, thyroiditis, vitiligo, and pernicious anemia.
  • SPS Spasmodic spasmodic spasmodic spasmodic spasmodic spasmodic spasmodic spasmodic spasmodic spasmodic spasmodic spasmodic spasmodic spasmodic spasmodic spasmodic spasmodic spasmodic spasmodic spasmodic spasmodic spasmodic sin.
  • GAD glutamic acid decarboxylase
  • SPS patients respond to high doses of diazepam and anti-convulsants, gabapentin, tiagabine, and intravenous immunoglobulin (IVIg) treatment has been shown to reduce stiffness and lower sensitivity to noise, touch, and stress.
  • Addison’s disease is a disorder that occurs when the adrenal glands don’t make enough cortisol and aldosterone, resulting in fatigue, muscle weakness, loss of appetite, weight loss, dehydration, hypotension, and abdominal pain.
  • the primary cause of Addison’s disease is an autoimmune disorder this is treated by replacing these hormones as well as high-sodium diets, and calcium and vitamin D supplementation.
  • Schmidt syndrome refers to the combination of autoimmune adrenal insufficiency (Addison’s disease) with autoimmune hypothyroidism and/or type 1 diabetes mellitus (T1DM) and is part of a larger syndrome known as autoimmune polyendocrine syndrome type II or polyglandular autoimmune syndrome type II (PAS II; the term Schmidt syndrome is used interchangeably with PAS II).
  • Schmidt Syndrome is a rare disorder with a prevalence of 1:20,000 in the general population, with 3:1 ratio of females to males affected, with peak incidence in the 3rd - 4th decade of life.
  • Diagnosis and treatment of Schmidt syndrome is the same as the underlying disorders (i.e., diagnosis and treatment of Addison’s disease, autoimmune hypothyroidism, and/or T1DM).
  • diagnosis and treatment of Addison’s disease i.e., diagnosis and treatment of Addison’s disease, autoimmune hypothyroidism, and/or T1DM.
  • T1DM ⁇ 1% of patients have Addison’s disease, whereas 2-5% have autoimmune thyroid disease (mainly hypothyroidism) and up to 5% have celiac disease. Up to 33% may have thyroid autoantibodies and 12% have transglutaminase autoantibodies.
  • the DR3-DQ2/DR4DQ8 is recognized as a susceptibility genotype in Schmidt syndrome patients that have type 1 diabetes and autoimmune thyroid disease but without Addison's disease.
  • Myasthenia gravis (MG) is an autoimmune disorder of the nervous system that affects the neuromuscular junctions, leading to muscle weakness and fatigue that worsens after periods of activity and improves after periods of rest. Antibodies against the acetylcholine receptor are detected in the majority (85-90%) of MG patients and are highly specific and pathogenic. MG affects both men and women and occurs across all racial and ethnic groups.
  • MHC Allele associations with MG seem to differ from population to population, and their contribution to the pathogenesis remains unclear, but human genotyping studies of MG patients has associated MG with HLA-DRB1*09, HLA-DRB1*14, DRB1*15, and HLA- DQB1*02 (DQ2) alleles.
  • the present invention provides compounds that can be used to prevent or reduce T cell activation through the presentation of antigens that bind MHC class II molecules on the surface of antigen presenting cells, as well as therapeutic uses of a compound of the invention and pharmaceutical compositions comprising a compound of the invention to prevent or slow the formation of autoimmune diseases in an individual.
  • Blocking allele-specific MHC class II antigen presentation by inhibiting DQ2- mediated T cell responses has been identified as a target for treating celiac disease.
  • DQ2 confers significant disease risk by presenting epitopes of antigens (for example, gluten and/or insulin antigens, or fragments or antigenic components thereof) to effector CD4+ T cells.
  • antigens for example, gluten and/or insulin antigens, or fragments or antigenic components thereof
  • Gliadins key components of gluten, are complex proteins unusually rich in prolines and glutamines and are not completely digestible by intestinal enzymes. Partial digestion of gliadins results in a mix of peptides that can trigger host responses (increased gut permeability and innate and adaptive immune response).
  • the compounds of the invention block or reduce gliadin peptide presentation to T cells. Without intending to be bound by theory, it is believed that the compounds disclosed herein occupy a pocket along the DQ2 peptide binding groove, thereby blocking major histocompatibility complex class II HLA-DQ2/8-antigen restricted T cells responses in vitro and inhibiting DQ2/8-antigen presentation in vivo. Blocking HLA-DQ2 antigen presentation in this way may decrease autoimmune T cell activation thereby preventing and/or treating and/or slowing the development of autoimmune disorders.
  • Ar 1 is optionally substituted aryl or optionally substituted heteroaryl
  • X is O, S, S(O), S(O) 2 , or NR
  • R 1 is optionally substituted C 1 -C 8 -alkyl
  • the present further provides methods of treating or slowing the progression or development of an autoimmune disease in a subject suffering from, or at risk of developing, the autoimmune disease, comprising administering the subject a therapeutically effective amount of one or more compounds of the invention.
  • the autoimmune disease can be, for example, celiac disease, type 1 diabetes (T1D), Stiff- person Syndrome (SPS), Addison’s disease (AD), Schmidt Syndrome (SS), or Myasthenia Gravis (MG).
  • the present invention further provides pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier or excipient.
  • These compounds of the invention are believed to inhibit the binding of an antigenic peptide to the DQ2 MHC class II molecule for presentation to CD4+ T cells and are useful for slowing the development or progression of an autoimmune disease.
  • the inhibition of the binding of an antigenic peptide to a DQ2 MHC class II molecule may result from a distortion of the spatial orientation of the complex so that the DQ2 MHC class II molecule-antigen complex is not properly presented to T cells, such that the trimolecular complex between 1) the MHC class II molecule on the surface of an antigen presenting cell, 2) the antigenic peptide, and 3) the CD4+ T cell, is not formed.
  • the invention provides a method of treating an autoimmune disease in a subject, including selecting a subject for treatment with one or more compounds of the invention on the basis of the subject having at least one of the diagnostic criteria of the autoimmune disease.
  • diagnostic criteria may include, for celiac disease, mucosal changes detected by duodenal biopsy and positivity of serological tests (anti-transglutaminase antibodies (tTG), anti-endomysium antibodies (EmA), and/or deamidated gliadin peptide (DGP) antibodies).
  • such diagnostic criteria may include the detection of autoantibodies directed toward insulin (IAA) and beta cell-specific antigens, glutamic acid decarboxylase 65 (GAD65), insulinoma-associated antigen 2 (IA- 2) and zinc transporter 8 (ZnT8), and/or a previous diagnosis of celiac disease.
  • IAA insulin
  • beta cell-specific antigens glutamic acid decarboxylase 65
  • IA- 2 insulinoma-associated antigen 2
  • ZnT8 zinc transporter 8
  • diagnostic criteria may include the detection of autoantibodies directed toward glutamic acid decarboxylase (GAD).
  • Addison’s disease such diagnostic criteria may include the finding of low blood levels of sodium or high levels of potassium, positive ACTH stimulation test, insulin-induced hypoglycemia test, and/or x- ray examination.
  • diagnostic criteria may include the diagnosis of two or more of Addison’s disease, autoimmune hypothyroidism, and/or T1DM.
  • diagnostic criteria may include detection of autoantibodies directed toward the acetylcholine receptor. Upon detection of one or more of these criteria diagnostic of a specific autoimmune disease, the subject is selectively administered a compound of the invention.
  • the subject has been tested for the presence of antibodies directed to an antigen selected from a gliadin peptide, insulin (IAA), a beta cell-specific antigen, glutamic acid decarboxylase (GAD), insulinoma-associated antigen 2 (IA-2), zinc transporter 8 (ZnT8), and the acetylcholine receptor, wherein the presence of such antibodies in the subject is indicative of the presence or likely development of an autoimmune disease.
  • an antigen selected from a gliadin peptide, insulin (IAA), a beta cell-specific antigen, glutamic acid decarboxylase (GAD), insulinoma-associated antigen 2 (IA-2), zinc transporter 8 (ZnT8), and the acetylcholine receptor
  • Another aspect of the invention provides methods of monitoring and adjusting the dosage of a compound of the invention administered to a subject suffering from, or at risk of developing, an autoimmune disease, including receiving a blood sample from a subject suffering from, or at risk of developing, the autoimmune disease who has been administered a compound of the invention and determining the DQ2-stimulated response of ICD4+ T cells in the blood sample.
  • the DQ2-stimulated response of CD4+ T cells in the blood sample is compared to a control level of DQ2-stimulated response of CD4+ T cells in blood samples from at least one of a patient suffering from the autoimmune disease and a control or ‘wild type’ subject known to be free of the autoimmune disease.
  • the dosage and/or the frequency of the compound of the invention administered to the subject is increased if the DQ2-stimulated response of CD4+ T cells in the blood sample from the subject is statistically similar to the DQ2-stimulated response of CD4+ T cells from the baseline level in the celiac disease patient.
  • the present invention relates to compounds of Formula (I) and methods of use thereof for treating or slowing the progression or development of an autoimmune disease.
  • the invention provides compounds of Formula (I), as described above, and pharmaceutically acceptable salts thereof.
  • the compounds of Formula (I) do not include one or more of the compounds set forth below.
  • Ar 1 is optionally substituted phenyl, optionally substituted naphthyl or optionally substituted 6,6- or 5,6- fused bicyclic heteroaryl, such as optionally substituted quinolyl or indolyl. In certain embodiments of the compounds of Formula (I), Ar 1 is optionally substituted phenyl, optionally substituted 2-naphthyl, optionally substituted 3-indolyl or optionally substituted 3-quinolyl.
  • Ar 1 is where R a , R b , R c , R d and R e are each independently H, optionally substituted C 1 -C 6 -alkyl, halo, R 6 O-, R 6 S-, R 6 C(O)-, R 7 OC(O)-, optionally substituted C 3 -C 8 -cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; alternatively, Ra and Rb or Rb and Rc, together with the carbon atoms to which they are attached, form an optionally substituted carbocyclic or heterocyclic; R 6 is optionally substituted C 1 -C 6 -alkyl, optionally substituted C 3 -C 8 -cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; and R 7 is H or optional
  • R b and R c together form –O-(CH 2 ) p -O-, where p is 1 or 2.
  • each of Ra, Rd and Re is preferably H.
  • Ra, Rb, Rc, Rd and Re are independently selected from H, optionally substituted C 1 -C 6 -alkyl, R 6 C(O)-, R 7 OC(O)-, optionally substituted aryl and optionally substituted heteroaryl.
  • at least two of R a , R b , R c , R d and R e are hydrogen.
  • R 1 is aryl, preferably phenyl, and is unsubstituted or substituted with 1 to 5 substituents.
  • the substituents are preferably independently selected from halo, C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkyl-S-, halo-C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkyl-S-, and (C 1 -C 4 -alkyl) 2 N-.
  • the substituents are independently selected from methyl, ethyl, CF 3 , chloro, fluoro, methoxy, ethoxy, trifluoromethoxy and dimethylamino.
  • R 1 is phenyl substituted with one methyl and one halogen, preferably chloro or fluoro.
  • R1 is selected from phenyl, 2-methylphenyl, 4-fluorophenyl, 2-chloro-4-methylphenyl, 2- chloro-3-methylphenyl, 3-chloro-4-methylphenyl, 3-chloro-5-methylphenyl, 3-methyl-4- chlorophenyl, 2-methyl-4-chlorophenyl, 2-methyl-3-chlorophenyl, 2-fluoro-4- methylphenyl, 2-fluoro-3-methylphenyl, 3-fluoro-4-methylphenyl, 3-fluoro-5- methylphenyl, 3-methyl-4-fluorophenyl, 2-methyl-4-fluorophenyl, and 2-methyl-3- fluorophenyl.
  • R 1 is heteroaryl, preferably a 5- or 6-membered heteroaryl, such as furanyl, oxazolyl, or thiadiazolyl, and is unsubstituted or substituted with 1 to 3 substituents preferably selected from halo, C 1 -C 6 - alkyl, halo-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkyl-S-, halo-C 1 -C 6 -alkoxy, halo-C 1 -C 6 - alkyl-S-, and (C 1 -C 4 -alkyl) 2 N-.
  • substituents preferably selected from halo, C 1 -C 6 - alkyl, halo-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkyl-S-, halo-C 1 -C 6
  • R 1 is C 3 -C 8 -cycloalkyl or 3- to 8-membered heterocycloalkyl and is unsubstituted or substituted with 1 to 3 substituents preferably selected from halo, C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkyl-S-, halo-C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkyl-S-, and (C 1 -C 4 -alkyl) 2 N-.
  • the substituents are independently selected from methyl, ethyl, CF 3 , chloro, fluoro, methoxy, ethoxy, trifluoromethoxy and dimethylamino.
  • R 1 is C 3 -C 8 -cycloalkyl, preferably C 4 -C 8 -cycloalkyl, and more preferably cyclopentyl, cyclohexyl or cycloheptyl.
  • X is O, S, SO, SO 2 or NR, where R is hydrogen or methyl.
  • X is O or S.
  • n is 1 and B is - CH 2 CH 2 -.
  • the compound of Formula (I) is represented by Formula (II), or a pharmaceutically acceptable salt thereof, where m is 0, 1 or 2, and X and R 1 are as defined above.
  • X is O or S.
  • the compound of Formula (I) is represented by Formula (III), or a pharmaceutically acceptable salt thereof, where X, Ar 1 and R 1 are as defined above.
  • X is O or S.
  • the compound of the invention is selected from the compounds 1-68 set forth below and pharmaceutically acceptable salts thereof. 7 12 17 22 37
  • Protected derivatives of the compounds of the invention also are contemplated. In general, protecting groups are removed under conditions which will not affect the remaining portion of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis, and the like.
  • One preferred method involves the removal of an ester, such as cleavage of a phosphonate ester using Lewis acidic conditions, such as in TMS-Br mediated ester cleavage to yield the free phosphonate.
  • a second preferred method involves removal of a protecting group, such as removal of a benzyl group by hydrogenolysis utilizing palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like or mixtures thereof.
  • a t-butoxy-based group, including t- butoxy carbonyl protecting groups can be removed utilizing an inorganic or organic acid, such as HCl or trifluoroacetic acid, in a suitable solvent system, such as water, dioxane and/or methylene chloride.
  • Another exemplary protecting group, suitable for protecting amino and hydroxy functions amino is trityl.
  • Other conventional protecting groups are known, and suitable protecting groups can be selected by those of skill in the art in consultation with Greene and Wuts, Protective Groups in Organic Synthesis; 3rd Ed.; John Wiley & Sons, New York, 1999.
  • an acid moiety such as a phosphonic acid moiety
  • the compound may be isolated as the acid compound or as a salt thereof.
  • the compounds of each formula herein are defined to include isotopically labelled compounds.
  • an “isotopically labelled compound” is a compound in which at least one atomic position is enriched in a specific isotope of the designated element to a level which is significantly greater than the natural abundance of that isotope.
  • one or more hydrogen atom positions in a compound can be enriched with deuterium to a level which is significantly greater than the natural abundance of deuterium, for example, enrichment to a level of at least 1%, preferably at least 20% or at least 50%.
  • Such a deuterated compound may, for example, be metabolized more slowly than its non-deuterated analog, and therefore exhibit a longer half-life when administered to a subject.
  • Such compounds can be synthesized using methods known in the art, for example by employing deuterated starting materials.
  • administering should be understood to mean providing a compound or agent, a prodrug of a compound or agent, or a pharmaceutical composition as described herein.
  • the compound, agent or composition can be administered by another person to the subject (e.g., intravenously) or it can be self- administered by the subject (e.g., tablets or capsules).
  • solvate refers to a solid crystalline form of a compound which includes molecules of a solvent within the crystal lattice. Suitable solvates include those with pharmaceutically acceptable solvents, such as ethanolates and hydrates, including monohydrates and hemi-hydrates.
  • gluten peptide or “gliadin peptide” is used to denote a peptide fragment of a gluten protein.
  • a gluten peptide may contain the entire amino acid sequence of a naturally occurring gluten protein.
  • the terms “individual” and “subject” are used interchangeably herein and refer to an animal, such as a mammal, including a non-primate (e.g., a cow, pig, horse, cat, dog, rat, and mouse), a nonhuman primate (e.g., a monkey such as a cynomolgus monkey, a chimpanzee), and a human.
  • the subject is refractory or non- responsive to current treatments for an autoimmune disease, such as celiac disease, T1D, SPS, AD, SS, and MG.
  • tissue means any biological sample taken from any individual, preferably a human. Tissues include blood, saliva, urine, biopsy samples, skin or buccal scrapings, and hair. Persons of skill in the art will appreciate that blood plasma drug concentrations obtained from individual subjects will vary due to inter-patient variability in the many parameters affecting drug absorption, distribution, metabolism, and excretion. For this reason, unless otherwise indicated, when a drug plasma concentration is listed, the value listed is the calculated mean value based on values obtained from a group of subjects tested.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 2-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid.
  • nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentane-propionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.
  • the term “therapeutically-effective amount” of compounds of the invention means an amount effective to modulate the formation or progression of autoimmune diseases celiac disease in an individual.
  • aryl refers to a mono- or polycyclic carbocyclic ring system comprising at least one aromatic ring, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, and indenyl.
  • a polycyclic aryl is a polycyclic ring system that comprises at least one aromatic ring.
  • Polycyclic aryls can comprise fused rings, covalently attached rings or a combination thereof.
  • heteroaryl refers to a mono- or polycyclic aromatic radical having one or more ring atom selected from S, O and N; and the remaining ring atoms are carbon, wherein any N or S contained within the ring may be optionally oxidized.
  • Heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, quinoxalinyl.
  • a polycyclic heteroaryl can comprise fused rings, covalently attached rings or a combination thereof. In accordance with the invention, aromatic groups can be substituted or unsubstituted.
  • alkyl refers to saturated, straight- or branched-chain hydrocarbon radicals.
  • exemplary alkyl groups include "C 1 -C 4 alkyl,” “C 1 -C 6 alkyl,” “C 1 -C 8 alkyl,” “C 1- C 12 alkyl,” “C 2 -C 4 alkyl,” or “C 3 -C 6 alkyl,” which refer to alkyl groups containing from one to four, one to six, one to eight, one to twelve, 2 to 4 and 3 to 6 carbon atoms respectively.
  • C 1- C 8 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl and octyl radicals.
  • alkenyl refers to straight- or branched-chain hydrocarbon radicals having at least one carbon-carbon double bond by the removal of a single hydrogen atom.
  • alkenyl groups include “C 2 -C 8 alkenyl,” “C 2 -C 12 alkenyl,” “C 2 -C 4 alkenyl,” “C 3 -C 4 alkenyl,” or “C 3 -C 6 alkenyl,” which refer to alkenyl groups containing from two to eight, two to twelve, two to four, three to four or three to six carbon atoms respectively.
  • Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 2-methyl-2-buten-2-yl, heptenyl, octenyl, and the like.
  • alkynyl refers to straight- or branched-chain hydrocarbon radicals having at least one carbon-carbon triple bond by the removal of a single hydrogen atom.
  • exemplary alkynyl groups include “C 2 -C 8 alkynyl,” “C 2 -C 12 alkynyl,” “C 2 -C 4 alkynyl,” “C 3 -C 4 alkynyl,” or “C 3 -C 6 alkynyl,” which refer to alkynyl groups containing from two to eight, two to twelve, two to four, three to four or three to six carbon atoms respectively.
  • alkynyl groups include, but are not limited to, for example, ethynyl, 2-propynyl, 2-butynyl, heptynyl, octynyl, and the like.
  • cycloalkyl refers to a monocyclic or polycyclic saturated carbocyclic ring or a bi- or tri-cyclic group fused, bridged or spiro system, and the carbon atoms may be optionally oxo-substituted or optionally substituted with exocyclic olefinic double bond.
  • Preferred cycloalkyl groups include C 3 -C 12 cycloalkyl, C 3 - C 6 cycloalkyl, C 3 -C 8 cycloalkyl and C 4 -C 7 cycloalkyl.
  • Examples of C 3 -C 12 cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl, 4-methylene-cyclohexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.0]hexyl, spiro[2.5]octyl, 3-methylenebicyclo[3.2.1]octyl, spiro[4.4]nonanyl, and the like.
  • cycloalkenyl refers to monocyclic or polycyclic carbocyclic ring or a bi- or tri-cyclic group fused, bridged or spiro system having at least one carbon-carbon double bond and the carbon atoms may be optionally oxo-substituted or optionally substituted with exocyclic olefinic double bond.
  • Preferred cycloalkenyl groups include C 3 -C 12 cycloalkenyl, C 3 -C 8 cycloalkenyl or C 5 -C 7 cycloalkenyl groups.
  • C 3 -C 12 cycloalkenyl examples include, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[2.2.1]hept-2-enyl, bicyclo[3.1.0]hex-2-enyl, spiro[2.5]oct-4-enyl, spiro[4.4]non-2-enyl, bicyclo[4.2.1]non-3- en-12-yl, and the like.
  • arylalkyl means a functional group wherein an alkylene chain is attached to an aryl group, e.g., -CH 2 CH 2 -phenyl.
  • substituted arylalkyl means an arylalkyl functional group in which the aryl group is substituted.
  • heteroarylalkyl means a functional group wherein an alkylene chain is attached to a heteroaryl group.
  • substituted heteroarylalkyl means a heteroarylalkyl functional group in which the heteroaryl group is substituted.
  • alkoxy employed alone or in combination with other terms means, unless otherwise stated, an alkyl group having the designated number of carbon atoms connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 2-propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers.
  • Preferred alkoxy are (C 2 -C 3 ) alkoxy.
  • heterocyclyl and “heterocycloalkyl” can be used interchangeably and refer to a non-aromatic ring, for example, a 3-to 12 membered ring, a 3-8-membered ring, or a bi- or tri-cyclic group fused, bridged or spiro system, where (i) each ring system contains at least one heteroatom independently selected from oxygen, sulfur and nitrogen, (ii) each ring system can be saturated or unsaturated (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) the nitrogen heteroatom may optionally be quaternized, (v) any of the above rings may be fused to an aromatic ring, and (vi) the remaining ring atoms are carbon atoms which may be optionally oxo-substituted or optionally substituted with exocyclic olefinic double bond.
  • heterocycloalkyl groups include, but are not limited to, 1,3-dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, 2-azabicyclo[2.2.1]-heptyl, 8-azabicyclo[3.2.1]octyl, 5-azaspiro[2.5]octyl, 2-oxa-7-azaspiro[4.4]nonanyl, 7-oxooxepan-4-yl, and tetrahydrofuryl.
  • heterocyclyl groups may be further substituted.
  • Heteroaryl or heterocyclyl groups can be C-attached or N-attached (where possible). It is understood that any alkyl, alkenyl, alkynyl, alicyclic, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aliphatic moiety or the like, described herein can also be a divalent or multivalent group when used as a linkage to connect two or more groups or substituents, which can be at the same or different atom(s).
  • One of skill in the art can readily determine the valence of any such group from the context in which it occurs.
  • substituted refers to substitution by independent replacement of one, two, or three or more of the hydrogen atoms with substituents including, but not limited to, -F, -Cl, -Br, -I, -OH, C 1- C 12 -alkyl; C 2 -C 12 -alkenyl, C 2 -C 12 -alkynyl, -C 3 -C 12 -cycloalkyl, protected hydroxy, -NO2, -N3, -CN, -NH 2 , protected amino, oxo, thioxo, -NH-C 1 -C 12 -alkyl, -NH-C 2 -C 8 -alkenyl, -NH-C 2 -C 8 -alkynyl, -NH-C 3 -C 12 -cycloalkyl, -NH-aryl, -NH- heteroaryl, -NH-heterocycloalkyl, -dialkyla
  • the substituents are independently selected from halo, preferably Cl and F; C 1 -C 4 -alkyl, preferably methyl and ethyl; halo-C 1- C 4 -alkyl, such as fluoromethyl, difluoromethyl, and trifluoromethyl; C 2 -C 4 -alkenyl; halo-C 2 -C 4 -alkenyl; C 3 -C 6 -cycloalkyl, such as cyclopropyl; C 1- C 4 -alkoxy, such as methoxy and ethoxy; halo-C 1- C 4 -alkoxy, such as fluoromethoxy, difluoromethoxy, and trifluoromethoxy; -CN; -OH;NH 2 ; C 1 -C 4 - alkylamino; di(C 1- C 4 -alkyl)amino; and NO 2 .
  • each substituent in a substituted moiety is additionally optionally substituted with one or more groups, each group being independently selected from C 1 -C 4 -alkyl; -CF 3 , -OCH 3 , -OCF 3 , -F, -Cl, -Br, -I, -OH, -NO 2 , -CN, and -NH 2 .
  • a substituted alkyl group is substituted with one or more halogen atoms, more preferably one or more fluorine or chlorine atoms.
  • halo or halogen alone or as part of another substituent, as used herein, refers to a fluorine, chlorine, bromine, or iodine atom.
  • optionally substituted means that the referenced group may be substituted or unsubstituted. In one embodiment, the referenced group is optionally substituted with zero substituents, i.e., the referenced group is unsubstituted. In another embodiment, the referenced group is optionally substituted with one or more additional group(s), which can be, for example, individually and independently selected from groups described herein.
  • hydroxyl activating group refers to a labile chemical moiety which is known in the art to activate a hydroxyl group so that it will depart during synthetic procedures such as in a substitution or an elimination reaction.
  • hydroxyl activating group include, but not limited to, mesylate, tosylate, triflate, p- nitrobenzoate, phosphonate and the like.
  • activated hydroxyl refers to a hydroxy group activated with a hydroxyl activating group, as defined above, including mesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups, for example.
  • hydroxy protecting group refers to a labile chemical moiety which is known in the art to protect a hydroxyl group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the hydroxy protecting group as described herein may be selectively removed. Hydroxy protecting groups as known in the art are described generally in T.H. Greene and P.G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).
  • hydroxyl protecting groups include benzyloxycarbonyl, 4- methoxybenzyloxycarbonyl, tert-butoxy-carbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t- butyl, 2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, allyl, benzyl, triphenyl-methyl (trityl), methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-(trimethylsilyl)-ethoxymethyl, methanesulfonyl, trimethylsilyl, triisopropylsilyl, and the like.
  • protected hydroxy refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups, for example.
  • hydroxy prodrug group refers to a promoiety group which is known in the art to change the physicochemical, and hence the biological properties of a parent drug in a transient manner by covering or masking the hydroxy group. After said synthetic procedure(s), the hydroxy prodrug group as described herein must be capable of reverting back to hydroxy group in vivo. Hydroxy prodrug groups as known in the art are described generally in Kenneth B.
  • amino protecting group refers to a labile chemical moiety which is known in the art to protect an amino group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the amino protecting group as described herein may be selectively removed.
  • Amino protecting groups as known in the art are described generally in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).
  • amino protecting groups include, but are not limited to, methoxycarbonyl, t- butoxycarbonyl, 12-fluorenyl-methoxycarbonyl, benzyloxycarbonyl, and the like.
  • protected amino refers to an amino group protected with an amino protecting group as defined above.
  • leaving group means a functional group or atom which can be displaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction.
  • representative leaving groups include chloro, bromo and iodo groups; sulfonic ester groups, such as mesylate, tosylate, brosylate, nosylate and the like; and acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.
  • aprotic solvent refers to a solvent that is relatively inert to proton activity, i.e., not acting as a proton-donor.
  • Examples include, but are not limited to, hydrocarbons, such as hexane and toluene, for example, halogenated hydrocarbons, such as, for example, methylene chloride, ethylene chloride, chloroform, and the like, heterocyclic compounds, such as, for example, tetrahydrofuran and N- methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether.
  • hydrocarbons such as hexane and toluene
  • halogenated hydrocarbons such as, for example, methylene chloride, ethylene chloride, chloroform, and the like
  • heterocyclic compounds such as, for example, tetrahydrofuran and N- methylpyrrolidinone
  • ethers such as diethyl ether, bis-methoxymethyl ether.
  • protic solvent refers to a solvent that tends to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like.
  • solvents are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of protogenic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick et al., Vol. II, in the Techniques of Chemistry Series, John Wiley & Sons, NY, 1986. Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds.
  • compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carrier means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or Formulation auxiliary of any type.
  • materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulf
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, or as an oral or nasal spray.
  • the pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection.
  • the pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically acceptable carriers, adjuvants or vehicles.
  • the pH of the Formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the Formulated compound or its delivery form.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzy
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection.
  • Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide- polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable Formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite
  • the dosage form may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragées, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical Formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic Formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound to the body.
  • dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • the methods provided herein encompass administering pharmaceutical compositions containing compounds of this disclosure, if appropriate in the salt form, either alone or in the form of a combination with one or more compatible and pharmaceutically acceptable carriers, such as diluents or adjuvants, or with another therapeutic agent.
  • the second or additional therapeutic agent can be formulated or packaged with a compound of the invention.
  • the second agent will only be formulated with a compound of the invention according to the judgment of those of skill in the art, as such co-formulation should not interfere with the activity of either agent or the method of administration.
  • the compound of the invention and the second agent may be formulated separately. They may also be packaged together, or packaged separately, for the convenience of the medical practitioner.
  • a preferred formulation of the invention is a mono-phasic pharmaceutical composition suitable for oral administration for the treatment, prophylaxis, or for slowing the progression or for delaying the onset of an autoimmune disease, consisting essentially of a therapeutically-effective amount of a compound of the invention, and a pharmaceutically acceptable carrier.
  • these methods include the treating a subject suffering from an autoimmune disease by the administration of an effective amount of a compound of the invention.
  • the autoimmune disease may be associated with the occurrence of certain DQ2 alleles.
  • the autoimmune disease can be, but is not limited to, one or more of celiac disease, T1D, SPS, AD, SS, and MG.
  • These methods may encompass the step of administering to the individual in need of such treatment an amount of a compound of the invention effective for treating or delaying the development or progression of the autoimmune disease.
  • the compounds of the invention that may be administered to an individual in these methods may be in the form of a pharmaceutical composition or single unit dosage form, as described above.
  • the invention includes methods of treating or slowing the progression or development of an autoimmune disease by reducing or preventing the binding of MHC class II molecules to antigenic peptides or fragments of antigenic peptides of the autoimmune disease by the administration of a compound of the invention to individuals suffering from, or at risk of developing, the autoimmune disease.
  • a specific method includes treating celiac disease in an individual comprising administering an effective amount of a compound of the invention to an individual in need of such treatment.
  • Another method provided herein includes treating an individual at risk of developing an autoimmune disease by administering an effective amount of a compound of the invention to the individual.
  • the invention provides for the use of a compound of the invention in the manufacture of a medicament for the treatment of an autoimmune disease.
  • the autoimmune disease may be one or more of celiac disease, T1D, SPS, AD, SS, and MG.
  • the invention also provides a compound of the invention for use in the treatment of an autoimmune disease selected from one or more of celiac disease, T1D, SPS, AD, SS, and MG.
  • a compound of the invention can be administered orally to the subject.
  • the compound of the invention may be administered to an individual once daily, or more frequently.
  • the compound of the invention can be administered to a subject as a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the compound of the invention, or a pharmaceutically acceptable salt thereof may be administered to a subject as a pharmaceutical composition, as described above.
  • a compound of the invention or a pharmaceutically acceptable salt thereof is administered to a subject suspected of suffering from, or at risk of developing the autoimmune disease.
  • the administration to a subject diagnosed with the autoimmune disease commences within 5 years of the initial diagnosis of the autoimmune disease in the subject, or more preferably, within 1 year of the initial diagnosis of the autoimmune disease in the subject, or more preferably, within 6 months of the initial diagnosis of the autoimmune disease in the subject, or more preferably, within 1 month of the initial diagnosis of the autoimmune disease in the subject.
  • the subject may be administered a dosage of a compound of the invention, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, that is therapeutically effective to treat or delay the development or progression of the autoimmune disease in the subject.
  • Another aspect of these methods includes an initial determination of which patients may benefit from the administration of a compound of the invention, prior to administration of a compound of the invention to the subject determined to be in need of such treatment.
  • DQ2 alleles confer significant risk of several autoimmune diseases.
  • subjects with certain known DQ2 alleles are subjects at risk of developing an autoimmune disease.
  • Such subject therefore may benefit from the administration of a compound of the invention, as described above.
  • the determination of which DQ2 alleles are present in a subject may enable a clinician to establish the subject’s risk of developing an autoimmune disease.
  • the finding of a heterozygote of a high risk DQ2 genotype in the subject may be used to modify the dosage and/or dosing regimen of a compound of the invention to the subject, which may include reducing the dose or frequency of administration of a compound of the invention to the subject.
  • the genotyping methods of the invention reveal homozygous wild type HLA alleles, in a nucleic acid sample obtained from the subject, then the clinician may rule out an elevated risk of developing an autoimmune disease in the subject and consider different treatments or diagnoses for that subject.
  • a number of methods are available for analyzing and determining the DQ2 and/or DQ8 genotype in a subject, which can be applied to a nucleic acid sample obtained from a subject.
  • Assays for detection of polymorphisms or mutations fall into several categories, including but not limited to, direct sequencing assays, fragment polymorphism assays, hybridization assays, and computer-based data analysis. Protocols and kits or services for performing these general methods are commercially available and well known to those of skill in the art. In some embodiments, assays are performed in combination or in hybrid (e.g., different reagents or technologies from several assays are combined to yield one assay). Thus, the presence or absence of DQ8 and/or DQ2 alleles may be determined using direct sequencing.
  • the DQ8 and/or DQ2 alleles may be determined using a PCR-based assay using oligonucleotide primers to amplify a DNA fragment containing the DQ8 and/or DQ2 polymorphism of interest.
  • the DQ8 and/or DQ2 alleles may be determined using a fragment length polymorphism assay, such as a restriction fragment length polymorphism assay (RFLP), to detect a unique DNA banding pattern indicative of an DQ8 and/or DQ2 genotype based on cleaving the DNA at a series of positions is generated using an enzyme (e.g., a restriction endonuclease).
  • RFLP restriction fragment length polymorphism assay
  • the DQ8 and/or DQ2 alleles may be determined using a hybridization assay, wherein the genotype is determined based on the ability of the DNA from the sample to hybridize to a complementary DNA molecule (e.g., an oligonucleotide probe).
  • a complementary DNA molecule e.g., an oligonucleotide probe.
  • the DQ8 and/or DQ2 polymorphisms of interest may be detected using a DNA chip hybridization assay, in which a series of oligonucleotide probes, designed to be unique to a given single nucleotide polymorphism, are affixed to a solid support, and the nucleic acid sample from the subject is contacted with the DNA “chip” and hybridization is detected.
  • the DQ8 and/or DQ2 alleles may be determined using a “bead array” (such as those described in PCT Publications WO99/67641 and WO00/39587, each of which is herein incorporated by reference).
  • the DQ8 and/or DQ2 alleles may be determined using an assay that detects hybridization by enzymatic cleavage of specific structures (such as those assays described in U.S. Pat. No.6,001,567, and Olivier, M., The Invader assay for SNP Genotyping, 2005 Mutat. Res.573(1-2):103-10, both of which are incorporated herein by reference).
  • Any known method of analyzing a sample for an analyte can be used to practice the present invention, so long as the method detects the presence, absence, or amount of autoimmune disease-associated antibodies, such as anti-gluten protein antibodies, anti- transglutaminase antibodies, antibodies against deamidated gliadin peptides, acetylcholine receptor antibodies, and/or anti-endomysium antibodies.
  • autoimmune disease-associated antibodies such as anti-gluten protein antibodies, anti- transglutaminase antibodies, antibodies against deamidated gliadin peptides, acetylcholine receptor antibodies, and/or anti-endomysium antibodies.
  • autoimmune disease-associated antibodies such as anti-gluten protein antibodies, anti- transglutaminase antibodies, antibodies against deamidated gliadin peptides, acetylcholine receptor antibodies, and/or anti-endomysium antibodies.
  • examples of such methods include, but are not limited to, immunological detection assays and non-
  • a binding compound is immobilized on a substrate, such as a microtiter dish well, a dipstick, an immunodot strip, or a lateral flow apparatus.
  • a sample collected from a subject is applied to the substrate and incubated under conditions suitable to allow the formation of a complex between the binding compound and any antibody present in the sample. Once formed, the complex is then detected.
  • Complex formation, or selective binding, between an antibody and a binding compound can be measured (i.e., detected, determined) using a variety of methods standard in the art including, but not limited to, an enzyme-linked immunoassay, a competitive enzyme-linked immunoassay, a radioimmunoassay, a fluorescence immunoassay, a chemiluminescent assay, a lateral flow assay, a flow-through assay, an agglutination assay, a particulate-based assay (e.g., using particulates such as, but not limited to, magnetic particles or plastic polymers, such as latex or polystyrene beads), an immunoprecipitation assay, a BIACORETM assay (e.g., using colloidal gold), an immunodot assay (e.g., CMG's Immunodot System, Fribourg, Switzerland), and an immunoblot assay (e.g., a western blot), an phosphorescence as
  • the assays may be used to give qualitative or quantitative results.
  • the assay results can be based on detecting the entire antibody or fragments, or degradation products.
  • Some assays, such as agglutination, particulate separation, and immunoprecipitation, can be observed visually (e.g., either by eye or by a machine, such as a densitometer or spectrophotometer) without the need for a detectable marker.
  • a detectable marker can be conjugated to the compound or reagent at a site that does not interfere with the ability of the compound to bind antibodies. Methods of conjugation are known to those of skill in the art.
  • detectable markers include, but are not limited to, a radioactive label, a fluorescent label, a chemiluminescent label, a chromophoric label, an enzyme label, a phosphorescent label, an electronic label, a metal sol label, a colored bead, a physical label, or a ligand.
  • a ligand refers to a molecule that binds selectively to another molecule.
  • Preferred detectable markers include, but are not limited to, fluorescein, a radioisotope, a phosphatase (e.g., alkaline phosphatase), biotin, avidin, a peroxidase (e.g., horseradish peroxidase), beta- galactosidase, and biotin-related compounds or avidin-related compounds (e.g., streptavidin or IMMUNOPURETM NeutrAvidin). Means of detecting such markers are well known to those of skill in the art.
  • a tri-molecular complex between a gliadin antigen, an MHC molecule, and T cell receptor can be detected by contacting a biological sample from a subject with an antibody specific for the complex, wherein the antibody is conjugated to a detectable marker.
  • a detectable marker can also be conjugated to a tri-molecular complex between a gliadin antigen, an MHC molecule, and T cell receptor such that contact of the labeled complex with a biological sample from a subject can detect the presence of antibodies to the complex present in the subject tested.
  • Detectable markers include, but are not limited to, fluorescein, a radioisotope, a phosphatase (e.g., alkaline phosphatase), biotin, avidin, a peroxidase (e.g., horseradish peroxidase), beta-galactosidase, and biotin- related compounds or avidin-related compounds (e.g., streptavidin or IMMUNOPURETM NeutrAvidin).
  • a tri-molecular complex may be detected by contacting the complex with an indicator molecule.
  • Suitable indicator molecules include molecules that can bind to the tri- molecular binding molecule complex.
  • an indicator molecule can comprise, for example, an antibody.
  • Preferred indicator molecules that are antibodies include, for example, antibodies reactive with the antibodies from animals in which the antibodies are produced.
  • An indicator molecule itself can be attached to a detectable marker of the present invention.
  • an antibody can be conjugated to biotin, horseradish peroxidase, alkaline phosphatase or fluorescein.
  • One or more layers and/or types of secondary molecules or other binding molecules capable of detecting the presence of an indicator molecule may be used.
  • an untagged (i.e., not conjugated to a detectable marker) secondary antibody that selectively binds to an indicator molecule can be bound to a tagged (i.e., conjugated to a detectable marker) tertiary antibody that selectively binds to the secondary antibody.
  • Suitable secondary antibodies, tertiary antibodies and other secondary or tertiary molecules can be readily selected by those skilled in the art. Preferred tertiary molecules can also be selected by those skilled in the art based upon the characteristics of the secondary molecule. The same strategy can be applied for subsequent layers.
  • a lateral flow assay may be used for detection, examples of which are described in U.S. Patent No.5,424,193; U.S. Pat. No.5,415,994; WO 94/29696; and WO 94/01775 (all of which are incorporated by reference herein).
  • the subject can be selected, or identified, as likely or unlikely to develop, or at higher or lower risk of developing, an autoimmune disease. Such a selection is made using the results from the analysis step of the disclosed methods. Those subjects selected as likely or at higher risk of developing an autoimmune disease may be treated with one or more compounds of the invention to treat or slow the development of the autoimmune disease in the subject.
  • Each publication or patent cited herein is incorporated herein by reference in its entirety. Additional objects, advantages, and novel features of the invention will become apparent to those skilled in the art upon examination of the following examples, which are not intended to be limiting.
  • Example 1 Compound Synthesis General Experimental Methods Unless otherwise noted, all materials/reagents are obtained from commercial suppliers and used without further purification. Reactions are monitored by LC-MS and/or thin layer chromatography (TLC) on silica gel 60 F254 (0.2mm) pre-coated aluminum foil or glass-backed and visualized using UV light. 1 HNMR (400 MHz) spectra are recorded on Bruker spectrometers at rt with TMS or the residual solvent peak as the internal standard. The line positions or multiples are given in ( ⁇ ) and the coupling constants (J) are given as absolute values in Hertz (Hz).
  • TLC thin layer chromatography
  • LC-MS is performed on Shimadzu LCMS-2020 equipped with LC-20AD or 30AD pumps, SPD-M20A PDA and Alltech 3300 ELSD; Mobile Phase: A: Water (0.1% Formic acid), B : CAN; 5 minute run; Column: Sepax BR- C184.6*50 mm, 3 um; Flow Rate: 1.0 ml/min; Oven Temperature: 40 o C; Gradient: 20% B for 0.2 min, increased to70% B within 1.8 min, 70% B for 2.8 min, back to 20% B within 0 .2 min, 20% B for 2 min).
  • Preparative TLC is performed on Whatman LK6F Silica Gel 60A size 20x20 cm plates with a thickness of 1000 ⁇ m or equivalent. General procedures for synthesizing intermediates in the synthesis of certain compounds disclosed herein are shown in the schemes below.
  • G eneral Method A General Method B
  • the resulting aqueous layer is washed with ethyl acetate, acidified to pH 2 with aqueous HCl (2N), and extracted with ethyl acetate.
  • the combined organic layers are washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the carboxylic acid thioether which is used in next step without further purification.
  • TCR transductants cultured with no gliadin peptide served as the negative control, and incubation with an anti-CD3 antibody (eBioscience; clone 2C11) served as a positive control for the TCR transductant.
  • Secreted IL-2 in the culture supernatant was measured using a highly sensitive enzyme-linked immunosorbent assay (ELISA).
  • ELISA enzyme-linked immunosorbent assay

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Abstract

Compounds and compositions useful in methods of treating, ameliorating, or inhibiting the development of an autoimmune disease by modulating the T cell response to antigenic peptide or fragments of antigenic peptides presented by the major histocompatibility (MHC) class II molecule, DQ2.

Description

COMPOUNDS AND METHODS FOR TREATING AUTOIMMUNE DISORDERS BY TARGETING HLA-DQ2 RELATED APPLICATION This application claims the benefit of U.S. Provisional Application No. 63/222,630, filed on July 16, 2021. The entire teachings of the above application are incorporated herein by reference. TECHNICAL FIELD The invention relates to the use of small organic molecules in the prevention or treatment of autoimmune diseases, such as Celiac disease and Type 1 Diabetes. BACKGROUND Autoimmune disorders are diseases caused by the body producing an inappropriate immune response against its’ own tissues, in which the immune system, T lymphocytes and autoantibodies, attack one’s own cells, tissues, and/or organs. The major genetic risk factor for developing an autoimmune disease resides within human leukocyte antigen (HLA) gene complex located on chromosome 6. The HLA complex is divided into three regions: class I, II, and III. Alleles of the class II genes, DQ and DR (and to a lesser extent DP), are the most important determinants for developing an autoimmune disease. The HLA class II genes are polymorphic and encode major histocompatibility complex (MHC) II proteins. These MHC class II molecules are expressed on antigen presenting cells (e.g., B cells, dendritic cells, and macrophages) and function to present antigens to CD4 T-cells. In the case of autoimmunity, self-peptides presented by MHC class II molecules activate T cells to target one’s own cells or tissues. Researchers have identified 80-100 different autoimmune diseases and suspect at least 40 additional diseases have an autoimmune basis. Celiac disease is one of the most common autoimmune disorders, with a reported prevalence of 0.5–1% of the general population, with the exception of areas showing low frequency of celiac disease-predisposing genes and low gluten consumption (e.g., sub- Saharan Africa and Japan). Studies have shown that most celiac disease cases remain undetected in the absence of serological screening due to heterogeneous symptoms and/or poor disease awareness. Celiac disease prevalence is increasing in Western countries. Between the years 1975 and 2000, celiac disease prevalence increased 5-fold in the US, for reasons that are currently unknown. The prevalence of celiac disease is higher in first- degree celiac disease relatives (10–15%) and in other at-risk groups, particularly patients with Down syndrome, type 1 diabetes, or IgA deficiency. Celiac disease is diagnosed more frequently in women with a female-to-male ratio ranging from 2:1 to 3:1. The disease can occur at any age from early childhood to the elderly, with two peaks of onset – one shortly after weaning with gluten in the first 2 years of life, and the other in the second or third decades of life. The diagnosis of celiac disease can be challenging because symptoms can vary significantly from patient to patient. Celiac disease is a unique autoimmune disease in that its key genetic elements (human leukocyte antigen (HLA)-DQ2 and HLA-DQ8), the auto-antigen involved (tissue transglutaminase (tTG)), and the environmental trigger (gluten) are all well-defined. DQ2 and DQ8 alleles are the predominant HLA alleles in Celiac disease, being present in about 99% of patients, with DQ2 being predominant at about 90%. The majority of individuals with Celiac disease carry one of the DQ2 subtypes defined as: DQ2.5cis (DQA1*05:01- DQB1*02:01), DQ2.5trans (present with the genotype of DQA1*02:01-DQB1*02:02 + DQA1*05:05-DQB1*03:01), DQ2.2 (DQA1*02:01-DQB1*02:02), and DQ2.3 (DQA1*03:01-DQB1*02:01). DQ8 (DQA1*03:01-DQB1*03:02) is the other risk allele for celiac disease. Gliadin, one of the two principle protein components of gluten, contains a number of well-studied T cell epitopes. Deamidation of gliadin peptides by tissue transglutaminase (TTG) type 2 converts glutamine into glutamic acid, resulting in immunogenic T cell epitopes. A major drawback in celiac disease research has been the lack of a reliable and reproducible animal model, with the possible exception of the Irish setter dog, which may develop a gluten-related disease. Nevertheless, new technologies pertinent to human gut biology and immunology are opening unprecedented opportunities for major research breakthroughs. As with any other autoimmune disease, celiac disease has a strong hereditary component as evidenced by its high familial recurrence (10–15%) and the high concordance of the disease among monozygotic twins (75–80%). Also common to other autoimmune diseases is the relevant role of HLA class II heterodimers, specifically DQ2 and DQ8, in the heritability of celiac disease. HLA-DQ2 homozygosis confers a much higher risk (25–30%) of developing early-onset celiac disease in infants with a first-degree family member affected by the disease. Currently, the only effective treatment available for celiac disease is a strict gluten free diet for life because it leads to the resolution of intestinal and extraintestinal symptoms, negativity of autoantibodies, and the regrowth of the intestinal villi. In addition, the diet offers a partial protective effect towards several complications. However, these crucial advantages are accompanied by disadvantages, including a negative impact on quality of life, psychological problems, fear of involuntary/inadvertent contamination with gluten (as demonstrated in multicenter gluten immunogenic protein (GIP) studies), possible vitamin and mineral deficiencies, metabolic syndrome, an increased cardiovascular risk, and often severe constipation. Due to the relevant burden induced by gluten withdrawal with consequent worsening of quality of life, about 40% of celiac disease patients are unsatisfied with their alimentary regimen and would be keen to explore alternative treatments. Type 1 diabetes (T1D), the immune mediated form of diabetes, is a chronic autoimmune disorder resulting in the destruction of insulin-producing beta cells within the pancreatic islets requiring lifelong daily insulin treatment. Autoantibodies directed toward insulin (IAA) and beta cell-specific antigens, glutamic acid decarboxylase 65 (GAD65), insulinoma-associated antigen 2 (IA-2) and zinc transporter 8 (ZnT8) are considered diagnostic and predictive of T1D. An association between T1D and CD has been recognized and intensely studied. The prevalence of CD ranges from 1% to 10% in patients with T1D, compared with 1% in the general population. In most subjects, the onset of T1D precedes the diagnosis of CD or the two diseases are diagnosed simultaneously. Shared susceptibility genes in the HLA region contribute to the coexistence of T1D and CD with HLA-DR3-DQ2 and HLA-DR4-DQ8 haplotypes being the strongest genetic risk factors for T1D and CD. For example, the DR3-DQ2 haplotype is found in about 90% of CD and 55% of T1D patients. The co-occurrence of T1D and CD is highly associated with the high-risk genotypes DR3-DQ2/DR3-DQ2 and DR3- DQ2/DR4-DQ8. Independent of the co-occurrence of celiac disease and type 1 diabetes, the DR3-DQ2 haplotype confers significant disease risk for the development of type 1 diabetes. Stiff-person syndrome (SPS) is a rare neurological disorder characterized by fluctuating muscle rigidity in the trunk and limbs and a heightened sensitivity to stimuli such as noise, touch, and emotional distress, which can set off muscle spasms. Abnormal postures, often hunched over and stiffened, are characteristic of the disorder, and people with SPS can be too disabled to walk or move. SPS affects twice as many women as men and is frequently associated with other autoimmune diseases such as diabetes, thyroiditis, vitiligo, and pernicious anemia. The cause of SPS is not fully understood, but research indicates that it is the result of an autoimmune response in the brain and spinal cord. The disorder is often misdiagnosed as Parkinson’s disease, multiple sclerosis, fibromyalgia, psychosomatic illness, or anxiety and phobia. A definitive diagnosis can be made with a blood test that measures the level of glutamic acid decarboxylase (GAD) antibodies in the patient’s blood. SPS patients respond to high doses of diazepam and anti-convulsants, gabapentin, tiagabine, and intravenous immunoglobulin (IVIg) treatment has been shown to reduce stiffness and lower sensitivity to noise, touch, and stress. Although these treatments will improve the symptoms of SPS, there is currently no cure for the disorder, and most SPS patients have frequent falls which can result in severe injuries because they lack the normal defensive reflexes. SPS is correlated with the HLA DQ2 DQB1*02:01 allele (present in approximately 70 % of patients with SPS). Addison’s disease (AD) is a disorder that occurs when the adrenal glands don’t make enough cortisol and aldosterone, resulting in fatigue, muscle weakness, loss of appetite, weight loss, dehydration, hypotension, and abdominal pain. The primary cause of Addison’s disease is an autoimmune disorder this is treated by replacing these hormones as well as high-sodium diets, and calcium and vitamin D supplementation. Addison’s disease is highly correlated with the DR3-DQ2/DR4-DQ8 genotype. Schmidt syndrome (SS) refers to the combination of autoimmune adrenal insufficiency (Addison’s disease) with autoimmune hypothyroidism and/or type 1 diabetes mellitus (T1DM) and is part of a larger syndrome known as autoimmune polyendocrine syndrome type II or polyglandular autoimmune syndrome type II (PAS II; the term Schmidt syndrome is used interchangeably with PAS II). Schmidt Syndrome is a rare disorder with a prevalence of 1:20,000 in the general population, with 3:1 ratio of females to males affected, with peak incidence in the 3rd - 4th decade of life. Diagnosis and treatment of Schmidt syndrome is the same as the underlying disorders (i.e., diagnosis and treatment of Addison’s disease, autoimmune hypothyroidism, and/or T1DM). Among patients with T1DM, < 1% of patients have Addison’s disease, whereas 2-5% have autoimmune thyroid disease (mainly hypothyroidism) and up to 5% have celiac disease. Up to 33% may have thyroid autoantibodies and 12% have transglutaminase autoantibodies. In addition to the DR3-DQ2/DR4DQ8 genotype associated with Addison’s disease, the DR3-DQ2/DR4-DQ8 is recognized as a susceptibility genotype in Schmidt syndrome patients that have type 1 diabetes and autoimmune thyroid disease but without Addison's disease. Myasthenia gravis (MG) is an autoimmune disorder of the nervous system that affects the neuromuscular junctions, leading to muscle weakness and fatigue that worsens after periods of activity and improves after periods of rest. Antibodies against the acetylcholine receptor are detected in the majority (85-90%) of MG patients and are highly specific and pathogenic. MG affects both men and women and occurs across all racial and ethnic groups. It most commonly impacts young adult women (under 40) and older men (over 60), but it can occur at any age, including childhood. Treatments for MG include thymectomy, eculizumab, anticholinesterase and immunosuppressive medications. MHC Allele associations with MG seem to differ from population to population, and their contribution to the pathogenesis remains unclear, but human genotyping studies of MG patients has associated MG with HLA-DRB1*09, HLA-DRB1*14, DRB1*15, and HLA- DQB1*02 (DQ2) alleles. Thus, there exists a need in the art for safer and more effective methods for treating or slowing the progression or development of autoimmune disorders, such as those associated with MHC class II, DQ2 and DQ8 alleles. The invention addresses these needs by providing molecules and formulations useful in the treatment and prevention of autoimmune diseases while achieving other advantages discussed more fully below. SUMMARY OF THE INVENTION The present invention provides compounds that can be used to prevent or reduce T cell activation through the presentation of antigens that bind MHC class II molecules on the surface of antigen presenting cells, as well as therapeutic uses of a compound of the invention and pharmaceutical compositions comprising a compound of the invention to prevent or slow the formation of autoimmune diseases in an individual. Blocking allele-specific MHC class II antigen presentation by inhibiting DQ2- mediated T cell responses has been identified as a target for treating celiac disease. DQ2 confers significant disease risk by presenting epitopes of antigens (for example, gluten and/or insulin antigens, or fragments or antigenic components thereof) to effector CD4+ T cells. Gliadins, key components of gluten, are complex proteins unusually rich in prolines and glutamines and are not completely digestible by intestinal enzymes. Partial digestion of gliadins results in a mix of peptides that can trigger host responses (increased gut permeability and innate and adaptive immune response). The present inventors have surprisingly found that the compounds of the invention block or reduce gliadin peptide presentation to T cells. Without intending to be bound by theory, it is believed that the compounds disclosed herein occupy a pocket along the DQ2 peptide binding groove, thereby blocking major histocompatibility complex class II HLA-DQ2/8-antigen restricted T cells responses in vitro and inhibiting DQ2/8-antigen presentation in vivo. Blocking HLA-DQ2 antigen presentation in this way may decrease autoimmune T cell activation thereby preventing and/or treating and/or slowing the development of autoimmune disorders. For example, blocking HLA-DQ2 gliadin presentation to CD4+ T cells may help preserve intestinal mucosal and epithelial barrier in new onset celiac disease and may also prevent or delay celiac disease onset. In one embodiment, the present invention provides compounds of Formula (I),
Figure imgf000007_0001
or a pharmaceutically acceptable salt or prodrug thereof, wherein: Ar1 is optionally substituted aryl or optionally substituted heteroaryl; X is O, S, S(O), S(O)2, or NR; R1 is optionally substituted C1-C8-alkyl, optionally substituted C3-C8-cycloalkyl; optionally substituted heterocycloalkyl, optionally substituted heteroaryl or optionally substituted aryl; R is H or optionally substituted C1-C6-alkyl; B is -CH2-, –CH2CH2-, -CH=CH- or –C≡C-; and n is 0, 1, or 2. The present further provides methods of treating or slowing the progression or development of an autoimmune disease in a subject suffering from, or at risk of developing, the autoimmune disease, comprising administering the subject a therapeutically effective amount of one or more compounds of the invention. The autoimmune disease can be, for example, celiac disease, type 1 diabetes (T1D), Stiff- person Syndrome (SPS), Addison’s disease (AD), Schmidt Syndrome (SS), or Myasthenia Gravis (MG). The present invention further provides pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier or excipient. These compounds of the invention are believed to inhibit the binding of an antigenic peptide to the DQ2 MHC class II molecule for presentation to CD4+ T cells and are useful for slowing the development or progression of an autoimmune disease. The inhibition of the binding of an antigenic peptide to a DQ2 MHC class II molecule may result from a distortion of the spatial orientation of the complex so that the DQ2 MHC class II molecule-antigen complex is not properly presented to T cells, such that the trimolecular complex between 1) the MHC class II molecule on the surface of an antigen presenting cell, 2) the antigenic peptide, and 3) the CD4+ T cell, is not formed. In another embodiment, the invention provides a method of treating an autoimmune disease in a subject, including selecting a subject for treatment with one or more compounds of the invention on the basis of the subject having at least one of the diagnostic criteria of the autoimmune disease. Such diagnostic criteria may include, for celiac disease, mucosal changes detected by duodenal biopsy and positivity of serological tests (anti-transglutaminase antibodies (tTG), anti-endomysium antibodies (EmA), and/or deamidated gliadin peptide (DGP) antibodies). For T1D, such diagnostic criteria may include the detection of autoantibodies directed toward insulin (IAA) and beta cell-specific antigens, glutamic acid decarboxylase 65 (GAD65), insulinoma-associated antigen 2 (IA- 2) and zinc transporter 8 (ZnT8), and/or a previous diagnosis of celiac disease. For Stiff- person syndrome, such diagnostic criteria may include the detection of autoantibodies directed toward glutamic acid decarboxylase (GAD). For Addison’s disease, such diagnostic criteria may include the finding of low blood levels of sodium or high levels of potassium, positive ACTH stimulation test, insulin-induced hypoglycemia test, and/or x- ray examination. For Schmidt syndrome, such diagnostic criteria may include the diagnosis of two or more of Addison’s disease, autoimmune hypothyroidism, and/or T1DM. For Myasthenia Gravis, such diagnostic criteria may include detection of autoantibodies directed toward the acetylcholine receptor. Upon detection of one or more of these criteria diagnostic of a specific autoimmune disease, the subject is selectively administered a compound of the invention. In certain embodiments of the methods of the invention, the subject has been tested for the presence of antibodies directed to an antigen selected from a gliadin peptide, insulin (IAA), a beta cell-specific antigen, glutamic acid decarboxylase (GAD), insulinoma-associated antigen 2 (IA-2), zinc transporter 8 (ZnT8), and the acetylcholine receptor, wherein the presence of such antibodies in the subject is indicative of the presence or likely development of an autoimmune disease. Thus, a related aspect of the invention provides methods of treating a subject found to have such autoantibodies by administering a compound of the invention to the subject. Another aspect of the invention provides methods of monitoring and adjusting the dosage of a compound of the invention administered to a subject suffering from, or at risk of developing, an autoimmune disease, including receiving a blood sample from a subject suffering from, or at risk of developing, the autoimmune disease who has been administered a compound of the invention and determining the DQ2-stimulated response of ICD4+ T cells in the blood sample. The DQ2-stimulated response of CD4+ T cells in the blood sample is compared to a control level of DQ2-stimulated response of CD4+ T cells in blood samples from at least one of a patient suffering from the autoimmune disease and a control or ‘wild type’ subject known to be free of the autoimmune disease. The dosage and/or the frequency of the compound of the invention administered to the subject is increased if the DQ2-stimulated response of CD4+ T cells in the blood sample from the subject is statistically similar to the DQ2-stimulated response of CD4+ T cells from the baseline level in the celiac disease patient. Other aspects of the invention will be set forth in the accompanying description of embodiments, which follows and will be apparent from the description. However, the following Detailed Description is given by way of illustration only, as various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art and are encompassed within the scope of the invention. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compounds of Formula (I) and methods of use thereof for treating or slowing the progression or development of an autoimmune disease. In certain embodiments, the invention provides compounds of Formula (I), as described above, and pharmaceutically acceptable salts thereof. In certain embodiments, the compounds of Formula (I) do not include one or more of the compounds set forth below. 1-Butanone, 1-[4-[2-[(4-bromophenyl)thio]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[[(4-methylphenyl)methyl]thio]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[(3-methylbutyl)thio]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[(2-benzothiazolylmethyl)thio]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(2-benzothiazolylthio)acetyl]-1-piperazinyl]-4-phenyl-; Acetamide, N-(4-methylphenyl)-2-[[2-oxo-2-[4-(1-oxo-4-phenylbutyl)-1- piperazinyl]ethyl]thio]-; 1-Butanone, 1-[4-[2-[[(4-chlorophenyl)methyl]thio]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[[4-(3,4-dimethylphenyl)-4H-1,2,4-triazol-3-yl]thio]acetyl]-1- piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[(4-chlorophenyl)sulfonyl]acetyl]-1-piperazinyl]-4- phenyl-; 1-Butanone, 1-[4-[2-[[2-(4-morpholinyl)-2-oxoethyl]thio]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[[4-(2-ethylphenyl)-4H-1,2,4-triazol-3-yl]thio]acetyl]-1-piperazinyl]- 4-phenyl-; 1-Butanone, 1-[4-[2-[[4-(1-methylethyl)-4H-1,2,4-triazol-3-yl]thio]acetyl]-1-piperazinyl]- 4-phenyl-; 1-Butanone, 1-[4-[2-[(2-methylphenyl)thio]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[(2,3-dihydro-1H-inden-5-yl)thio]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[[4-(4-methylphenyl)-4H-1,2,4-triazol-3-yl]thio]acetyl]-1- piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[(4,6-dimethyl-2-pyrimidinyl)thio]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[[4-ethyl-5-(2-furanyl)-4H-1,2,4-triazol-3-yl]thio]acetyl]-1- piperazinyl]-4-phenyl-; Propanamide, N-(5-methyl-3-isoxazolyl)-2-[[2-oxo-2-[4-(1-oxo-4-phenylbutyl)-1- piperazinyl]ethyl]thio]-; 1-Butanone, 4-phenyl-1-[4-[2-[[5-(trifluoromethyl)-2-pyridinyl]thio]acetyl]-1- piperazinyl]-; 1-Butanone, 1-[4-[2-[(4-methylphenyl)thio]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[[(4-methoxy-3-nitrophenyl)methyl]thio]acetyl]-1-piperazinyl]-4- phenyl-; 1-Butanone, 1-[4-[2-[[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]thio]acetyl]-1-piperazinyl]- 4-phenyl-; 1-Butanone, 1-[4-[2-[[5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl]thio]acetyl]-1- piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(pentylsulfonyl)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[(4-fluorophenyl)thio]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[(4-acetyl-2-fluorophenyl)thio]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[[(3-chlorophenyl)methyl]thio]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[(3,4-difluorophenyl)thio]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[[4-(4-methoxyphenyl)-4H-1,2,4-triazol-3-yl]thio]acetyl]-1- piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[(1-cyclopentyl-1H-tetrazol-5-yl)thio]acetyl]-1-piperazinyl]-4- phenyl-; 1-Butanone, 1-[4-[2-[(4-chlorophenyl)thio]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[(2-fluorophenyl)thio]acetyl]-1-piperazinyl]-4-phenyl-; 1-Piperazineethanesulfonamide, N-(4-methylcyclohexyl)-b-oxo-4-(1-oxo-4-phenylbutyl)-; 5H-Thiazolo[3,2-a]pyrimidin-5-one, 7-[[[2-oxo-2-[4-(1-oxo-4-phenylbutyl)-1- piperazinyl]ethyl]thio]methyl]-; 1-Butanone, 1-[4-[2-[[(3,5-dimethyl-4-isoxazolyl)methyl]thio]acetyl]-1-piperazinyl]-4- phenyl-; 1-Butanone, 1-[4-[2-[(2,3-dihydro-1,4-benzodioxin-6-yl)thio]acetyl]-1-piperazinyl]-4- phenyl-; 1-Butanone, 1-[4-[2-[[4-(2,5-dimethylphenyl)-5-methyl-4H-1,2,4-triazol-3-yl]thio]acetyl]- 1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[(4-nitrophenyl)thio]acetyl]-1-piperazinyl]-4-phenyl-; Benzonitrile, 4-[[[2-oxo-2-[4-(1-oxo-4-phenylbutyl)-1-piperazinyl]ethyl]thio]methyl]-; 1-Butanone, 1-[4-[2-[(4-ethoxyphenyl)thio]acetyl]-1-piperazinyl]-4- phenyl-; 1-Butanone, 1-[4-[2-[(2,5-dimethylphenyl)thio]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[[4-(3-chlorophenyl)-4H-1,2,4-triazol-3-yl]thio]acetyl]-1- piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[[1-(2-methylphenyl)-1H-imidazol-2-yl]thio]acetyl]-1-piperazinyl]-4- phenyl-; 1-Butanone, 1-[4-[2-[[4-ethyl-5-(3-methylphenyl)-4H-1,2,4-triazol-3-yl]thio]acetyl]- 1-piperazinyl]-4-phenyl-; 1-Butanone, 4-phenyl-1-[4-[2-[(tetrahydro-1,1-dioxido-3-thienyl)thio]acetyl]-1- piperazinyl]-; 1-Butanone, 1-[4-[2-[(1-ethyl-1H-benzimidazol-2-yl)thio]acetyl]-1-piperazinyl] -4-phenyl-; 1-Butanone, 1-[4-[2-[(2-chlorophenyl)thio]acetyl]-1-piperazinyl]-4-phenyl-; Acetamide, N-(5-methyl-3-isoxazolyl)-2-[[2-oxo-2-[4-(1-oxo-4-phenylbutyl)-1- piperazinyl]ethyl]thio]-; 1-Butanone, 1-[4-[2-[[4-(3-chloro-4-methylphenyl)-4H-1,2,4-triazol-3-yl]thio]acetyl]- 1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[[5-methyl-4-(phenylmethyl)-4H-1,2,4-triazol-3-yl]thio]acetyl]-1- piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[[4-[4-(1-methylethyl)phenyl]-4H-1,2,4-triazol-3-yl]thio]acetyl]-1- piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[[4-ethyl-5-(2-methylphenyl)-4H-1,2,4-triazol-3-yl]thio]acetyl]- 1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[(1-cyclopropyl-1H-tetrazol-5-yl)thio]acetyl]-1-piperazinyl]-4- phenyl-; 1-Butanone, 1-[4-[2-[[(3-methylphenyl)methyl]thio]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(2-benzoxazolylthio)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 4-phenyl-1-[4-[2-[(3-phenylpropyl)sulfonyl]acetyl]-1-piperazinyl]-; 1-Butanone, 1-[4-[2-[(1-methyl-4-piperidinyl)oxy]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(1-naphthalenyloxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 4-phenyl-1-[4-[2-(3-piperidinylmethoxy)acetyl]-1-piperazinyl]-; 1-Butanone, 1-[4-[2-(2-aminoethoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[2-methoxy-4-(1-propen-1-yl)phenoxy]acetyl]-1-piperazinyl]-4- phenyl-; 1-Butanone, 1-[4-[2-[2-methoxy-4-(2-propen-1-yl)phenoxy]acetyl]-1-piperazinyl]-4- phenyl-; 1-Butanone, 1-[4-[2-(3,4-dichlorophenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(2,5-dichlorophenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(3-chloro-4-fluorophenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(2-chlorophenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(4-ethylphenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(4-chloro-3-methylphenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(3,4-dimethylphenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(4-bromo-2-fluorophenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 4-phenyl-1-[4-[2-[4-(trifluoromethyl)phenoxy]acetyl]-1-piperazinyl]-; 1-Butanone, 1-[4-[2-(2,4-dimethylphenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(3-chlorophenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[(2,3-dihydro-2,2-dimethyl-7-benzofuranyl)oxy]acetyl]-1- piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[4-(1-methylethyl)phenoxy]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[4-(1,3-dithian-2-yl)phenoxy]acetyl]-1-piperazinyl]-4-phenyl-; 2(1H)-Quinolinone, 3,4-dihydro-6-[2-oxo-2-[4-(1-oxo-4-phenylbutyl)-1- piperazinyl]ethoxy]-; 1-Butanone, 1-[4-[2-(3-nitrophenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(4-acetyl-2-methoxyphenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 4-phenyl-1-[4-[2-(4-propoxyphenoxy)acetyl]-1-piperazinyl]-; 1-Butanone, 1-[4-[2-(2,6-dimethylphenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(2-nitrophenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[5-methyl-2-(1-methylethyl)phenoxy]acetyl]-1-piperazinyl]-4- phenyl-; Butanone, 4-phenyl-1-[4-[2-[(1,4,6-trimethyl-1H-pyrazolo[3,4-b]pyridin-3-yl)oxy]acetyl]- 1-piperazinyl]-; 1-Butanone, 1-[4-[2-(2-methoxy-4-methylphenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 2H-1-Benzopyran-2-one, 7-[2-oxo-2-[4-(1-oxo-4-phenylbutyl)-1-piperazinyl]ethoxy]-; 1-Butanone, 1-[4-[2-[4-(1-oxopropyl)phenoxy]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(4-iodophenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(2-ethoxyphenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 2-Pyrrolidinone, 1-[4-[2-oxo-2-[4-(1-oxo-4-phenylbutyl)-1-piperazinyl]ethoxy]phenyl]-; 1-Butanone, 1-[4-[2-(3-acetylphenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[2-(1-methylpropyl)phenoxy]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(4-nitrophenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 4-phenyl-1-[4-[2-[2-(trifluoromethyl)phenoxy]acetyl]-1-piperazinyl]-; 1-Butanone, 1-[4-[2-(2,4-dichlorophenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(2-naphthalenyloxy)acetyl]-1-piperazinyl]-4-phenyl-; Benzonitrile, 3-methoxy-4-[2-oxo-2-[4-(1-oxo-4-phenylbutyl)-1-piperazinyl]ethoxy]-; Benzeneacetamide, 4-[2-oxo-2-[4-(1-oxo-4-phenylbutyl)-1-piperazinyl]ethoxy]-; 1-Butanone, 4-phenyl-1-[4-[2-[3-(trifluoromethyl)phenoxy]acetyl]-1-piperazinyl]-; 1-Butanone, 1-[4-[2-(diphenylmethoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[(2,3-dihydro-1H-inden-5-yl)oxy]acetyl]-1-piperazinyl]-4-phenyl-; 2-Furancarboxamide, N-[3-[2-oxo-2-[4-(1-oxo-4-phenylbutyl)-1- piperazinyl]ethoxy]phenyl]-; 1-Butanone, 1-[4-[2-[(2-chlorophenyl)methoxy]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[4-(3-oxobutyl)phenoxy]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(4-bromophenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[3-(1-methylethyl)phenoxy]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(2,5-dimethylphenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(4-chloro-2-methylphenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(2-ethylphenoxy)acetyl]-1-piperazinyl]-4-phenyl-; Cyclopropanecarboxamide, N-[3-[2-oxo-2-[4-(1-oxo-4-phenylbutyl)-1- piperazinyl]ethoxy]phenyl]-; 1-Butanone, 1-[4-[2-(2-phenoxyethoxy)acetyl]-1-piperazinyl]-4-phenyl-; and 1-Butanone, 1-[4-(2-methoxyacetyl)-1-piperazinyl]-4-phenyl-; 1-Propanone, 3-phenyl-1-[4-[2-(phenylthio)acetyl]-1-piperazinyl]-; 1-Propanone, 3-phenyl-1-[4-[2-[(3-phenylpropyl)thio]acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-[(2-methylphenyl)thio]acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 3-(4-methoxyphenyl)-1-[4-[2-[(4-methylphenyl)thio]acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-[(4-fluorophenyl)thio]acetyl]-1-piperazinyl]-3-(4-methoxyphenyl)-; 1-Propanone, 3-(4-methoxyphenyl)-1-[4-[2-(pentylsulfonyl)acetyl]-1-piperazinyl]-; Benzonitrile, 4-[[[2-oxo-2-[4-(1-oxo-3-phenylpropyl)-1-iperazinyl]ethyl]sulfonyl] methyl]-; Acetamide, N-(3-methylphenyl)-2-[[2-oxo-2-[4-(1-oxo-3-phenylpropyl)-1- piperazinyl]ethyl]thio]-1-Propanone, 1-[2-methyl-4-[2-[(6-phenyl-3- pyridazinyl)thio]acetyl]-1-piperazinyl]-3- phenyl-; 1-Propanone, 1-[4-[2-[[1-(3,4-dimethylphenyl)-1H-imidazol-2-yl]thio]acetyl]-1- piperazinyl]-3-(4-methoxyphenyl)-; 1-Propanone, 3-phenyl-1-[4-[2-[[[5-(2-thienyl)-3-isoxazolyl]methyl]thio]acetyl]-1- piperazinyl]-; 1-Propanone, 1-[4-(2-methoxyacetyl)-1-piperazinyl]-3-phenyl-; 1-Propanone, 1-[4-(2-methoxyacetyl)-1-piperazinyl]-3-(4-methylphenyl)-; 1-Propanone, 1-[4-[2-(2-aminoethoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 1-[4-(2-methoxyacetyl)-1-piperazinyl]-3-(4-methoxyphenyl)-; 1-Propanone, 1-[4-[2-(2-methoxyethoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 3-(3-hydroxyphenyl)-1-[4-(2-methoxyacetyl)-1-piperazinyl]-; 1-Propanone, 3-(2-aminophenyl)-1-[4-(2-methoxyacetyl)-1-piperazinyl]-; 1-Propanone, 3-(4-chlorophenyl)-1-[4-(2-methoxyacetyl)-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(2-methoxyethoxy)acetyl]-1-piperazinyl]-3-(4-methylphenyl)-; 1-Propanone, 3-(3-fluorophenyl)-1-[4-(2-methoxyacetyl)-1-piperazinyl]-; 1-Propanone, 1-[4-(2-phenoxyacetyl)-1-piperazinyl]-3-phenyl-; Benzoic acid, 4-[3-[4-(2-methoxyacetyl)-1-piperazinyl]-3-oxopropyl]-; 1-Propanone, 3-phenyl-1-[4-[2-(phenylmethoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-(4-chlorophenyl)-1-[4-[2-(2-methoxyethoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-(4-methylphenyl)-1-[4-(2-phenoxyacetyl)-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(4-methylphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 3-(4-ethylphenyl)-1-[4-(2-phenoxyacetyl)-1-piperazinyl]-; 1-Propanone, 3-phenyl-1-[4-[2-(4-propylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-[4-(1-methylethyl)phenyl]-1-[4-(2-phenoxyacetyl)-1-piperazinyl]-; 1-Propanone, 3-(2-methylphenyl)-1-[4-(2-phenoxyacetyl)-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(2-methylphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 1-[4-[2-(3-methylphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 3-(3-chloro-4-hydroxyphenyl)-1-[4-(2-methoxyacetyl)-1-piperazinyl]-; 1-Propanone, 3-(3-methylphenyl)-1-[4-(2-phenoxyacetyl)-1-piperazinyl]-; Benzoic acid, 2-[3-[4-(2-methoxyacetyl)-1-piperazinyl]-3-oxopropyl]-; 1-Propanone, 3-(2,3-dichlorophenyl)-1-[4-(2-methoxyacetyl)-1-piperazinyl]-; 1-Propanone, 3-(4-ethylphenyl)-1-[4-[2-(4-methylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(4-methoxyphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 1-[4-[2-(4-methylphenoxy)acetyl]-1-piperazinyl]-3-(4-methylphenyl)-; 1-Propanone, 1-[4-[2-(4-ethoxyphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 3-(4-methoxyphenyl)-1-[4-(2-phenoxyacetyl)-1-piperazinyl]-; 1-Propanone, 3-phenyl-1-[4-[2-(2,2,2-trifluoroethoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-phenyl-1-[4-[2-(3-piperidinylmethoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(2-naphthalenyloxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 3-(4-methylphenyl)-1-[4-[2-(4-propylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-(4-methoxyphenyl)-1-[4-[2-(4-methylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-(4-chlorophenyl)-1-[4-(2-phenoxyacetyl)-1-piperazinyl]-; 1-Propanone, 3-(4-fluorophenyl)-1-[4-(2-phenoxyacetyl)-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(2-ethylphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 3-(3,4-dimethoxyphenyl)-1-[4-(2-methoxyacetyl)-1-piperazinyl]-; 1-Propanone, 3-(4-ethylphenyl)-1-[4-[2-(3-methylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-(4-ethylphenyl)-1-[4-[2-(2-methylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 3-(3-methoxyphenyl)-1-[4-(2-phenoxyacetyl)-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(4-fluorophenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 1-[4-[2-(2-ethoxyphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 1-[4-[2-(4-ethoxyphenoxy)acetyl]-1-piperazinyl]-3-(4-methylphenyl)-; 1-Propanone, 1-[4-[2-(2-methoxyphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 3-(3-chlorophenyl)-1-[4-(2-phenoxyacetyl)-1-piperazinyl]-; 1-Propanone, 3-(3-fluorophenyl)-1-[4-(2-phenoxyacetyl)-1-piperazinyl]-; 1-Propanone, 3-(2-methoxyphenyl)-1-[4-(2-phenoxyacetyl)-1-piperazinyl]-; 1-Propanone, 3-(3-methoxyphenyl)-1-[4-[2-(3-methylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-(2-fluorophenyl)-1-[4-(2-phenoxyacetyl)-1-piperazinyl]-; 1-Propanone, 3-(4-ethoxy-3-methoxyphenyl)-1-[4-(2-methoxyacetyl)-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(diphenylmethoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 3-(4-methoxyphenyl)-1-[4-[2-(2-phenoxyethoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-[(3-methoxyphenyl)methoxy]acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 3-(4-fluorophenyl)-1-[4-[2-(4-methylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(3-fluorophenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 1-[4-[2-(2-fluorophenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 3-(4-methoxyphenyl)-1-[4-[2-(3-methylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-(4-methoxyphenyl)-1-[4-[2-(2-methylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(2-chlorophenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 1-[4-[2-(2,4-dimethylphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 1-[4-[2-(3,4-dimethylphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 1-[4-[2-(2-ethylphenoxy)acetyl]-1-piperazinyl]-3-(4-methylphenyl)-; 1-Propanone, 3-(4-chlorophenyl)-1-[4-[2-(4-methylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-(1,3-benzodioxol-4-yl)-1-[4-(2-methoxyacetyl)-1-piperazinyl]-; 1-Propanone, 3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-[4-(2-methoxyacetyl)-1- piperazinyl]-; 1-Propanone, 3-phenyl-1-[4-[2-[1-(2-pyridinyl)ethoxy]acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-[(2,3-dihydro-1H-inden-5-yl)oxy]acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 3-(2-methoxyphenyl)-1-[4-[2-(2-methylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-(3-methoxyphenyl)-1-[4-[2-(4-methylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(2,3-dimethylphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-(4-methylphenyl)-; 1-Propanone, 3-(4-chlorophenyl)-1-[4-[2-(4-propylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(2-methoxyphenoxy)acetyl]-1-piperazinyl]-3-(4- methylphenyl)-; 1-Propanone, 3-phenyl-1-[4-[2-(2,4,6-trimethylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(2-ethoxyphenoxy)acetyl]-1-piperazinyl]-3-(4-methylphenyl)-; 1-Propanone, 1-[4-[2-(3-methoxyphenoxy)acetyl]-1-piperazinyl]-3-(4- methoxyphenyl)-; 1-Propanone, 3-(3-fluorophenyl)-1-[4-[2-(4-methylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-(2-methoxyphenyl)-1-[4-[2-(4-methylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-(4-methoxyphenyl)-1-[4-[2-(1-naphthalenyloxy)acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(2,4-dimethylphenoxy)acetyl]-1-piperazinyl]-3-(4-methylphenyl)- 1-Propanone, 1-[4-[2-(3,4-dimethylphenoxy)acetyl]-1-piperazinyl]-3-(4-methylphenyl)-; 1-Propanone, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-(4-chlorophenyl)-; 1-Propanone, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-(4-fluorophenyl)-; 1-Propanone, 3-(2-fluorophenyl)-1-[4-[2-(4-methylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-(3-methoxyphenyl)-1-[4-[2-(2-methylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(4-bromophenoxy)acetyl]-1-piperazinyl]-3-(4-methoxyphenyl)-; 1-Propanone, 3-(4-methoxyphenyl)-1-[4-[2-[(3-methylcyclohexyl)oxy]acetyl]-1- piperazinyl]-1-Propanone, 3-(4-chlorophenyl)-1-[4-[2-(4-ethoxyphenoxy)acetyl]-1- piperazinyl]-; 1-Propanone, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-(4-methoxyphenyl)-; 1-Propanone, 1-[4-[2-(3,5-dimethylphenoxy)acetyl]-1-piperazinyl]-3-(4-methoxyphenyl)- 1-Propanone, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-(3-methylphenyl)-; 1-Propanone, 1-[4-[2-(2,3-dimethylphenoxy)acetyl]-1-piperazinyl]-3-(4-methylphenyl)-; 1-Propanone, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-(3-chlorophenyl)-; 1-Propanone, 3-(4-methoxyphenyl)-1-[4-[2-[3-(1-methylethyl)phenoxy]acetyl]-1- piperazinyl]-; 1-Propanone, 1-[4-[2-(2-methoxy-4-methylphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 3-(2-methoxyphenyl)-1-[4-[2-(3-methylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-phenyl-1-[4-[2-(2,3,6-trimethylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-(3,4-dimethoxyphenyl)-1-[4-[2-(2-methoxyethoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-(3-fluorophenyl)-; 1-Propanone, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-(2-fluorophenyl)-; 1-Propanone, 1-[4-[2-(2,4-dimethylphenoxy)acetyl]-1-piperazinyl]-3-(4-methoxyphenyl)-; 1-Propanone, 1-[4-[2-(3,4-dimethylphenoxy)acetyl]-1-piperazinyl]-3-(4-methoxyphenyl)-; 1-Propanone, 1-[4-[2-(2,6-dimethylphenoxy)acetyl]-1-piperazinyl]-3-(4-methoxyphenyl)-; 1-Propanone, 3-(4-chlorophenyl)-1-[4-[2-(2-ethylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-(4-chlorophenyl)-1-[4-[2-(2-methoxyphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-(2-aminophenyl)-1-[4-[2-(4-fluorophenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-(4-chlorophenyl)-1-[4-[2-(2-ethoxyphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-(4-ethoxy-3-methoxyphenyl)-1-[4-(2-phenoxyacetyl)-1-piperazinyl]-; 1-Propanone, 3-(3,4-dimethoxyphenyl)-1-[4-(2-phenoxyacetyl)-1-piperazinyl]-; 1-Propanone, 3-(4-methylphenyl)-1-[4-[2-(2,3,6-trimethylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-(2-methoxyphenyl)-; 1-Propanone, 1-[4-[2-(3,4-dimethylphenoxy)acetyl]-1-piperazinyl]-3-(4-fluorophenyl)-; 1-Propanone, 1-[4-[2-(3,4-dimethylphenoxy)acetyl]-1-piperazinyl]-3-(3-fluorophenyl)-; 1-Propanone, 3-(4-chlorophenyl)-1-[4-[2-(2,4-dimethylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-(4-chlorophenyl)-1-[4-[2-(3,4-dimethylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(2,4-dichlorophenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 1-[4-[2-(4-chloro-3,5-dimethylphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 3-(3,4-dimethoxyphenyl)-1-[4-[2-(4-methylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-[(2-chlorophenyl)methoxy]acetyl]-1-piperazinyl]-3-(4- methoxyphenyl)-; 1-Propanone, 1-[4-[2-(2,5-dichlorophenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 1-[4-[2-(3,4-dimethylphenoxy)acetyl]-1-piperazinyl]-3-(2-fluorophenyl)-; 1-Propanone, 1-[4-[2-[2-(1,1-dimethylethyl)-4-methylphenoxy]acetyl]-1-piperazinyl]-3- phenyl-; 1-Propanone, 3-(4-ethoxy-3-methoxyphenyl)-1-[4-[2-(4-methylphenoxy)acetyl]-1- piperazinyl]-; 1-Propanone, 3-(3,4-dimethoxyphenyl)-1-[4-[2-(2-methoxyphenoxy)acetyl]-1- piperazinyl]-; 1-Propanone, 3-(4-chlorophenyl)-1-[4-[2-(2,3-dimethylphenoxy)acetyl]-1-piperazinyl]-; Benzoic acid, 4-[3-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-oxopropyl]-; 1-Propanone, 1-[4-[2-[(4-chloro-1-naphthalenyl)oxy]acetyl]-1-piperazinyl]-3-(4- methoxyphenyl)-; 1-Propanone, 1-[4-[2-(4-chloro-3,5-dimethylphenoxy)acetyl]-1-piperazinyl]-3-(4- methylphenyl)-; 1-Propanone, 1-[4-[2-[2-(1,1-dimethylethyl)-4-methylphenoxy]acetyl]-1-piperazinyl]-3- (4-methylphenyl)-; 1-Propanone, 1-[4-[2-(2,4-dichlorophenoxy)acetyl]-1-piperazinyl]-3-(4-methylphenyl)-; 1-Propanone, 1-[4-[2-(4-chloro-3-methylphenoxy)acetyl]-1-piperazinyl]-3-(4- methoxyphenyl)-; 1-Propanone, 3-phenyl-1-[4-[2-[2-(trifluoromethyl)phenoxy]acetyl]-1-piperazinyl]-; 1-Propanone, 3-(4-methoxyphenyl)-1-[4-[2-[4-(trifluoromethyl)phenoxy]acetyl]-1- piperazinyl]-; 1-Propanone, 3-(3,4-dimethoxyphenyl)-1-[4-[2-(3,4-dimethylphenoxy)acetyl]-1- piperazinyl]-; 1-Propanone, 1-[(4aR,7aS)-hexahydro-4-(2-methoxyacetyl)-6,6-dioxidothieno[3,4- b]pyrazin-1(2H)-yl]-3-(4-methylphenyl)-, rel-; 1-Propanone, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-(2,5-difluorophenyl)-; 1-Propanone, 3-(3,4-dimethoxyphenyl)-1-[4-[2-(2-ethylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-(4-chlorophenyl)-1-[4-[2-(2,3,6-trimethylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-(4-chlorophenyl)-1-[4-[2-(2,4-dichlorophenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(2,4-dichlorophenoxy)acetyl]-1-piperazinyl]-3-(4-fluorophenyl)-; 1-Propanone, 1-[4-[2-(4-chloro-3,5-dimethylphenoxy)acetyl]-1-piperazinyl]-3-(4- chlorophenyl)-; 1-Propanone, 3-(3,4-dimethoxyphenyl)-1-[4-[2-(2,4-dimethylphenoxy)acetyl]-1- piperazinyl]-; 1-Propanone, 3-(3,4-dimethoxyphenyl)-1-[4-[2-(2,3-dimethylphenoxy)acetyl]-1- piperazinyl]-; 1-Propanone, 3-(3-chlorophenyl)-1-[4-[2-(2,4-dichlorophenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(2,4-dichlorophenoxy)acetyl]-1-piperazinyl]-3-(3-fluorophenyl)-; 1-Propanone, 1-[4-[2-(2,4-dichlorophenoxy)acetyl]-1-piperazinyl]-3-(2-fluorophenyl)-; 1-Propanone, 3-(4-methoxyphenyl)-1-[4-[2-(3-nitrophenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(3-chloro-4-fluorophenoxy)acetyl]-1-piperazinyl]-3-(4- methoxyphenyl)-; 1-Propanone, 1-[4-[2-(2-chloro-4-fluorophenoxy)acetyl]-1-piperazinyl]-3-(4- methoxyphenyl)-; 1-Propanone, 1-[4-[2-(4-bromo-2-chlorophenoxy)acetyl]-1-piperazinyl]-3-(4- methoxyphenyl)-; 1-Propanone, 1-[4-[2-(2,4-dichlorophenoxy)acetyl]-1-piperazinyl]-3-(4-methoxyphenyl)-; 1-Propanone, 1-[4-(2-methoxyacetyl)-1-piperazinyl]-3-[3-methoxy-4-(2,2,2- trifluoroethoxy)phenyl]-; 1-Propanone, 1-[4-[2-(4-acetyl-2-methoxyphenoxy)acetyl]-1-piperazinyl]-3-(4- methoxyphenyl)-; 1-Propanone, 1-[4-[2-(2,5-dichlorophenoxy)acetyl]-1-piperazinyl]-3-(4-methoxyphenyl)-; 1-Propanone, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-(3,4-dimethoxyphenyl)-; 1-Propanone, 1-[4-[2-(2,4-dichlorophenoxy)acetyl]-1-piperazinyl]-3-(2-methoxyphenyl)-; 1-Propanone, 1-[4-[2-[(5-chloro-8-quinolinyl)oxy]acetyl]-1-piperazinyl]-3-(4- methoxyphenyl)-; 1-Propanone, 3-(3-fluorophenyl)-1-[(4aR,7aS)-hexahydro-4-(2-methoxyacetyl)-6,6- dioxidothieno[3,4-b]pyrazin-1(2H)-yl]-, rel-; 1-Propanone, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-(3,4,5- trimethoxyphenyl)-; Piperazine, 1-[3-(3-methylphenyl)-1-oxopropyl]-4-[[(2-phenoxyphenyl)methoxy]acetyl]- :(9CI); 1-Propanone, 3-(4-methoxyphenyl)-1-[4-[2-(2,4,5-trichlorophenoxy)acetyl]-1- piperazinyl]-; Cyclopropanecarboxamide, N-[3-[2-oxo-2-[4-(1-oxo-3-phenylpropyl)-1- piperazinyl]ethoxy]phenyl]-; 2H-1-Benzopyran-2-one, 4-methyl-6-[2-oxo-2-[4-(1-oxo-3-phenylpropyl)-1- piperazinyl]ethoxy]-; 1-Propanone, 3-phenyl-1-[4-[2-[(1,4,6-trimethyl-1H-pyrazolo[3,4-b]pyridin-3- yl)oxy]acetyl]-1-piperazinyl]-; 1-Propanone, 3-[4-[(4,10-dihydro-1,8-dimethylpyrazolo[3,4-b][1,5]benzodiazepin- 5(1H)-yl)carbonyl]-2-methylphenyl]-1-[4-(2-phenoxyacetyl)-1-piperazinyl]-; 1-Propanone, 3-[4-[(4,10-dihydro-1,8-dimethylpyrazolo[3,4-b][1,5]benzodiazepin- 5(1H)-yl)carbonyl]-2-methylphenyl]-1-[4-[2-(phenylmethoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-[4-[(8-chloro-4,10-dihydro-1-methylpyrazolo[3,4-b][1,5]benzodiazepin- 5(1H)-yl)carbonyl]-2-methylphenyl]-1-[4-(2-phenoxyacetyl)-1-piperazinyl]-; 1-Propanone, 3-[4-[(8-chloro-4,10-dihydro-1-methylpyrazolo[3,4-b][1,5]benzodiazepin- 5(1H)-yl)carbonyl]-2-methylphenyl]-1-[4-[2-(phenylmethoxy)acetyl]-1-piperazinyl]-; 2-Propen-1-one, 1-[4-(2-methoxyacetyl)-1-piperazinyl]-3-phenyl-; 2-Propen-1-one, 1-[4-[2-(2-methoxyethoxy)acetyl]-1-piperazinyl]-3-phenyl-; Benzoic acid, 4-[3-[4-(2-methoxyacetyl)-1-piperazinyl]-3-oxo-1-propen-1-yl]-; 2-Propen-1-one, 1-[4-(2-phenoxyacetyl)-1-piperazinyl]-3-phenyl-; 2-Propen-1-one, 1-[4-(2-methoxyacetyl)-1-piperazinyl]-3-[3-(1-methylethoxy)phenyl]-; 2-Propen-1-one, 3-(3-chloro-4-methylphenyl)-1-[4-(2-methoxyacetyl)-1-piperazinyl]-; 2-Propen-1-one, 3-(2,3-dichlorophenyl)-1-[4-(2-methoxyacetyl)-1-piperazinyl]-; 2-Propen-1-one, 1-[4-[2-(4-methylphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 2-Propen-1-one, 3-phenyl-1-[4-[2-(4-propylphenoxy)acetyl]-1-piperazinyl]-; 2-Propen-1-one, 1-[4-[2-(4-ethoxyphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 2-Propen-1-one, 1-[4-[2-(2-ethylphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 2-Propen-1-one, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 2-Propen-1-one, 1-[4-[2-(2-ethoxyphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 2-Propen-1-one, 1-[4-[2-(2-methoxyphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 2-Propen-1-one, 1-[4-(2-methoxyacetyl)-1-piperazinyl]-3-[4- [(trifluoromethyl)thio]phenyl]-; 2-Propen-1-one, 1-[4-[2-(2,4-dimethylphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 2-Propen-1-one, 1-[4-[2-(3,4-dimethylphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 2-Propen-1-one, 1-[4-[2-(2,3-dimethylphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 2-Propen-1-one, 3-(4-fluoro-2-nitrophenyl)-1-[4-(2-methoxyacetyl)-1-piperazinyl]-; 2-Propen-1-one, 3-phenyl-1-[4-[2-(2,3,6-trimethylphenoxy)acetyl]-1-piperazinyl]-; 2-Propen-1-one, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-(2-fluorophenyl)-; 2-Propen-1-one, 3-[4-chloro-3-(trifluoromethyl)phenyl]-1-[4-(2-methoxyacetyl)-1- piperazinyl]-; 2-Propen-1-one, 3-[2-chloro-5-(trifluoromethyl)phenyl]-1-[4-(2-methoxyacetyl)-1- piperazinyl]-; 2-Propen-1-one, 1-[4-[2-(2,4-dichlorophenoxy)acetyl]-1-piperazinyl]-3-phenyl-; Benzonitrile, 2-[3-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-oxo-1-propen-1-yl]-; 2-Propen-1-one, 1-[4-[2-(4-chloro-3,5-dimethylphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 2-Propen-1-one, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-(2-ethoxyphenyl)-; 2-Propen-1-one, 1-[4-[2-[2-(1,1-dimethylethyl)-4-methylphenoxy]acetyl]-1-piperazinyl]- 3-phenyl-; Benzoic acid, 4-[3-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-oxo-1-propen-1-yl]-; 2-Propen-1-one, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-(4-nitrophenyl)-; 2-Propen-1-one, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-(2,6-difluorophenyl)-; 2-Propen-1-one, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-(3-fluoro-4- methoxyphenyl)-; 2-Propen-1-one, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-(3-nitrophenyl)-; 2-Propen-1-one, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-(2,5- dimethoxyphenyl)-; Acetamide, N-[4-[3-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-oxo-1-propen-1- yl]phenyl]-; 2-Propen-1-one, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-(3,4,5- trimethoxyphenyl)-2-Propen-1-one, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-[4- (difluoromethoxy)-3-methoxyphenyl]-; 2-Propen-1-one, 1-[4-[2-[[1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5- l]oxy]acetyl]-1-piperazinyl]-3-phenyl-, (2E)-. In certain embodiments of the compounds of Formula (I), Ar1 is optionally substituted phenyl, optionally substituted naphthyl or optionally substituted 6,6- or 5,6- fused bicyclic heteroaryl, such as optionally substituted quinolyl or indolyl. In certain embodiments of the compounds of Formula (I), Ar1 is optionally substituted phenyl, optionally substituted 2-naphthyl, optionally substituted 3-indolyl or optionally substituted 3-quinolyl. In certain embodiments of the compounds of Formula (I), Ar1 is
Figure imgf000022_0001
where Ra, Rb, Rc, Rd and Re are each independently H, optionally substituted C1-C6-alkyl, halo, R6O-, R6S-, R6C(O)-, R7OC(O)-, optionally substituted C3-C8-cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; alternatively, Ra and Rb or Rb and Rc, together with the carbon atoms to which they are attached, form an optionally substituted carbocyclic or heterocyclic; R6 is optionally substituted C1-C6-alkyl, optionally substituted C3-C8-cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; and R7 is H or optionally substituted C1-C6-alkyl. In certain embodiments of the compounds of Formula (I), Rb and Rc together form –O-(CH2)p-O-, where p is 1 or 2. In this embodiment, each of Ra, Rd and Re is preferably H. In certain embodiments of the compounds of Formula (I), Ra, Rb, Rc, Rd and Re are independently selected from H, optionally substituted C1-C6-alkyl, R6C(O)-, R7OC(O)-, optionally substituted aryl and optionally substituted heteroaryl. In certain embodiments of the compounds of Formula (I), at least two of Ra, Rb, Rc, Rd and Re are hydrogen. In certain embodiments of the compounds of Formula (I), R1 is aryl, preferably phenyl, and is unsubstituted or substituted with 1 to 5 substituents. The substituents are preferably independently selected from halo, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkyl-S-, halo-C1-C6-alkoxy, halo-C1-C6-alkyl-S-, and (C1-C4-alkyl)2N-. Preferably, the substituents are independently selected from methyl, ethyl, CF3, chloro, fluoro, methoxy, ethoxy, trifluoromethoxy and dimethylamino. In certain embodiments of the compounds of Formula (I), R1 is phenyl substituted with one methyl and one halogen, preferably chloro or fluoro. In certain embodiments, R1 is selected from phenyl, 2-methylphenyl, 4-fluorophenyl, 2-chloro-4-methylphenyl, 2- chloro-3-methylphenyl, 3-chloro-4-methylphenyl, 3-chloro-5-methylphenyl, 3-methyl-4- chlorophenyl, 2-methyl-4-chlorophenyl, 2-methyl-3-chlorophenyl, 2-fluoro-4- methylphenyl, 2-fluoro-3-methylphenyl, 3-fluoro-4-methylphenyl, 3-fluoro-5- methylphenyl, 3-methyl-4-fluorophenyl, 2-methyl-4-fluorophenyl, and 2-methyl-3- fluorophenyl. In certain embodiments of the compounds of Formula (I), R1 is heteroaryl, preferably a 5- or 6-membered heteroaryl, such as furanyl, oxazolyl, or thiadiazolyl, and is unsubstituted or substituted with 1 to 3 substituents preferably selected from halo, C1-C6- alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkyl-S-, halo-C1-C6-alkoxy, halo-C1-C6- alkyl-S-, and (C1-C4-alkyl)2N-. Preferably, the substituents are independently selected from methyl, ethyl, CF3, chloro, fluoro, methoxy, ethoxy, trifluoromethoxy and dimethylamino. In certain embodiments of the compounds of Formula (I), R1 is C3-C8-cycloalkyl or 3- to 8-membered heterocycloalkyl and is unsubstituted or substituted with 1 to 3 substituents preferably selected from halo, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkyl-S-, halo-C1-C6-alkoxy, halo-C1-C6-alkyl-S-, and (C1-C4-alkyl)2N-. Preferably, the substituents are independently selected from methyl, ethyl, CF3, chloro, fluoro, methoxy, ethoxy, trifluoromethoxy and dimethylamino. In certain embodiments of the compounds of Formula (I), R1 is C3-C8-cycloalkyl, preferably C4-C8-cycloalkyl, and more preferably cyclopentyl, cyclohexyl or cycloheptyl. In certain embodiments of the compounds of Formula (I), X is O, S, SO, SO2 or NR, where R is hydrogen or methyl. Preferably, X is O or S. In certain embodiments of the compounds of Formula (I), n is 0 and B is -CH2-, - CH=CH-, –C≡C-, or -CH2CH2-. When B is -CH=CH-, B can be (Z)-CH=CH- or (E)- CH=CH- and is preferably (E)-CH=CH-. In certain embodiments, n is 1 and B is - CH2CH2-. In certain embodiments, the compound of Formula (I) is represented by Formula (II),
Figure imgf000024_0001
or a pharmaceutically acceptable salt thereof, where m is 0, 1 or 2, and X and R1 are as defined above. Preferably X is O or S. In certain embodiments, the compound of Formula (I) is represented by Formula (III),
Figure imgf000024_0002
or a pharmaceutically acceptable salt thereof, where X, Ar1 and R1 are as defined above. Preferably X is O or S. In certain embodiments, the compound of the invention is selected from the compounds 1-68 set forth below and pharmaceutically acceptable salts thereof.
Figure imgf000024_0003
Figure imgf000025_0001
7
Figure imgf000026_0001
12
Figure imgf000027_0001
17
Figure imgf000028_0001
22
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
37
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Protected derivatives of the compounds of the invention also are contemplated. In general, protecting groups are removed under conditions which will not affect the remaining portion of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis, and the like. One preferred method involves the removal of an ester, such as cleavage of a phosphonate ester using Lewis acidic conditions, such as in TMS-Br mediated ester cleavage to yield the free phosphonate. A second preferred method involves removal of a protecting group, such as removal of a benzyl group by hydrogenolysis utilizing palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like or mixtures thereof. A t-butoxy-based group, including t- butoxy carbonyl protecting groups can be removed utilizing an inorganic or organic acid, such as HCl or trifluoroacetic acid, in a suitable solvent system, such as water, dioxane and/or methylene chloride. Another exemplary protecting group, suitable for protecting amino and hydroxy functions amino is trityl. Other conventional protecting groups are known, and suitable protecting groups can be selected by those of skill in the art in consultation with Greene and Wuts, Protective Groups in Organic Synthesis; 3rd Ed.; John Wiley & Sons, New York, 1999. When an acid moiety, such as a phosphonic acid moiety is unveiled, the compound may be isolated as the acid compound or as a salt thereof. In certain embodiments, the compounds of each formula herein are defined to include isotopically labelled compounds. An “isotopically labelled compound” is a compound in which at least one atomic position is enriched in a specific isotope of the designated element to a level which is significantly greater than the natural abundance of that isotope. For example, one or more hydrogen atom positions in a compound can be enriched with deuterium to a level which is significantly greater than the natural abundance of deuterium, for example, enrichment to a level of at least 1%, preferably at least 20% or at least 50%. Such a deuterated compound may, for example, be metabolized more slowly than its non-deuterated analog, and therefore exhibit a longer half-life when administered to a subject. Such compounds can be synthesized using methods known in the art, for example by employing deuterated starting materials. Unless stated to the contrary, the isotopically labelled compounds are pharmaceutically acceptable. Definitions Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group. The singular terms “a,” “an,” and “the” include plural referents unless context clearly indicates otherwise. Similarly, the word “or” is intended to include “and” unless the context clearly indicates otherwise. The term “comprises” means “includes.” Also, “comprising A or B” means including A or B, or A and B, unless the context clearly indicates otherwise. It is to be further understood that all molecular weight or molecular mass values given for compounds are approximate and are provided for description. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, suitable methods and materials are described below. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. “Administration of” and “administering a” compound or agent should be understood to mean providing a compound or agent, a prodrug of a compound or agent, or a pharmaceutical composition as described herein. The compound, agent or composition can be administered by another person to the subject (e.g., intravenously) or it can be self- administered by the subject (e.g., tablets or capsules). Where two or more compounds are administered, co-administration is typically preferred with the co-administration being either via a combination formulation, or via parallel or subsequent administration of the two compounds. More typically, sequential co-administration will be performed such that the first compound is present in the patient’s body in measurable quantities when the second compound is administered. The term “solvate” refers to a solid crystalline form of a compound which includes molecules of a solvent within the crystal lattice. Suitable solvates include those with pharmaceutically acceptable solvents, such as ethanolates and hydrates, including monohydrates and hemi-hydrates. The term “gluten peptide” or “gliadin peptide” is used to denote a peptide fragment of a gluten protein. Although the fragment is typically a subset of the amino acid sequence of a gluten protein, a gluten peptide may contain the entire amino acid sequence of a naturally occurring gluten protein. The terms “individual” and “subject” are used interchangeably herein and refer to an animal, such as a mammal, including a non-primate (e.g., a cow, pig, horse, cat, dog, rat, and mouse), a nonhuman primate (e.g., a monkey such as a cynomolgus monkey, a chimpanzee), and a human. In certain embodiments, the subject is refractory or non- responsive to current treatments for an autoimmune disease, such as celiac disease, T1D, SPS, AD, SS, and MG. “Tissue” means any biological sample taken from any individual, preferably a human. Tissues include blood, saliva, urine, biopsy samples, skin or buccal scrapings, and hair. Persons of skill in the art will appreciate that blood plasma drug concentrations obtained from individual subjects will vary due to inter-patient variability in the many parameters affecting drug absorption, distribution, metabolism, and excretion. For this reason, unless otherwise indicated, when a drug plasma concentration is listed, the value listed is the calculated mean value based on values obtained from a group of subjects tested. The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 2-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Examples of pharmaceutically acceptable salts include, but are not limited to, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentane-propionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate. The term “therapeutically-effective amount” of compounds of the invention means an amount effective to modulate the formation or progression of autoimmune diseases celiac disease in an individual. The term "aryl," as used herein, refers to a mono- or polycyclic carbocyclic ring system comprising at least one aromatic ring, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, and indenyl. A polycyclic aryl is a polycyclic ring system that comprises at least one aromatic ring. Polycyclic aryls can comprise fused rings, covalently attached rings or a combination thereof. The term "heteroaryl," as used herein, refers to a mono- or polycyclic aromatic radical having one or more ring atom selected from S, O and N; and the remaining ring atoms are carbon, wherein any N or S contained within the ring may be optionally oxidized. Heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, quinoxalinyl. A polycyclic heteroaryl can comprise fused rings, covalently attached rings or a combination thereof. In accordance with the invention, aromatic groups can be substituted or unsubstituted. The term “alkyl” as used herein, refers to saturated, straight- or branched-chain hydrocarbon radicals. Exemplary alkyl groups include "C1-C4 alkyl,” "C1-C6 alkyl,” “C1-C8 alkyl,” “C1-C12 alkyl," "C2-C4 alkyl,” or "C3-C6 alkyl,” which refer to alkyl groups containing from one to four, one to six, one to eight, one to twelve, 2 to 4 and 3 to 6 carbon atoms respectively. Examples of C1-C8 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl and octyl radicals. The term “alkenyl” as used herein, refers to straight- or branched-chain hydrocarbon radicals having at least one carbon-carbon double bond by the removal of a single hydrogen atom. Exemplary alkenyl groups include “C2-C8 alkenyl,” “C2-C12 alkenyl," “C2-C4 alkenyl,” “C3-C4 alkenyl,” or “C3-C6 alkenyl,” which refer to alkenyl groups containing from two to eight, two to twelve, two to four, three to four or three to six carbon atoms respectively. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 2-methyl-2-buten-2-yl, heptenyl, octenyl, and the like. The term “alkynyl” as used herein, refers to straight- or branched-chain hydrocarbon radicals having at least one carbon-carbon triple bond by the removal of a single hydrogen atom. Exemplary alkynyl groups include “C2-C8 alkynyl,” “C2-C12 alkynyl," “C2-C4 alkynyl,” “C3-C4 alkynyl,” or “C3-C6 alkynyl,” which refer to alkynyl groups containing from two to eight, two to twelve, two to four, three to four or three to six carbon atoms respectively. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 2-propynyl, 2-butynyl, heptynyl, octynyl, and the like. The term “cycloalkyl”, as used herein, refers to a monocyclic or polycyclic saturated carbocyclic ring or a bi- or tri-cyclic group fused, bridged or spiro system, and the carbon atoms may be optionally oxo-substituted or optionally substituted with exocyclic olefinic double bond. Preferred cycloalkyl groups include C3-C12 cycloalkyl, C3- C6 cycloalkyl, C3-C8 cycloalkyl and C4-C7 cycloalkyl. Examples of C3-C12 cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl, 4-methylene-cyclohexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.0]hexyl, spiro[2.5]octyl, 3-methylenebicyclo[3.2.1]octyl, spiro[4.4]nonanyl, and the like. The term “cycloalkenyl”, as used herein, refers to monocyclic or polycyclic carbocyclic ring or a bi- or tri-cyclic group fused, bridged or spiro system having at least one carbon-carbon double bond and the carbon atoms may be optionally oxo-substituted or optionally substituted with exocyclic olefinic double bond. Preferred cycloalkenyl groups include C3-C12 cycloalkenyl, C3-C8 cycloalkenyl or C5-C7 cycloalkenyl groups. Examples of C3-C12 cycloalkenyl include, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[2.2.1]hept-2-enyl, bicyclo[3.1.0]hex-2-enyl, spiro[2.5]oct-4-enyl, spiro[4.4]non-2-enyl, bicyclo[4.2.1]non-3- en-12-yl, and the like. As used herein, the term “arylalkyl” means a functional group wherein an alkylene chain is attached to an aryl group, e.g., -CH2CH2-phenyl. The term “substituted arylalkyl” means an arylalkyl functional group in which the aryl group is substituted. Similarly, the term “heteroarylalkyl” means a functional group wherein an alkylene chain is attached to a heteroaryl group. The term “substituted heteroarylalkyl” means a heteroarylalkyl functional group in which the heteroaryl group is substituted. As used herein, the term “alkoxy” employed alone or in combination with other terms means, unless otherwise stated, an alkyl group having the designated number of carbon atoms connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 2-propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers. Preferred alkoxy are (C2-C3) alkoxy. The terms “heterocyclyl” and “heterocycloalkyl” can be used interchangeably and refer to a non-aromatic ring, for example, a 3-to 12 membered ring, a 3-8-membered ring, or a bi- or tri-cyclic group fused, bridged or spiro system, where (i) each ring system contains at least one heteroatom independently selected from oxygen, sulfur and nitrogen, (ii) each ring system can be saturated or unsaturated (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) the nitrogen heteroatom may optionally be quaternized, (v) any of the above rings may be fused to an aromatic ring, and (vi) the remaining ring atoms are carbon atoms which may be optionally oxo-substituted or optionally substituted with exocyclic olefinic double bond. Representative heterocycloalkyl groups include, but are not limited to, 1,3-dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, 2-azabicyclo[2.2.1]-heptyl, 8-azabicyclo[3.2.1]octyl, 5-azaspiro[2.5]octyl, 2-oxa-7-azaspiro[4.4]nonanyl, 7-oxooxepan-4-yl, and tetrahydrofuryl. Such heterocyclyl groups may be further substituted. Heteroaryl or heterocyclyl groups can be C-attached or N-attached (where possible). It is understood that any alkyl, alkenyl, alkynyl, alicyclic, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aliphatic moiety or the like, described herein can also be a divalent or multivalent group when used as a linkage to connect two or more groups or substituents, which can be at the same or different atom(s). One of skill in the art can readily determine the valence of any such group from the context in which it occurs. The term “substituted” refers to substitution by independent replacement of one, two, or three or more of the hydrogen atoms with substituents including, but not limited to, -F, -Cl, -Br, -I, -OH, C1-C12-alkyl; C2-C12-alkenyl, C2-C12-alkynyl, -C3-C12-cycloalkyl, protected hydroxy, -NO2, -N3, -CN, -NH2, protected amino, oxo, thioxo, -NH-C1-C12-alkyl, -NH-C2-C8-alkenyl, -NH-C2-C8-alkynyl, -NH-C3-C12-cycloalkyl, -NH-aryl, -NH- heteroaryl, -NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, -O-C1- C12-alkyl, -O-C2-C8-alkenyl, -O-C2-C8-alkynyl, -O-C3-C12-cycloalkyl, -O-aryl, -O- heteroaryl, -O-heterocycloalkyl, -C(O)-C1-C12-alkyl, -C(O)-C2-C8-alkenyl, -C(O)-C2-C8- alkynyl, -C(O)-C3-C12-cycloalkyl, -C(O)-aryl, -C(O)-heteroaryl, -C(O)-heterocycloalkyl, - CONH2, -CONH-C1-C12-alkyl, -CONH-C2-C8-alkenyl, -CONH-C2-C8-alkynyl, -CONH- C3-C12-cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl, -OCO2-C1- C12-alkyl, -OCO2-C2-C8-alkenyl, -OCO2-C2-C8-alkynyl, -OCO2-C3-C12-cycloalkyl, - OCO2-aryl, -OCO2-heteroaryl, -OCO2-heterocycloalkyl, -CO2-C1-C12 alkyl, -CO2-C2-C8 alkenyl, -CO2-C2-C8 alkynyl, CO2-C3-C12-cycloalkyl, -CO2- aryl, CO2-heteroaryl, CO2- heterocyloalkyl, -OCONH2, -OCONH-C1-C12-alkyl, -OCONH-C2-C8-alkenyl, -OCONH- C2-C8-alkynyl, -OCONH-C3-C12-cycloalkyl, -OCONH-aryl, -OCONH-heteroaryl, - OCONH- heterocyclo-alkyl, -NHC(O)H, -NHC(O)-C1-C12-alkyl, -NHC(O)-C2-C8-alkenyl, -NHC(O)-C2-C8-alkynyl, -NHC(O)-C3-C12-cycloalkyl, -NHC(O)-aryl, -NHC(O)- heteroaryl, -NHC(O)-heterocyclo-alkyl, -NHCO2-C1-C12-alkyl, -NHCO2-C2-C8-alkenyl, - NHCO2- C2-C8-alkynyl, -NHCO2-C3-C12-cycloalkyl, -NHCO2-aryl, -NHCO2-heteroaryl, - NHCO2- heterocycloalkyl, -NHC(O)NH2, -NHC(O)NH-C1-C12-alkyl, -NHC(O)NH-C2-C8-alkenyl, -NHC(O)NH-C2-C8-alkynyl, -NHC(O)NH-C3-C12- cycloalkyl, -NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, -NHC(O)NH-heterocycloalkyl, NHC(S)NH2, -NHC(S)NH-C1-C12-alkyl, -NHC(S)NH-C2-C8-alkenyl, -NHC(S)NH-C2-C8- alkynyl, -NHC(S)NH-C3-C12-cycloalkyl, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, - NHC(S)NH-heterocycloalkyl, -NHC(NH)NH2, -NHC(NH)NH-C1-C12-alkyl, - NHC(NH)NH-C2-C8-alkenyl, -NHC(NH)NH-C2-C8-alkynyl, -NHC(NH)NH-C3-C12- cycloalkyl, -NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, -NHC(NH)NH- heterocycloalkyl, -NHC(NH)-C1-C12-alkyl, -NHC(NH)-C2-C8-alkenyl, -NHC(NH)-C2-C8- alkynyl, -NHC(NH)-C3-C12-cycloalkyl, -NHC(NH)-aryl, -NHC(NH)-heteroaryl, - NHC(NH)-heterocycloalkyl, -C(NH)NH-C1-C12-alkyl, -C(NH)NH-C2-C8-alkenyl, - C(NH)NH-C2-C8-alkynyl, -C(NH)NH-C3-C12-cycloalkyl, -C(NH)NH-aryl, -C(NH)NH- heteroaryl, -C(NH)NH-heterocycloalkyl, -S(O)-C1-C12-alkyl, -S(O)-C2-C8-alkenyl, - S(O)- C2-C8-alkynyl, -S(O)-C3-C12-cycloalkyl, -S(O)-aryl, -S(O)-heteroaryl, -S(O)- heterocycloalkyl, -SO2NH2, -SO2NH-C1-C12-alkyl, -SO2NH-C2-C8-alkenyl, -SO2NH- C2- C8-alkynyl, -SO2NH-C3-C12-cycloalkyl, -SO2NH-aryl, -SO2NH-heteroaryl, -SO2NH- heterocycloalkyl, -NHSO2-C1-C12-alkyl, -NHSO2-C2-C8-alkenyl, - NHSO2-C2-C8-alkynyl, -NHSO2-C3-C12-cycloalkyl, -NHSO2-aryl, -NHSO2-heteroaryl, -NHSO2-heterocycloalkyl, -CH2NH2, -CH2SO2CH3, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -C3-C12-cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, - SH, -S-C1-C12-alkyl, -S-C2-C8-alkenyl, -S-C2-C8-alkynyl, -S-C3-C12-cycloalkyl, -S-aryl, - S-heteroaryl, -S-heterocycloalkyl, or methylthio-methyl. In certain embodiments, the substituents are independently selected from halo, preferably Cl and F; C1-C4-alkyl, preferably methyl and ethyl; halo-C1-C4-alkyl, such as fluoromethyl, difluoromethyl, and trifluoromethyl; C2-C4-alkenyl; halo-C2-C4-alkenyl; C3-C6-cycloalkyl, such as cyclopropyl; C1-C4-alkoxy, such as methoxy and ethoxy; halo-C1-C4-alkoxy, such as fluoromethoxy, difluoromethoxy, and trifluoromethoxy; -CN; -OH;NH2; C1-C4- alkylamino; di(C1-C4-alkyl)amino; and NO2. It is understood that the aryls, heteroaryls, alkyls, and the like can be further substituted. In some cases, each substituent in a substituted moiety is additionally optionally substituted with one or more groups, each group being independently selected from C1-C4-alkyl; -CF3, -OCH3, -OCF3, -F, -Cl, -Br, -I, -OH, -NO2, -CN, and -NH2. Preferably, a substituted alkyl group is substituted with one or more halogen atoms, more preferably one or more fluorine or chlorine atoms. The term “halo” or halogen” alone or as part of another substituent, as used herein, refers to a fluorine, chlorine, bromine, or iodine atom. The term “optionally substituted”, as used herein, means that the referenced group may be substituted or unsubstituted. In one embodiment, the referenced group is optionally substituted with zero substituents, i.e., the referenced group is unsubstituted. In another embodiment, the referenced group is optionally substituted with one or more additional group(s), which can be, for example, individually and independently selected from groups described herein. The term “hydroxyl activating group,” as used herein, refers to a labile chemical moiety which is known in the art to activate a hydroxyl group so that it will depart during synthetic procedures such as in a substitution or an elimination reaction. Examples of hydroxyl activating group include, but not limited to, mesylate, tosylate, triflate, p- nitrobenzoate, phosphonate and the like. The term “activated hydroxyl,” as used herein, refers to a hydroxy group activated with a hydroxyl activating group, as defined above, including mesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups, for example. The term “hydroxy protecting group,” as used herein, refers to a labile chemical moiety which is known in the art to protect a hydroxyl group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the hydroxy protecting group as described herein may be selectively removed. Hydroxy protecting groups as known in the art are described generally in T.H. Greene and P.G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples of hydroxyl protecting groups include benzyloxycarbonyl, 4- methoxybenzyloxycarbonyl, tert-butoxy-carbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t- butyl, 2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, allyl, benzyl, triphenyl-methyl (trityl), methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-(trimethylsilyl)-ethoxymethyl, methanesulfonyl, trimethylsilyl, triisopropylsilyl, and the like. The term "protected hydroxy," as used herein, refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups, for example. The term “hydroxy prodrug group,” as used herein, refers to a promoiety group which is known in the art to change the physicochemical, and hence the biological properties of a parent drug in a transient manner by covering or masking the hydroxy group. After said synthetic procedure(s), the hydroxy prodrug group as described herein must be capable of reverting back to hydroxy group in vivo. Hydroxy prodrug groups as known in the art are described generally in Kenneth B. Sloan, Prodrugs, Topical and Ocular Drug Delivery, (Drugs and the Pharmaceutical Sciences; Volume 53), Marcel Dekker, Inc., New York (1992). The term “amino protecting group,” as used herein, refers to a labile chemical moiety which is known in the art to protect an amino group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the amino protecting group as described herein may be selectively removed. Amino protecting groups as known in the art are described generally in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples of amino protecting groups include, but are not limited to, methoxycarbonyl, t- butoxycarbonyl, 12-fluorenyl-methoxycarbonyl, benzyloxycarbonyl, and the like. The term “protected amino,” as used herein, refers to an amino group protected with an amino protecting group as defined above. The term "leaving group" means a functional group or atom which can be displaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction. By way of example, representative leaving groups include chloro, bromo and iodo groups; sulfonic ester groups, such as mesylate, tosylate, brosylate, nosylate and the like; and acyloxy groups, such as acetoxy, trifluoroacetoxy and the like. The term "aprotic solvent," as used herein, refers to a solvent that is relatively inert to proton activity, i.e., not acting as a proton-donor. Examples include, but are not limited to, hydrocarbons, such as hexane and toluene, for example, halogenated hydrocarbons, such as, for example, methylene chloride, ethylene chloride, chloroform, and the like, heterocyclic compounds, such as, for example, tetrahydrofuran and N- methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether. Such compounds are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of aprotic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick et al., Vol. II, in the Techniques of Chemistry Series, John Wiley & Sons, NY, 1986. The term “protic solvent,” as used herein, refers to a solvent that tends to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like. Such solvents are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of protogenic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick et al., Vol. II, in the Techniques of Chemistry Series, John Wiley & Sons, NY, 1986. Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. The term “stable,” as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject). Pharmaceutical Compositions The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers. As used herein, the term "pharmaceutically acceptable carrier" means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or Formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the Formulator. The pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, or as an oral or nasal spray. The pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically acceptable carriers, adjuvants or vehicles. In some cases, the pH of the Formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the Formulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide- polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable Formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragées, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical Formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic Formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention. The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons. Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel. The methods provided herein encompass administering pharmaceutical compositions containing compounds of this disclosure, if appropriate in the salt form, either alone or in the form of a combination with one or more compatible and pharmaceutically acceptable carriers, such as diluents or adjuvants, or with another therapeutic agent. The second or additional therapeutic agent can be formulated or packaged with a compound of the invention. The second agent will only be formulated with a compound of the invention according to the judgment of those of skill in the art, as such co-formulation should not interfere with the activity of either agent or the method of administration. The compound of the invention and the second agent may be formulated separately. They may also be packaged together, or packaged separately, for the convenience of the medical practitioner. A preferred formulation of the invention is a mono-phasic pharmaceutical composition suitable for oral administration for the treatment, prophylaxis, or for slowing the progression or for delaying the onset of an autoimmune disease, consisting essentially of a therapeutically-effective amount of a compound of the invention, and a pharmaceutically acceptable carrier. Methods of Use Provided herein are methods for the treatment and/or prophylaxis of an autoimmune disease in a subject. These methods include the treating a subject suffering from an autoimmune disease by the administration of an effective amount of a compound of the invention. In these methods, the autoimmune disease may be associated with the occurrence of certain DQ2 alleles. In these methods, the autoimmune disease can be, but is not limited to, one or more of celiac disease, T1D, SPS, AD, SS, and MG. These methods may encompass the step of administering to the individual in need of such treatment an amount of a compound of the invention effective for treating or delaying the development or progression of the autoimmune disease. The compounds of the invention that may be administered to an individual in these methods may be in the form of a pharmaceutical composition or single unit dosage form, as described above. The invention includes methods of treating or slowing the progression or development of an autoimmune disease by reducing or preventing the binding of MHC class II molecules to antigenic peptides or fragments of antigenic peptides of the autoimmune disease by the administration of a compound of the invention to individuals suffering from, or at risk of developing, the autoimmune disease. A specific method includes treating celiac disease in an individual comprising administering an effective amount of a compound of the invention to an individual in need of such treatment. Another method provided herein includes treating an individual at risk of developing an autoimmune disease by administering an effective amount of a compound of the invention to the individual. Thus, the invention provides for the use of a compound of the invention in the manufacture of a medicament for the treatment of an autoimmune disease. In this use, the autoimmune disease may be one or more of celiac disease, T1D, SPS, AD, SS, and MG. The invention also provides a compound of the invention for use in the treatment of an autoimmune disease selected from one or more of celiac disease, T1D, SPS, AD, SS, and MG. In these methods, a compound of the invention can be administered orally to the subject. The compound of the invention may be administered to an individual once daily, or more frequently. The compound of the invention can be administered to a subject as a pharmaceutically acceptable salt, solvate, or hydrate thereof. The compound of the invention, or a pharmaceutically acceptable salt thereof, may be administered to a subject as a pharmaceutical composition, as described above. In the methods of treating or slowing the progression or development of an autoimmune disease of the invention, a compound of the invention or a pharmaceutically acceptable salt thereof, is administered to a subject suspected of suffering from, or at risk of developing the autoimmune disease. Preferably, the administration to a subject diagnosed with the autoimmune disease commences within 5 years of the initial diagnosis of the autoimmune disease in the subject, or more preferably, within 1 year of the initial diagnosis of the autoimmune disease in the subject, or more preferably, within 6 months of the initial diagnosis of the autoimmune disease in the subject, or more preferably, within 1 month of the initial diagnosis of the autoimmune disease in the subject. In any of these methods, the subject may be administered a dosage of a compound of the invention, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, that is therapeutically effective to treat or delay the development or progression of the autoimmune disease in the subject. Another aspect of these methods includes an initial determination of which patients may benefit from the administration of a compound of the invention, prior to administration of a compound of the invention to the subject determined to be in need of such treatment. As described above, DQ2 alleles confer significant risk of several autoimmune diseases. Thus, subjects with certain known DQ2 alleles are subjects at risk of developing an autoimmune disease. Additionally, subjects with anti-transglutaminase antibodies, EmA anti-endomysium antibodies, and/or antibodies against deamidated gliadin peptides, or autoantibodies that recognize an MHC class II molecule bound to a gliadin peptide, or to gliadin peptide fragment(s), wherein the presence of such antibodies in the subject is indicative of the presence or likely development of celiac disease in that subject. Such subject therefore may benefit from the administration of a compound of the invention, as described above. The determination of which DQ2 alleles are present in a subject may enable a clinician to establish the subject’s risk of developing an autoimmune disease. For example, the finding of a heterozygote of a high risk DQ2 genotype in the subject may be used to modify the dosage and/or dosing regimen of a compound of the invention to the subject, which may include reducing the dose or frequency of administration of a compound of the invention to the subject. Alternatively, if the genotyping methods of the invention reveal homozygous wild type HLA alleles, in a nucleic acid sample obtained from the subject, then the clinician may rule out an elevated risk of developing an autoimmune disease in the subject and consider different treatments or diagnoses for that subject. A number of methods are available for analyzing and determining the DQ2 and/or DQ8 genotype in a subject, which can be applied to a nucleic acid sample obtained from a subject. Assays for detection of polymorphisms or mutations fall into several categories, including but not limited to, direct sequencing assays, fragment polymorphism assays, hybridization assays, and computer-based data analysis. Protocols and kits or services for performing these general methods are commercially available and well known to those of skill in the art. In some embodiments, assays are performed in combination or in hybrid (e.g., different reagents or technologies from several assays are combined to yield one assay). Thus, the presence or absence of DQ8 and/or DQ2 alleles may be determined using direct sequencing. Alternatively or additionally, the DQ8 and/or DQ2 alleles may be determined using a PCR-based assay using oligonucleotide primers to amplify a DNA fragment containing the DQ8 and/or DQ2 polymorphism of interest. Alternatively or additionally, the DQ8 and/or DQ2 alleles may be determined using a fragment length polymorphism assay, such as a restriction fragment length polymorphism assay (RFLP), to detect a unique DNA banding pattern indicative of an DQ8 and/or DQ2 genotype based on cleaving the DNA at a series of positions is generated using an enzyme (e.g., a restriction endonuclease). Alternatively or additionally, the DQ8 and/or DQ2 alleles may be determined using a hybridization assay, wherein the genotype is determined based on the ability of the DNA from the sample to hybridize to a complementary DNA molecule (e.g., an oligonucleotide probe). The DQ8 and/or DQ2 polymorphisms of interest may be detected using a DNA chip hybridization assay, in which a series of oligonucleotide probes, designed to be unique to a given single nucleotide polymorphism, are affixed to a solid support, and the nucleic acid sample from the subject is contacted with the DNA “chip” and hybridization is detected. Alternatively or additionally, the DQ8 and/or DQ2 alleles may be determined using a “bead array” (such as those described in PCT Publications WO99/67641 and WO00/39587, each of which is herein incorporated by reference). Alternatively or additionally, the DQ8 and/or DQ2 alleles may be determined using an assay that detects hybridization by enzymatic cleavage of specific structures (such as those assays described in U.S. Pat. No.6,001,567, and Olivier, M., The Invader assay for SNP Genotyping, 2005 Mutat. Res.573(1-2):103-10, both of which are incorporated herein by reference). Any known method of analyzing a sample for an analyte can be used to practice the present invention, so long as the method detects the presence, absence, or amount of autoimmune disease-associated antibodies, such as anti-gluten protein antibodies, anti- transglutaminase antibodies, antibodies against deamidated gliadin peptides, acetylcholine receptor antibodies, and/or anti-endomysium antibodies. Examples of such methods include, but are not limited to, immunological detection assays and non-immunological methods (e.g., enzymatic detection assays). Alternatively or additionally, a binding compound is immobilized on a substrate, such as a microtiter dish well, a dipstick, an immunodot strip, or a lateral flow apparatus. A sample collected from a subject is applied to the substrate and incubated under conditions suitable to allow the formation of a complex between the binding compound and any antibody present in the sample. Once formed, the complex is then detected. Complex formation, or selective binding, between an antibody and a binding compound can be measured (i.e., detected, determined) using a variety of methods standard in the art including, but not limited to, an enzyme-linked immunoassay, a competitive enzyme-linked immunoassay, a radioimmunoassay, a fluorescence immunoassay, a chemiluminescent assay, a lateral flow assay, a flow-through assay, an agglutination assay, a particulate-based assay (e.g., using particulates such as, but not limited to, magnetic particles or plastic polymers, such as latex or polystyrene beads), an immunoprecipitation assay, a BIACORE™ assay (e.g., using colloidal gold), an immunodot assay (e.g., CMG's Immunodot System, Fribourg, Switzerland), and an immunoblot assay (e.g., a western blot), an phosphorescence assay, a flow-through assay, a chromatography assay, a PAGE-based assay, a surface plasmon resonance assay, a spectrophotometric assay, a particulate-based assay, and an electronic sensory assay. The assays may be used to give qualitative or quantitative results. The assay results can be based on detecting the entire antibody or fragments, or degradation products. Some assays, such as agglutination, particulate separation, and immunoprecipitation, can be observed visually (e.g., either by eye or by a machine, such as a densitometer or spectrophotometer) without the need for a detectable marker. A detectable marker can be conjugated to the compound or reagent at a site that does not interfere with the ability of the compound to bind antibodies. Methods of conjugation are known to those of skill in the art. Examples of detectable markers include, but are not limited to, a radioactive label, a fluorescent label, a chemiluminescent label, a chromophoric label, an enzyme label, a phosphorescent label, an electronic label, a metal sol label, a colored bead, a physical label, or a ligand. A ligand refers to a molecule that binds selectively to another molecule. Preferred detectable markers include, but are not limited to, fluorescein, a radioisotope, a phosphatase (e.g., alkaline phosphatase), biotin, avidin, a peroxidase (e.g., horseradish peroxidase), beta- galactosidase, and biotin-related compounds or avidin-related compounds (e.g., streptavidin or IMMUNOPURE™ NeutrAvidin). Means of detecting such markers are well known to those of skill in the art. For example, a tri-molecular complex between a gliadin antigen, an MHC molecule, and T cell receptor can be detected by contacting a biological sample from a subject with an antibody specific for the complex, wherein the antibody is conjugated to a detectable marker. A detectable marker can also be conjugated to a tri-molecular complex between a gliadin antigen, an MHC molecule, and T cell receptor such that contact of the labeled complex with a biological sample from a subject can detect the presence of antibodies to the complex present in the subject tested. Detectable markers include, but are not limited to, fluorescein, a radioisotope, a phosphatase (e.g., alkaline phosphatase), biotin, avidin, a peroxidase (e.g., horseradish peroxidase), beta-galactosidase, and biotin- related compounds or avidin-related compounds (e.g., streptavidin or IMMUNOPURE™ NeutrAvidin). A tri-molecular complex may be detected by contacting the complex with an indicator molecule. Suitable indicator molecules include molecules that can bind to the tri- molecular binding molecule complex. As such, an indicator molecule can comprise, for example, an antibody. Preferred indicator molecules that are antibodies include, for example, antibodies reactive with the antibodies from animals in which the antibodies are produced. An indicator molecule itself can be attached to a detectable marker of the present invention. For example, an antibody can be conjugated to biotin, horseradish peroxidase, alkaline phosphatase or fluorescein. One or more layers and/or types of secondary molecules or other binding molecules capable of detecting the presence of an indicator molecule may be used. For example, an untagged (i.e., not conjugated to a detectable marker) secondary antibody that selectively binds to an indicator molecule can be bound to a tagged (i.e., conjugated to a detectable marker) tertiary antibody that selectively binds to the secondary antibody. Suitable secondary antibodies, tertiary antibodies and other secondary or tertiary molecules can be readily selected by those skilled in the art. Preferred tertiary molecules can also be selected by those skilled in the art based upon the characteristics of the secondary molecule. The same strategy can be applied for subsequent layers. A lateral flow assay may be used for detection, examples of which are described in U.S. Patent No.5,424,193; U.S. Pat. No.5,415,994; WO 94/29696; and WO 94/01775 (all of which are incorporated by reference herein). Once a biological sample from a subject has been analyzed to determine which DQ2 allele is present, the subject can be selected, or identified, as likely or unlikely to develop, or at higher or lower risk of developing, an autoimmune disease. Such a selection is made using the results from the analysis step of the disclosed methods. Those subjects selected as likely or at higher risk of developing an autoimmune disease may be treated with one or more compounds of the invention to treat or slow the development of the autoimmune disease in the subject. Each publication or patent cited herein is incorporated herein by reference in its entirety. Additional objects, advantages, and novel features of the invention will become apparent to those skilled in the art upon examination of the following examples, which are not intended to be limiting. Examples Example 1 Compound Synthesis General Experimental Methods Unless otherwise noted, all materials/reagents are obtained from commercial suppliers and used without further purification. Reactions are monitored by LC-MS and/or thin layer chromatography (TLC) on silica gel 60 F254 (0.2mm) pre-coated aluminum foil or glass-backed and visualized using UV light.1HNMR (400 MHz) spectra are recorded on Bruker spectrometers at rt with TMS or the residual solvent peak as the internal standard. The line positions or multiples are given in (δ) and the coupling constants (J) are given as absolute values in Hertz (Hz). The multiplicities in 1HNMR spectra are abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br or broad (broadened). Preparative HPLC purifications are performed on Shimadzu LC-6AD. All purification work is performed using Shim-pack PREP-DDS (H) KIT Column. The mobile phases are water (with 0.1%HCO2H) and acetonitrile. All reagents used are of HPLC grade. The flow rate is 10 ml/min. LC-MS is performed on Shimadzu LCMS-2020 equipped with LC-20AD or 30AD pumps, SPD-M20A PDA and Alltech 3300 ELSD; Mobile Phase: A: Water (0.1% Formic acid), B : CAN; 5 minute run; Column: Sepax BR- C184.6*50 mm, 3 um; Flow Rate: 1.0 ml/min; Oven Temperature: 40oC; Gradient: 20% B for 0.2 min, increased to70% B within 1.8 min, 70% B for 2.8 min, back to 20% B within 0.2 min, 20% B for 2 min). Preparative TLC is performed on Whatman LK6F Silica Gel 60A size 20x20 cm plates with a thickness of 1000 μm or equivalent. General procedures for synthesizing intermediates in the synthesis of certain compounds disclosed herein are shown in the schemes below. General Method A
Figure imgf000058_0001
General Method B
Figure imgf000058_0002
General Method C
Figure imgf000059_0001
General Method A To a stirred solution of NaH (24 mmol) in tetrahydrofuran (20 mL) at 0℃ under N2 is added the alcohol (8 mmol). After stirring at 0℃ for 0.5 h, BrCH2COOH (1.0 g, 7.2 mmol) was added; the resulting mixture is stirred at 0℃ for 5 mins and then refluxed (80℃) for 4 h. Reflux is continued until the reaction is complete by TLC showed the reaction was complete. The reaction mixture is quenched with water and washed with hexane. The aqueous layer is adjusted to pH 1-2 and extracted with dichloromethane. The combined organic layers are washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the product carboxylic acid ether. General Method B To a stirred solution of sodium hydroxide (344 mg, 8.60 mmol) in tetrahydrofuran (6 ml) and water (6 mL) under N2 at RT is added the thiol (4.30 mmol). The resulting mixture is stirred at RT for 5 min, followed by addition of 2-bromoacetic acid (596 mg, 4.30 mmol). The temperature is raised to 7℃ and stirred until the reaction is complete by TLC. The reaction mixture is concentrated to remove THF. The resulting aqueous layer is washed with ethyl acetate, acidified to pH 2 with aqueous HCl (2N), and extracted with ethyl acetate. The combined organic layers are washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the carboxylic acid thioether which is used in next step without further purification. General Method C Synthesis of Intermediate A To a stirred solution of an aryl alkyl, aryl alkenyl or aryl alkynyl carboxylic acid (5.9 mmol), and HATU (2.14 g, 5.6 mmol) in N, N-Dimethylformamide (20 ml) is added DIPEA (2.1 g, 16 mmol) under N2 at 0℃, the resulting mixture is stirred for 5 mins, followed by addition of tert-butyl piperazine-1-carboxylate (1 g, 5.4 mmol) at 0℃. The resulting mixture is stirred at 0℃ for 0.5 h, allowed to warm to RT and stirred overnight. The reaction mixture is concentrated to remove N, N-Dimethylformamide. The resulting residue is diluted with ethyl acetate and washed with water. The organic layer is collected and the aqueous layer extracted with ethyl acetate. The combined organic layers are washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude which is purified by silica gel flash column chromatography to afford intermediate A. Synthesis of Intermediate B To a solution of Intermediate A (2.5 g) in dichloromethane (10 mL) with ice-water bath is added dropwise TFA (10 mL), the resulting mixture is stirred at room temperature for 2h. or until TLC indicates that the reaction is complete. The reaction mixture is basified with aqueous NaOH solution to pH 9, extracted with dichloromethane, washed with H2O, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford intermediate B which was used in next step without further purification. Synthesis of Compounds 1-68 To a solution of Intermediate B (0.90 mmol), the carboxylic acid product of Method A or B (0.95 mmol), and DIPEA (340 mg, 2.6 mmol) in acetonitrile (5 mL) is added HATU (350 mg, 0.91 mmol). The mixture was stirred at room temperature overnight. The reaction mixture is concentrated to dryness in vacuo, diluted with ethyl acetate, washed with semi-saturated brine (3 X 5 mL), saturated aqueous NH4Cl solution, and saturated aqueous NaHCO3 solution respectively. The resulting solution is dried over anhydrous sodium sulfate and concentrated to give a crude residue which was purified by Preparative TLC to afford the target compounds 1- 68. Example 2 In vitro testing of DQ2 inhibitory compounds Three commercially available analogues of the DQ2 binding molecules of the invention were tested for their ability to inhibit stimulation of T cell receptor (TCR) transductants in the presence of HLA-DQ2 expressing cells presenting known α-gliadin epitopes. Using a previously published in vitro assay (Ostrov D, et al. Methyldopa blocks MHC class II binding to disease specific antigens in autoimmune diabetes. J Clin Invest. 2018:128(5)) the ability of these DQ2 binding analogues to inhibit interleukin-2 (IL-2) secretion by TCR transductants stimulated by α-gliadin peptides presented by HLA-DQ2 was determined. Individual TCR transductants (recognizing α I-gliadin or α II-gliadin) were cultured with a gliadin peptide plus the small molecule analogues in the presence of HLA-DQ2 expressing K562 cells serving as antigen presenting cells. TCR transductants cultured with no gliadin peptide served as the negative control, and incubation with an anti-CD3 antibody (eBioscience; clone 2C11) served as a positive control for the TCR transductant. Secreted IL-2 in the culture supernatant was measured using a highly sensitive enzyme-linked immunosorbent assay (ELISA). A dose-response curve was generated for each of the tested analogs and the concentration at which the compound exhibited maximum % inhibition was determined. Assays for effects on cell viability and for specificity, assayed in the absence of gliadin peptide or in the presence of a stimulating anti-CD3 antibody, were performed. The results are set forth in the table below. EC50: A = <25 µM; B = 25-50 µM; C = 50-100 µM; D = >100 µM. %Inhibition at 200 µL: A= >75%; B = 50-74%; C= 25-49%; D = 0-24%.
Figure imgf000061_0001
Figure imgf000062_0001
It will be apparent to those skilled in the art that many more modifications besides those already described are possible without departing from the inventive concepts herein. The inventive subject matter, therefore, is not to be restricted except in the scope of the appended claims.

Claims

CLAIMS What is claimed is: 1. A compound of Formula (I),
Figure imgf000063_0001
or a pharmaceutically acceptable salt or prodrug thereof, wherein Ar1 is optionally substituted aryl or optionally substituted heteroaryl; X is O, S, S(O), S(O)2, or NR; R1 is optionally substituted C1-C8-alkyl, optionally substituted C3-C8-cycloalkyl; optionally substituted heterocycloalkyl, optionally substituted heteroaryl or optionally substituted aryl; R is H or optionally substituted C1-C6-alkyl; B is -CH2-, –CH2CH2-, -CH=CH- or –C≡C-; and n is 0, 1, or 2; provided that the compound of Formula (I) is not a compound selected from the group consisting of 1-Butanone, 1-[4-[2-[(4-bromophenyl)thio]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[[(4-methylphenyl)methyl]thio]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[(3-methylbutyl)thio]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[(2-benzothiazolylmethyl)thio]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(2-benzothiazolylthio)acetyl]-1-piperazinyl]-4-phenyl-; Acetamide, N-(4-methylphenyl)-2-[[2-oxo-2-[4-(1-oxo-4-phenylbutyl)-1- piperazinyl]ethyl]thio]-; 1-Butanone, 1-[4-[2-[[(4-chlorophenyl)methyl]thio]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[[4-(3,4-dimethylphenyl)-4H-1,2,4-triazol-3-yl]thio]acetyl]-1- piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[(4-chlorophenyl)sulfonyl]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[[2-(4-morpholinyl)-2-oxoethyl]thio]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[[4-(2-ethylphenyl)-4H-1,2,4-triazol-3-yl]thio]acetyl]-1-piperazinyl]- 4-phenyl-; 1-Butanone, 1-[4-[2-[[4-(1-methylethyl)-4H-1,2,4-triazol-3-yl]thio]acetyl]-1-piperazinyl]- 4-phenyl-; 1-Butanone, 1-[4-[2-[(2-methylphenyl)thio]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[(2,3-dihydro-1H-inden-5-yl)thio]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[[4-(4-methylphenyl)-4H-1,2,4-triazol-3-yl]thio]acetyl]-1- piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[(4,6-dimethyl-2-pyrimidinyl)thio]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[[4-ethyl-5-(2-furanyl)-4H-1,2,4-triazol-3-yl]thio]acetyl]-1- piperazinyl]-4-phenyl-; Propanamide, N-(5-methyl-3-isoxazolyl)-2-[[2-oxo-2-[4-(1-oxo-4-phenylbutyl)-1- piperazinyl]ethyl]thio]-; 1-Butanone, 4-phenyl-1-[4-[2-[[5-(trifluoromethyl)-2-pyridinyl]thio]acetyl]-1- piperazinyl]-; 1-Butanone, 1-[4-[2-[(4-methylphenyl)thio]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[[(4-methoxy-3-nitrophenyl)methyl]thio]acetyl]-1-piperazinyl]-4- phenyl-; 1-Butanone, 1-[4-[2-[[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]thio]acetyl]-1-piperazinyl]- 4-phenyl-; 1-Butanone, 1-[4-[2-[[5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl]thio]acetyl]-1- piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(pentylsulfonyl)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[(4-fluorophenyl)thio]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[(4-acetyl-2-fluorophenyl)thio]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[[(3-chlorophenyl)methyl]thio]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[(3,4-difluorophenyl)thio]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[[4-(4-methoxyphenyl)-4H-1,2,4-triazol-3-yl]thio]acetyl]-1- piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[(1-cyclopentyl-1H-tetrazol-5-yl)thio]acetyl]-1-piperazinyl]-4- phenyl-; 1-Butanone, 1-[4-[2-[(4-chlorophenyl)thio]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[(2-fluorophenyl)thio]acetyl]-1-piperazinyl]-4-phenyl-; 1-Piperazineethanesulfonamide, N-(4-methylcyclohexyl)-b-oxo-4-(1-oxo-4-phenylbutyl)-; 5H-Thiazolo[3,2-a]pyrimidin-5-one, 7-[[[2-oxo-2-[4-(1-oxo-4-phenylbutyl)-1- piperazinyl]ethyl]thio]methyl]-; 1-Butanone, 1-[4-[2-[[(3,5-dimethyl-4-isoxazolyl)methyl]thio]acetyl]-1-piperazinyl]-4- phenyl-; 1-Butanone, 1-[4-[2-[(2,3-dihydro-1,4-benzodioxin-6-yl)thio]acetyl]-1-piperazinyl]-4- phenyl-; 1-Butanone, 1-[4-[2-[[4-(2,5-dimethylphenyl)-5-methyl-4H-1,2,4-triazol-3-yl]thio]acetyl]- 1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[(4-nitrophenyl)thio]acetyl]-1-piperazinyl]-4-phenyl-; Benzonitrile, 4-[[[2-oxo-2-[4-(1-oxo-4-phenylbutyl)-1-piperazinyl]ethyl]thio]methyl]-; 1-Butanone, 1-[4-[2-[(4-ethoxyphenyl)thio]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[(2,5-dimethylphenyl)thio]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[[4-(3-chlorophenyl)-4H-1,2,4-triazol-3-yl]thio]acetyl]-1- piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[[1-(2-methylphenyl)-1H-imidazol-2-yl]thio]acetyl]-1-piperazinyl]-4- phenyl-; 1-Butanone, 1-[4-[2-[[4-ethyl-5-(3-methylphenyl)-4H-1,2,4-triazol-3-yl]thio]acetyl]- 1-piperazinyl]-4-phenyl-; 1-Butanone, 4-phenyl-1-[4-[2-[(tetrahydro-1,1-dioxido-3-thienyl)thio]acetyl]-1- piperazinyl]-; 1-Butanone, 1-[4-[2-[(1-ethyl-1H-benzimidazol-2-yl)thio]acetyl]-1-piperazinyl] -4-phenyl-; 1-Butanone, 1-[4-[2-[(2-chlorophenyl)thio]acetyl]-1-piperazinyl]-4-phenyl-; Acetamide, N-(5-methyl-3-isoxazolyl)-2-[[2-oxo-2-[4-(1-oxo-4-phenylbutyl)-1- piperazinyl]ethyl]thio]-; 1-Butanone, 1-[4-[2-[[4-(3-chloro-4-methylphenyl)-4H-1,2,4-triazol-3-yl]thio]acetyl]- 1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[[5-methyl-4-(phenylmethyl)-4H-1,2,4-triazol-3-yl]thio]acetyl]-1- piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[[4-[4-(1-methylethyl)phenyl]-4H-1,2,4-triazol-3-yl]thio]acetyl]-1- piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[[4-ethyl-5-(2-methylphenyl)-4H-1,2,4-triazol-3-yl]thio]acetyl]- 1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[(1-cyclopropyl-1H-tetrazol-5-yl)thio]acetyl]-1-piperazinyl]-4- phenyl-; 1-Butanone, 1-[4-[2-[[(3-methylphenyl)methyl]thio]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(2-benzoxazolylthio)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 4-phenyl-1-[4-[2-[(3-phenylpropyl)sulfonyl]acetyl]-1-piperazinyl]-; 1-Butanone, 1-[4-[2-[(1-methyl-4-piperidinyl)oxy]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(1-naphthalenyloxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 4-phenyl-1-[4-[2-(3-piperidinylmethoxy)acetyl]-1-piperazinyl]-; 1-Butanone, 1-[4-[2-(2-aminoethoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[2-methoxy-4-(1-propen-1-yl)phenoxy]acetyl]-1-piperazinyl]-4- phenyl-; 1-Butanone, 1-[4-[2-[2-methoxy-4-(2-propen-1-yl)phenoxy]acetyl]-1-piperazinyl]-4- phenyl-; 1-Butanone, 1-[4-[2-(3,4-dichlorophenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(2,5-dichlorophenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(3-chloro-4-fluorophenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(2-chlorophenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(4-ethylphenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(4-chloro-3-methylphenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(3,4-dimethylphenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(4-bromo-2-fluorophenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 4-phenyl-1-[4-[2-[4-(trifluoromethyl)phenoxy]acetyl]-1-piperazinyl]-; 1-Butanone, 1-[4-[2-(2,4-dimethylphenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(3-chlorophenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[(2,3-dihydro-2,2-dimethyl-7-benzofuranyl)oxy]acetyl]-1- piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[4-(1-methylethyl)phenoxy]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[4-(1,3-dithian-2-yl)phenoxy]acetyl]-1-piperazinyl]-4-phenyl-; 2(1H)-Quinolinone, 3,4-dihydro-6-[2-oxo-2-[4-(1-oxo-4-phenylbutyl)-1- piperazinyl]ethoxy]-; 1-Butanone, 1-[4-[2-(3-nitrophenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(4-acetyl-2-methoxyphenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 4-phenyl-1-[4-[2-(4-propoxyphenoxy)acetyl]-1-piperazinyl]-; 1-Butanone, 1-[4-[2-(2,6-dimethylphenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(2-nitrophenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[5-methyl-2-(1-methylethyl)phenoxy]acetyl]-1-piperazinyl]-4- phenyl-; Butanone, 4-phenyl-1-[4-[2-[(1,4,6-trimethyl-1H-pyrazolo[3,4-b]pyridin-3-yl)oxy]acetyl]- 1-piperazinyl]-; 1-Butanone, 1-[4-[2-(2-methoxy-4-methylphenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 2H-1-Benzopyran-2-one, 7-[2-oxo-2-[4-(1-oxo-4-phenylbutyl)-1-piperazinyl]ethoxy]-; 1-Butanone, 1-[4-[2-[4-(1-oxopropyl)phenoxy]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(4-iodophenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(2-ethoxyphenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 2-Pyrrolidinone, 1-[4-[2-oxo-2-[4-(1-oxo-4-phenylbutyl)-1-piperazinyl]ethoxy]phenyl]-; 1-Butanone, 1-[4-[2-(3-acetylphenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[2-(1-methylpropyl)phenoxy]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(4-nitrophenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 4-phenyl-1-[4-[2-[2-(trifluoromethyl)phenoxy]acetyl]-1-piperazinyl]-; 1-Butanone, 1-[4-[2-(2,4-dichlorophenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(2-naphthalenyloxy)acetyl]-1-piperazinyl]-4-phenyl-; Benzonitrile, 3-methoxy-4-[2-oxo-2-[4-(1-oxo-4-phenylbutyl)-1-piperazinyl]ethoxy]-; Benzeneacetamide, 4-[2-oxo-2-[4-(1-oxo-4-phenylbutyl)-1-piperazinyl]ethoxy]-; 1-Butanone, 4-phenyl-1-[4-[2-[3-(trifluoromethyl)phenoxy]acetyl]-1-piperazinyl]-; 1-Butanone, 1-[4-[2-(diphenylmethoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[(2,3-dihydro-1H-inden-5-yl)oxy]acetyl]-1-piperazinyl]-4-phenyl-; 2-Furancarboxamide, N-[3-[2-oxo-2-[4-(1-oxo-4-phenylbutyl)-1- piperazinyl]ethoxy]phenyl]-; 1-Butanone, 1-[4-[2-[(2-chlorophenyl)methoxy]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[4-(3-oxobutyl)phenoxy]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(4-bromophenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-[3-(1-methylethyl)phenoxy]acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(2,5-dimethylphenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(4-chloro-2-methylphenoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-[2-(2-ethylphenoxy)acetyl]-1-piperazinyl]-4-phenyl-; Cyclopropanecarboxamide, N-[3-[2-oxo-2-[4-(1-oxo-4-phenylbutyl)-1- piperazinyl]ethoxy]phenyl]-; 1-Butanone, 1-[4-[2-(2-phenoxyethoxy)acetyl]-1-piperazinyl]-4-phenyl-; 1-Butanone, 1-[4-(2-methoxyacetyl)-1-piperazinyl]-4-phenyl-; 1-Propanone, 3-phenyl-1-[4-[2-(phenylthio)acetyl]-1-piperazinyl]-; 1-Propanone, 3-phenyl-1-[4-[2-[(3-phenylpropyl)thio]acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-[(2-methylphenyl)thio]acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 3-(4-methoxyphenyl)-1-[4-[2-[(4-methylphenyl)thio]acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-[(4-fluorophenyl)thio]acetyl]-1-piperazinyl]-3-(4-methoxyphenyl)-; 1-Propanone, 3-(4-methoxyphenyl)-1-[4-[2-(pentylsulfonyl)acetyl]-1-piperazinyl]-; Benzonitrile, 4-[[[2-oxo-2-[4-(1-oxo-3-phenylpropyl)-1- piperazinyl]ethyl]sulfonyl]methyl]-; Acetamide, N-(3-methylphenyl)-2-[[2-oxo-2-[4-(1-oxo-3-phenylpropyl)-1- piperazinyl]ethyl]thio]-1-Propanone, 1-[2-methyl-4-[2-[(6-phenyl-3- pyridazinyl)thio]acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 1-[4-[2-[[1-(3,4-dimethylphenyl)-1H-imidazol-2-yl]thio]acetyl]-1- piperazinyl]-3-(4-methoxyphenyl)-; 1-Propanone, 3-phenyl-1-[4-[2-[[[5-(2-thienyl)-3-isoxazolyl]methyl]thio]acetyl]-1- piperazinyl]-; 1-Propanone, 1-[4-(2-methoxyacetyl)-1-piperazinyl]-3-phenyl-; 1-Propanone, 1-[4-(2-methoxyacetyl)-1-piperazinyl]-3-(4-methylphenyl)-; 1-Propanone, 1-[4-[2-(2-aminoethoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 1-[4-(2-methoxyacetyl)-1-piperazinyl]-3-(4-methoxyphenyl)-; 1-Propanone, 1-[4-[2-(2-methoxyethoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 3-(3-hydroxyphenyl)-1-[4-(2-methoxyacetyl)-1-piperazinyl]-; 1-Propanone, 3-(2-aminophenyl)-1-[4-(2-methoxyacetyl)-1-piperazinyl]-; 1-Propanone, 3-(4-chlorophenyl)-1-[4-(2-methoxyacetyl)-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(2-methoxyethoxy)acetyl]-1-piperazinyl]-3-(4-methylphenyl)-; 1-Propanone, 3-(3-fluorophenyl)-1-[4-(2-methoxyacetyl)-1-piperazinyl]-; 1-Propanone, 1-[4-(2-phenoxyacetyl)-1-piperazinyl]-3-phenyl-; Benzoic acid, 4-[3-[4-(2-methoxyacetyl)-1-piperazinyl]-3-oxopropyl]-; 1-Propanone, 3-phenyl-1-[4-[2-(phenylmethoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-(4-chlorophenyl)-1-[4-[2-(2-methoxyethoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-(4-methylphenyl)-1-[4-(2-phenoxyacetyl)-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(4-methylphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 3-(4-ethylphenyl)-1-[4-(2-phenoxyacetyl)-1-piperazinyl]-; 1-Propanone, 3-phenyl-1-[4-[2-(4-propylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-[4-(1-methylethyl)phenyl]-1-[4-(2-phenoxyacetyl)-1-piperazinyl]-; 1-Propanone, 3-(2-methylphenyl)-1-[4-(2-phenoxyacetyl)-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(2-methylphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 1-[4-[2-(3-methylphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 3-(3-chloro-4-hydroxyphenyl)-1-[4-(2-methoxyacetyl)-1-piperazinyl]-; 1-Propanone, 3-(3-methylphenyl)-1-[4-(2-phenoxyacetyl)-1-piperazinyl]-; Benzoic acid, 2-[3-[4-(2-methoxyacetyl)-1-piperazinyl]-3-oxopropyl]-; 1-Propanone, 3-(2,3-dichlorophenyl)-1-[4-(2-methoxyacetyl)-1-piperazinyl]-; 1-Propanone, 3-(4-ethylphenyl)-1-[4-[2-(4-methylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(4-methoxyphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 1-[4-[2-(4-methylphenoxy)acetyl]-1-piperazinyl]-3-(4-methylphenyl)-; 1-Propanone, 1-[4-[2-(4-ethoxyphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 3-(4-methoxyphenyl)-1-[4-(2-phenoxyacetyl)-1-piperazinyl]-; 1-Propanone, 3-phenyl-1-[4-[2-(2,2,2-trifluoroethoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-phenyl-1-[4-[2-(3-piperidinylmethoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(2-naphthalenyloxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 3-(4-methylphenyl)-1-[4-[2-(4-propylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-(4-methoxyphenyl)-1-[4-[2-(4-methylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-(4-chlorophenyl)-1-[4-(2-phenoxyacetyl)-1-piperazinyl]-; 1-Propanone, 3-(4-fluorophenyl)-1-[4-(2-phenoxyacetyl)-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(2-ethylphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 3-(3,4-dimethoxyphenyl)-1-[4-(2-methoxyacetyl)-1-piperazinyl]-; 1-Propanone, 3-(4-ethylphenyl)-1-[4-[2-(3-methylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-(4-ethylphenyl)-1-[4-[2-(2-methylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 3-(3-methoxyphenyl)-1-[4-(2-phenoxyacetyl)-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(4-fluorophenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 1-[4-[2-(2-ethoxyphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 1-[4-[2-(4-ethoxyphenoxy)acetyl]-1-piperazinyl]-3-(4-methylphenyl)-; 1-Propanone, 1-[4-[2-(2-methoxyphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 3-(3-chlorophenyl)-1-[4-(2-phenoxyacetyl)-1-piperazinyl]-; 1-Propanone, 3-(3-fluorophenyl)-1-[4-(2-phenoxyacetyl)-1-piperazinyl]-; 1-Propanone, 3-(2-methoxyphenyl)-1-[4-(2-phenoxyacetyl)-1-piperazinyl]-; 1-Propanone, 3-(3-methoxyphenyl)-1-[4-[2-(3-methylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-(2-fluorophenyl)-1-[4-(2-phenoxyacetyl)-1-piperazinyl]-; 1-Propanone, 3-(4-ethoxy-3-methoxyphenyl)-1-[4-(2-methoxyacetyl)-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(diphenylmethoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 3-(4-methoxyphenyl)-1-[4-[2-(2-phenoxyethoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-[(3-methoxyphenyl)methoxy]acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 3-(4-fluorophenyl)-1-[4-[2-(4-methylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(3-fluorophenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 1-[4-[2-(2-fluorophenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 3-(4-methoxyphenyl)-1-[4-[2-(3-methylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-(4-methoxyphenyl)-1-[4-[2-(2-methylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(2-chlorophenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 1-[4-[2-(2,4-dimethylphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 1-[4-[2-(3,4-dimethylphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 1-[4-[2-(2-ethylphenoxy)acetyl]-1-piperazinyl]-3-(4-methylphenyl)-; 1-Propanone, 3-(4-chlorophenyl)-1-[4-[2-(4-methylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-(1,3-benzodioxol-4-yl)-1-[4-(2-methoxyacetyl)-1-piperazinyl]-; 1-Propanone, 3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-[4-(2-methoxyacetyl)-1- piperazinyl]-; 1-Propanone, 3-phenyl-1-[4-[2-[1-(2-pyridinyl)ethoxy]acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-[(2,3-dihydro-1H-inden-5-yl)oxy]acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 3-(2-methoxyphenyl)-1-[4-[2-(2-methylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-(3-methoxyphenyl)-1-[4-[2-(4-methylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(2,3-dimethylphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-(4-methylphenyl)-; 1-Propanone, 3-(4-chlorophenyl)-1-[4-[2-(4-propylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(2-methoxyphenoxy)acetyl]-1-piperazinyl]-3-(4-methylphenyl)-; 1-Propanone, 3-phenyl-1-[4-[2-(2,4,6-trimethylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(2-ethoxyphenoxy)acetyl]-1-piperazinyl]-3-(4-methylphenyl)-; 1-Propanone, 1-[4-[2-(3-methoxyphenoxy)acetyl]-1-piperazinyl]-3-(4-methoxyphenyl)-; 1-Propanone, 3-(3-fluorophenyl)-1-[4-[2-(4-methylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-(2-methoxyphenyl)-1-[4-[2-(4-methylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-(4-methoxyphenyl)-1-[4-[2-(1-naphthalenyloxy)acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(2,4-dimethylphenoxy)acetyl]-1-piperazinyl]-3-(4-methylphenyl)- 1-Propanone, 1-[4-[2-(3,4-dimethylphenoxy)acetyl]-1-piperazinyl]-3-(4-methylphenyl)-; 1-Propanone, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-(4-chlorophenyl)-; 1-Propanone, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-(4-fluorophenyl)-; 1-Propanone, 3-(2-fluorophenyl)-1-[4-[2-(4-methylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-(3-methoxyphenyl)-1-[4-[2-(2-methylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(4-bromophenoxy)acetyl]-1-piperazinyl]-3-(4-methoxyphenyl)-; 1-Propanone, 3-(4-methoxyphenyl)-1-[4-[2-[(3-methylcyclohexyl)oxy]acetyl]-1- piperazinyl]- 1-Propanone, 3-(4-chlorophenyl)-1-[4-[2-(4-ethoxyphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-(4-methoxyphenyl)-; 1-Propanone, 1-[4-[2-(3,5-dimethylphenoxy)acetyl]-1-piperazinyl]-3-(4-methoxyphenyl)- 1-Propanone, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-(3-methylphenyl)-; 1-Propanone, 1-[4-[2-(2,3-dimethylphenoxy)acetyl]-1-piperazinyl]-3-(4-methylphenyl)-; 1-Propanone, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-(3-chlorophenyl)-; 1-Propanone, 3-(4-methoxyphenyl)-1-[4-[2-[3-(1-methylethyl)phenoxy]acetyl]-1- piperazinyl]-; 1-Propanone, 1-[4-[2-(2-methoxy-4-methylphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 3-(2-methoxyphenyl)-1-[4-[2-(3-methylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-phenyl-1-[4-[2-(2,3,6-trimethylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-(3,4-dimethoxyphenyl)-1-[4-[2-(2-methoxyethoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-(3-fluorophenyl)-; 1-Propanone, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-(2-fluorophenyl)-; 1-Propanone, 1-[4-[2-(2,4-dimethylphenoxy)acetyl]-1-piperazinyl]-3-(4-methoxyphenyl)-; 1-Propanone, 1-[4-[2-(3,4-dimethylphenoxy)acetyl]-1-piperazinyl]-3-(4-methoxyphenyl)-; 1-Propanone, 1-[4-[2-(2,6-dimethylphenoxy)acetyl]-1-piperazinyl]-3-(4-methoxyphenyl)-; 1-Propanone, 3-(4-chlorophenyl)-1-[4-[2-(2-ethylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-(4-chlorophenyl)-1-[4-[2-(2-methoxyphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-(2-aminophenyl)-1-[4-[2-(4-fluorophenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-(4-chlorophenyl)-1-[4-[2-(2-ethoxyphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-(4-ethoxy-3-methoxyphenyl)-1-[4-(2-phenoxyacetyl)-1-piperazinyl]-; 1-Propanone, 3-(3,4-dimethoxyphenyl)-1-[4-(2-phenoxyacetyl)-1-piperazinyl]-; 1-Propanone, 3-(4-methylphenyl)-1-[4-[2-(2,3,6-trimethylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-(2-methoxyphenyl)-; 1-Propanone, 1-[4-[2-(3,4-dimethylphenoxy)acetyl]-1-piperazinyl]-3-(4-fluorophenyl)-; 1-Propanone, 1-[4-[2-(3,4-dimethylphenoxy)acetyl]-1-piperazinyl]-3-(3-fluorophenyl)-; 1-Propanone, 3-(4-chlorophenyl)-1-[4-[2-(2,4-dimethylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-(4-chlorophenyl)-1-[4-[2-(3,4-dimethylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(2,4-dichlorophenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 1-[4-[2-(4-chloro-3,5-dimethylphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 1-Propanone, 3-(3,4-dimethoxyphenyl)-1-[4-[2-(4-methylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-[(2-chlorophenyl)methoxy]acetyl]-1-piperazinyl]-3-(4- methoxyphenyl)-1-Propanone, 1-[4-[2-(2,5-dichlorophenoxy)acetyl]-1-piperazinyl]-3- phenyl-; 1-Propanone, 1-[4-[2-(3,4-dimethylphenoxy)acetyl]-1-piperazinyl]-3-(2-fluorophenyl)-; 1-Propanone, 1-[4-[2-[2-(1,1-dimethylethyl)-4-methylphenoxy]acetyl]-1-piperazinyl]-3- phenyl-; 1-Propanone, 3-(4-ethoxy-3-methoxyphenyl)-1-[4-[2-(4-methylphenoxy)acetyl]-1- piperazinyl]-; 1-Propanone, 3-(3,4-dimethoxyphenyl)-1-[4-[2-(2-methoxyphenoxy)acetyl]-1- piperazinyl]-; 1-Propanone, 3-(4-chlorophenyl)-1-[4-[2-(2,3-dimethylphenoxy)acetyl]-1-piperazinyl]-; Benzoic acid, 4-[3-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-oxopropyl]-; 1-Propanone, 1-[4-[2-[(4-chloro-1-naphthalenyl)oxy]acetyl]-1-piperazinyl]-3-(4- methoxyphenyl)-; 1-Propanone, 1-[4-[2-(4-chloro-3,5-dimethylphenoxy)acetyl]-1-piperazinyl]-3-(4- methylphenyl)-; 1-Propanone, 1-[4-[2-[2-(1,1-dimethylethyl)-4-methylphenoxy]acetyl]-1-piperazinyl]-3- (4-methylphenyl)-; 1-Propanone, 1-[4-[2-(2,4-dichlorophenoxy)acetyl]-1-piperazinyl]-3-(4-methylphenyl)-; 1-Propanone, 1-[4-[2-(4-chloro-3-methylphenoxy)acetyl]-1-piperazinyl]-3-(4- methoxyphenyl)-; 1-Propanone, 3-phenyl-1-[4-[2-[2-(trifluoromethyl)phenoxy]acetyl]-1-piperazinyl]-; 1-Propanone, 3-(4-methoxyphenyl)-1-[4-[2-[4-(trifluoromethyl)phenoxy]acetyl]-1- piperazinyl]-; 1-Propanone, 3-(3,4-dimethoxyphenyl)-1-[4-[2-(3,4-dimethylphenoxy)acetyl]-1- piperazinyl]-; 1-Propanone, 1-[(4aR,7aS)-hexahydro-4-(2-methoxyacetyl)-6,6-dioxidothieno[3,4- b]pyrazin-1(2H)-yl]-3-(4-methylphenyl)-, rel-; 1-Propanone, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-(2,5-difluorophenyl)-; 1-Propanone, 3-(3,4-dimethoxyphenyl)-1-[4-[2-(2-ethylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-(4-chlorophenyl)-1-[4-[2-(2,3,6-trimethylphenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-(4-chlorophenyl)-1-[4-[2-(2,4-dichlorophenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(2,4-dichlorophenoxy)acetyl]-1-piperazinyl]-3-(4-fluorophenyl)-; 1-Propanone, 1-[4-[2-(4-chloro-3,5-dimethylphenoxy)acetyl]-1-piperazinyl]-3-(4- chlorophenyl)-; 1-Propanone, 3-(3,4-dimethoxyphenyl)-1-[4-[2-(2,4-dimethylphenoxy)acetyl]-1- piperazinyl]-; 1-Propanone, 3-(3,4-dimethoxyphenyl)-1-[4-[2-(2,3-dimethylphenoxy)acetyl]-1- piperazinyl]-; 1-Propanone, 3-(3-chlorophenyl)-1-[4-[2-(2,4-dichlorophenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(2,4-dichlorophenoxy)acetyl]-1-piperazinyl]-3-(3-fluorophenyl)-; 1-Propanone, 1-[4-[2-(2,4-dichlorophenoxy)acetyl]-1-piperazinyl]-3-(2-fluorophenyl)-; 1-Propanone, 3-(4-methoxyphenyl)-1-[4-[2-(3-nitrophenoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 1-[4-[2-(3-chloro-4-fluorophenoxy)acetyl]-1-piperazinyl]-3-(4- methoxyphenyl)-; 1-Propanone, 1-[4-[2-(2-chloro-4-fluorophenoxy)acetyl]-1-piperazinyl]-3-(4- methoxyphenyl)-; 1-Propanone, 1-[4-[2-(4-bromo-2-chlorophenoxy)acetyl]-1-piperazinyl]-3-(4- methoxyphenyl)-; 1-Propanone, 1-[4-[2-(2,4-dichlorophenoxy)acetyl]-1-piperazinyl]-3-(4-methoxyphenyl)-; 1-Propanone, 1-[4-(2-methoxyacetyl)-1-piperazinyl]-3-[3-methoxy-4-(2,2,2- trifluoroethoxy)phenyl]-; 1-Propanone, 1-[4-[2-(4-acetyl-2-methoxyphenoxy)acetyl]-1-piperazinyl]-3-(4- methoxyphenyl)-; 1-Propanone, 1-[4-[2-(2,5-dichlorophenoxy)acetyl]-1-piperazinyl]-3-(4-methoxyphenyl)-; 1-Propanone, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-(3,4-dimethoxyphenyl)-; 1-Propanone, 1-[4-[2-(2,4-dichlorophenoxy)acetyl]-1-piperazinyl]-3-(2-methoxyphenyl)-; 1-Propanone, 1-[4-[2-[(5-chloro-8-quinolinyl)oxy]acetyl]-1-piperazinyl]-3-(4- methoxyphenyl)-; 1-Propanone, 3-(3-fluorophenyl)-1-[(4aR,7aS)-hexahydro-4-(2-methoxyacetyl)-6,6- dioxidothieno[3,4-b]pyrazin-1(2H)-yl]-, rel-; 1-Propanone, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-(3,4,5- trimethoxyphenyl)-; Piperazine, 1-[3-(3-methylphenyl)-1-oxopropyl]-4-[[(2-phenoxyphenyl)methoxy]acetyl]- :(9CI); 1-Propanone, 3-(4-methoxyphenyl)-1-[4-[2-(2,4,5-trichlorophenoxy)acetyl]-1- piperazinyl]-; Cyclopropanecarboxamide, N-[3-[2-oxo-2-[4-(1-oxo-3-phenylpropyl)-1- piperazinyl]ethoxy]phenyl]-; 2H-1-Benzopyran-2-one, 4-methyl-6-[2-oxo-2-[4-(1-oxo-3-phenylpropyl)-1- piperazinyl]ethoxy]-; 1-Propanone, 3-phenyl-1-[4-[2-[(1,4,6-trimethyl-1H-pyrazolo[3,4-b]pyridin-3- yl)oxy]acetyl]-1-piperazinyl]-; 1-Propanone, 3-[4-[(4,10-dihydro-1,8-dimethylpyrazolo[3,4-b][1,5]benzodiazepin- 5(1H)-yl)carbonyl]-2-methylphenyl]-1-[4-(2-phenoxyacetyl)-1-piperazinyl]-; 1-Propanone, 3-[4-[(4,10-dihydro-1,8-dimethylpyrazolo[3,4-b][1,5]benzodiazepin- 5(1H)-yl)carbonyl]-2-methylphenyl]-1-[4-[2-(phenylmethoxy)acetyl]-1-piperazinyl]-; 1-Propanone, 3-[4-[(8-chloro-4,10-dihydro-1-methylpyrazolo[3,4-b][1,5]benzodiazepin- 5(1H)-yl)carbonyl]-2-methylphenyl]-1-[4-(2-phenoxyacetyl)-1-piperazinyl]-; 1-Propanone, 3-[4-[(8-chloro-4,10-dihydro-1-methylpyrazolo[3,4-b][1,5]benzodiazepin- 5(1H)-yl)carbonyl]-2-methylphenyl]-1-[4-[2-(phenylmethoxy)acetyl]-1-piperazinyl]-; 2-Propen-1-one, 1-[4-(2-methoxyacetyl)-1-piperazinyl]-3-phenyl-; 2-Propen-1-one, 1-[4-[2-(2-methoxyethoxy)acetyl]-1-piperazinyl]-3-phenyl-; Benzoic acid, 4-[3-[4-(2-methoxyacetyl)-1-piperazinyl]-3-oxo-1-propen-1-yl]-; 2-Propen-1-one, 1-[4-(2-phenoxyacetyl)-1-piperazinyl]-3-phenyl-; 2-Propen-1-one, 1-[4-(2-methoxyacetyl)-1-piperazinyl]-3-[3-(1-methylethoxy)phenyl]-; 2-Propen-1-one, 3-(3-chloro-4-methylphenyl)-1-[4-(2-methoxyacetyl)-1-piperazinyl]-; 2-Propen-1-one, 3-(2,3-dichlorophenyl)-1-[4-(2-methoxyacetyl)-1-piperazinyl]-; 2-Propen-1-one, 1-[4-[2-(4-methylphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 2-Propen-1-one, 3-phenyl-1-[4-[2-(4-propylphenoxy)acetyl]-1-piperazinyl]-; 2-Propen-1-one, 1-[4-[2-(4-ethoxyphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 2-Propen-1-one, 1-[4-[2-(2-ethylphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 2-Propen-1-one, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 2-Propen-1-one, 1-[4-[2-(2-ethoxyphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 2-Propen-1-one, 1-[4-[2-(2-methoxyphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 2-Propen-1-one, 1-[4-(2-methoxyacetyl)-1-piperazinyl]-3-[4- [(trifluoromethyl)thio]phenyl]-; 2-Propen-1-one, 1-[4-[2-(2,4-dimethylphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 2-Propen-1-one, 1-[4-[2-(3,4-dimethylphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 2-Propen-1-one, 1-[4-[2-(2,3-dimethylphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 2-Propen-1-one, 3-(4-fluoro-2-nitrophenyl)-1-[4-(2-methoxyacetyl)-1-piperazinyl]-; 2-Propen-1-one, 3-phenyl-1-[4-[2-(2,3,6-trimethylphenoxy)acetyl]-1-piperazinyl]-; 2-Propen-1-one, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-(2-fluorophenyl)-; 2-Propen-1-one, 3-[4-chloro-3-(trifluoromethyl)phenyl]-1-[4-(2-methoxyacetyl)-1- piperazinyl]-; 2-Propen-1-one, 3-[2-chloro-5-(trifluoromethyl)phenyl]-1-[4-(2-methoxyacetyl)-1- piperazinyl]-; 2-Propen-1-one, 1-[4-[2-(2,4-dichlorophenoxy)acetyl]-1-piperazinyl]-3-phenyl-; Benzonitrile, 2-[3-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-oxo-1-propen-1-yl]-; 2-Propen-1-one, 1-[4-[2-(4-chloro-3,5-dimethylphenoxy)acetyl]-1-piperazinyl]-3-phenyl-; 2-Propen-1-one, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-(2-ethoxyphenyl)-; 2-Propen-1-one, 1-[4-[2-[2-(1,1-dimethylethyl)-4-methylphenoxy]acetyl]-1-piperazinyl]- 3-phenyl-; Benzoic acid, 4-[3-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-oxo-1-propen-1-yl]-; 2-Propen-1-one, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-(4-nitrophenyl)-; 2-Propen-1-one, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-(2,6-difluorophenyl)-; 2-Propen-1-one, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-(3-fluoro-4- methoxyphenyl)-; 2-Propen-1-one, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-(3-nitrophenyl)-; 2-Propen-1-one, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-(2,5- dimethoxyphenyl)-; Acetamide, N-[4-[3-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-oxo-1-propen-1- yl]phenyl]-; 2-Propen-1-one, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-(3,4,5- trimethoxyphenyl)-2-Propen-1-one, 1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]-3-[4- (difluoromethoxy)-3-methoxyphenyl]-; and 2-Propen-1-one, 1-[4-[2-[[1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5- l]oxy]acetyl]-1-piperazinyl]-3-phenyl-, (2E)-.
2. The compound of claim 1, wherein Ar1 is optionally substituted phenyl, optionally substituted naphthyl or optionally substituted 6,6- or 5,6-fused bicyclic heteroaryl, such as optionally substituted quinolyl or indolyl.
3. The compound of claim 2, wherein Ar1 is optionally substituted phenyl, optionally substituted 2-naphthyl, optionally substituted 3-indolyl or optionally substituted 3- quinolyl.
4. The compound of claim 3, wherein Ar1 is
Figure imgf000076_0001
where Ra, Rb, Rc, Rd and Re are each independently H, optionally substituted C1-C6-alkyl, halo, R7O-, R7S-, R6C(O)-, R7OC(O)-, optionally substituted C3-C8-cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; alternatively, Ra and Rb or Rb and Rc, together with the carbon atoms to which they are attached, form an optionally substituted carbocyclic or heterocyclic; R6 is optionally substituted C1-C6-alkyl, optionally substituted C3-C8-cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; and R7 is H or optionally substituted C1-C6-alkyl.
5. The compound of claim 4, wherein Rb and Rc together form –O-(CH2)p-O-, wherein p is 1 or 2, and each of Ra, Rd and Re is H.
6. The compound of any one of claims 1-5, wherein R1 is phenyl optionally substituted with 1 to 5 substituents independently selected from halogen, C1-C6-alkyl, halo-C1-C6- alkyl, C1-C6-alkoxy, C1-C6-alkyl-S-, halo-C1-C6-alkoxy, halo-C1-C6-alkyl-S-, and (C1-C4- alkyl)2N-.
7. The compound of claim 6, wherein R1 is phenyl substituted with one methyl and one halogen.
8. The compound of claim 6, wherein R1 is selected from phenyl, 2-methylphenyl, 4- fluorophenyl, 2-chloro-4-methylphenyl, 2-chloro-3-methylphenyl, 3-chloro-4- methylphenyl, 3-chloro-5-methylphenyl, 3-methyl-4-chlorophenyl, 2-methyl-4- chlorophenyl, 2-methyl-3-chlorophenyl, 2-fluoro-4-methylphenyl, 2-fluoro-3- methylphenyl, 3-fluoro-4-methylphenyl, 3-fluoro-5-methylphenyl, 3-methyl-4- fluorophenyl, 2-methyl-4-fluorophenyl, and 2-methyl-3-fluorophenyl.
9. The compound of any one of claims 1-5, wherein R1 is optionally substituted C3-C8- cycloalkyl or optionally substituted 3- to 8-membered heterocycloalkyl.
10. The compound of claim 9, wherein R1 is C4-C8-cycloalkyl.
11. The compound of claim 10, wherein R1 is cyclopentyl, cyclohexyl or cycloheptyl.
12. The compound of any one of claims 1 to 11, wherein X is O or S.
13. The compound of any one of claims 1-12, wherein n is 0 and B is -CH2-, -CH=CH-, – C≡C-, or -CH2CH2-.
14. The compound of any one of claims 1 to 13, wherein B is (E)-CH=CH-
15. The compound of any one of claims 1 to 12, wherein n is 1 and B is -CH2CH2-.
16. The compound of claim 1, represented by Formula (II),
Figure imgf000077_0001
(II), or a pharmaceutically acceptable salt thereof, where m is 0, 1 or 2.
17. The compound of claim 1, represented by Formula (III), O
Figure imgf000078_0001
or a pharmaceutically acceptable salt thereof.
18. The compound of claim 16 or claim 17, wherein X is O or S.
19. The compound of claim 1, which is selected from the compounds set forth below and pharmaceutically acceptable salts thereof:
Figure imgf000078_0002
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
.
20. A pharmaceutical composition comprising a compound of Formula (I),
Figure imgf000091_0001
or a pharmaceutically acceptable salt or prodrug thereof, wherein Ar1 is optionally substituted aryl or optionally substituted heteroaryl; X is O, S, S(O), S(O)2, or NR; R1 is optionally substituted C1-C8-alkyl, optionally substituted C3-C8-cycloalkyl; optionally substituted heterocycloalkyl, optionally substituted heteroaryl or optionally substituted aryl; R is H or optionally substituted C1-C6-alkyl; B is -CH2-, –CH2CH2-, -CH=CH- or –C≡C-; and n is 0, 1, or 2; and a pharmaceutically acceptable carrier or excipient.
21. The pharmaceutical composition of claim 20, wherein Ar1 is optionally substituted phenyl, optionally substituted naphthyl or optionally substituted 6,6- or 5,6-fused bicyclic heteroaryl, such as optionally substituted quinolyl or indolyl.
22. The pharmaceutical composition of claim 20, wherein Ar1 is optionally substituted phenyl, optionally substituted 2-naphthyl, optionally substituted 3-indolyl or optionally substituted 3-quinolyl.
23. The pharmaceutical composition of claim 20, wherein Ar1 is
Figure imgf000091_0002
, where Ra, Rb, Rc, Rd and Re are each independently H, optionally substituted C1-C6-alkyl, halo, R7O-, R7S-, R6C(O)-, R7OC(O)-, optionally substituted C3-C8-cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; alternatively, Ra and Rb or Rb and Rc, together with the carbon atoms to which they are attached, form an optionally substituted carbocyclic or heterocyclic; R6 is optionally substituted C1-C6-alkyl, optionally substituted C3-C8-cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; and R7 is H or optionally substituted C1-C6-alkyl.
24. The pharmaceutical composition of claim 23, wherein Rb and Rc together form –O- (CH2)p-O-, wherein p is 1 or 2, and each of Ra, Rd and Re is H.
25. The pharmaceutical composition of any one of claims 20-24, wherein R1 is phenyl optionally substituted with 1 to 5 substituents independently selected from halogen, C1-C6- alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkyl-S-, halo-C1-C6-alkoxy, halo-C1-C6- alkyl-S-, and (C1-C4-alkyl)2N-.
26. The pharmaceutical composition of claim 25, wherein R1 is phenyl substituted with one methyl and one halogen.
27. The pharmaceutical composition of claim 26, wherein R1 is selected from phenyl, 2- methylphenyl, 4-fluorophenyl, 2-chloro-4-methylphenyl, 2-chloro-3-methylphenyl, 3- chloro-4-methylphenyl, 3-chloro-5-methylphenyl, 3-methyl-4-chlorophenyl, 2-methyl-4- chlorophenyl, 2-methyl-3-chlorophenyl, 2-fluoro-4-methylphenyl, 2-fluoro-3- methylphenyl, 3-fluoro-4-methylphenyl, 3-fluoro-5-methylphenyl, 3-methyl-4- fluorophenyl, 2-methyl-4-fluorophenyl, and 2-methyl-3-fluorophenyl.
28. The pharmaceutical composition of any one of claims 20-24, wherein R1 is optionally substituted C3-C8-cycloalkyl or optionally substituted 3- to 8-membered heterocycloalkyl.
29. The pharmaceutical composition of claim 28, wherein R1 is C4-C8-cycloalkyl.
30. The pharmaceutical composition of claim 29, wherein R1 is cyclopentyl, cyclohexyl or cycloheptyl.
31. The pharmaceutical composition of any one of claims 20 to 30, wherein X is O or S.
32. The pharmaceutical composition of any one of claims 20-31, wherein n is 0 and B is - CH2-, -CH=CH-, –C≡C-, or -CH2CH2-.
33. The pharmaceutical composition of any one of claims 20 to 32 wherein B is (E)- CH=CH-.
34. The pharmaceutical composition of any one of claims 20 to 31 wherein n is 1 and B is -CH2CH2-.
35. The pharmaceutical composition of claim 20, wherein the compound is represented by Formula (II),
Figure imgf000093_0001
where m is 0, 1 or 2.
36. The pharmaceutical composition of claim 20, wherein the compound is represented by Formula (III),
Figure imgf000093_0002
37. The pharmaceutical composition of claim 35 or claim 36, wherein X is O or S.
38. The pharmaceutical composition of claim 20, wherein the compound is selected from the compounds set forth below and pharmaceutically acceptable salts thereof:
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
.
39. A method of treating or preventing an autoimmune disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I),
Figure imgf000105_0002
or a pharmaceutically acceptable salt or prodrug thereof, wherein Ar1 is optionally substituted aryl or optionally substituted heteroaryl; X is O, S, S(O), S(O)2, or NR; R1 is optionally substituted C1-C8-alkyl, optionally substituted C3-C8-cycloalkyl; optionally substituted heterocycloalkyl, optionally substituted heteroaryl or optionally substituted aryl; R is H or optionally substituted C1-C6-alkyl; B is -CH2-, –CH2CH2-, -CH=CH- or –C≡C-; and n is 0, 1, or 2; and a pharmaceutically acceptable carrier or excipient.
40. The method of claim 39, wherein Ar1 is optionally substituted phenyl, optionally substituted naphthyl or optionally substituted 6,6- or 5,6-fused bicyclic heteroaryl, such as optionally substituted quinolyl or indolyl.
41. The method of claim 39, wherein Ar1 is optionally substituted phenyl, optionally substituted 2-naphthyl, optionally substituted 3-indolyl or optionally substituted 3- quinolyl.
42. The method of claim 41, wherein Ar1 is
Figure imgf000106_0001
where Ra, Rb, Rc, Rd and Re are each independently H, optionally substituted C1-C6-alkyl, halo, R7O-, R7S-, R6C(O)-, R7OC(O)-, optionally substituted C3-C8-cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; alternatively, Ra and Rb or Rb and Rc, together with the carbon atoms to which they are attached, form an optionally substituted carbocyclic or heterocyclic; R6 is optionally substituted C1-C6-alkyl, optionally substituted C3-C8-cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; and R7 is H or optionally substituted C1-C6-alkyl.
43. The method of claim 42, wherein Rb and Rc together form –O-(CH2)p-O-, wherein p is 1 or 2, and each of Ra, Rd and Re is H.
44. The method of any one of claims 39-43, wherein R1 is phenyl optionally substituted with 1 to 5 substituents independently selected from halogen, C1-C6-alkyl, halo-C1-C6- alkyl, C1-C6-alkoxy, C1-C6-alkyl-S-, halo-C1-C6-alkoxy, halo-C1-C6-alkyl-S-, and (C1-C4- alkyl)2N-.
45. The method of claim 44, wherein R1 is phenyl substituted with one methyl and one halogen.
46. The method of claim 45, wherein R1 is selected from phenyl, 2-methylphenyl, 4- fluorophenyl, 2-chloro-4-methylphenyl, 2-chloro-3-methylphenyl, 3-chloro-4- methylphenyl, 3-chloro-5-methylphenyl, 3-methyl-4-chlorophenyl, 2-methyl-4- chlorophenyl, 2-methyl-3-chlorophenyl, 2-fluoro-4-methylphenyl, 2-fluoro-3- methylphenyl, 3-fluoro-4-methylphenyl, 3-fluoro-5-methylphenyl, 3-methyl-4- fluorophenyl, 2-methyl-4-fluorophenyl, and 2-methyl-3-fluorophenyl.
47. The method of any one of claims 39-43, wherein R1 is optionally substituted C3-C8- cycloalkyl or optionally substituted 3- to 8-membered heterocycloalkyl.
48. The method of claim 47, wherein R1 is C4-C8-cycloalkyl.
49. The method of claim 48, wherein R1 is cyclopentyl, cyclohexyl or cycloheptyl.
50. The method of any one of claims 39 to 49, wherein X is O or S.
51. The method of any one of claims 39-50, wherein n is 0 and B is -CH2-, -CH=CH-, –C≡C-, or -CH2CH2-.
52. The method of any one of claims 39 to 51 wherein B is (E)-CH=CH-.
53. The method of any one of claims 39 to 50 wherein n is 1 and B is -CH2CH2-.
54. The method of claim 39, wherein the compound is represented by Formula (II),
Figure imgf000107_0001
where m is 0, 1 or 2.
55. The method of claim 39, wherein the compound is represented by Formula (III),
Figure imgf000108_0001
56. The method of claim 54 or claim 55, wherein X is O or S. 57. The method of claim 39, wherein the compound is selected from the compounds set forth below and pharmaceutically acceptable salts thereof:
Figure imgf000108_0002
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
. 58. The method of any one of claims 39-57, wherein the subject is a human. 59. The method of claim 57 or 58, wherein the autoimmune disease is selected from the group consisting of celiac disease, type 1 diabetes (T1D), Stiff-person Syndrome (SPS), Addison’s disease (AD), Schmidt Syndrome (SS), and Myasthenia Gravis (MG).
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Citations (1)

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Publication number Priority date Publication date Assignee Title
US20220204471A1 (en) * 2020-12-22 2022-06-30 Immunomolecular Therapeutics, Inc. Compounds and Methods for Treating Autoimmune Disorders by Targeting HLA-DQ2

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Publication number Priority date Publication date Assignee Title
US20220204471A1 (en) * 2020-12-22 2022-06-30 Immunomolecular Therapeutics, Inc. Compounds and Methods for Treating Autoimmune Disorders by Targeting HLA-DQ2

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
DATABASE PUBCHEM COMPOUND ANONYMOUS : "(E)-1-[4-[2-(4-chlorophenoxy)acetyl]piperazin-1- yl]-3-phenylprop-2-en-1-one", XP093025461, retrieved from PUBCHEM *
DATABASE PUBCHEM COMPOUND ANONYMOUS : "-[4-(2-Methoxyacetyl)piperazin-1-yl]-2- phenylethanone ", XP093025449, retrieved from PUBCHEM *
DATABASE PUBCHEM COMPOUND ANONYMOUS : "-[4-[2-(4-Fluorophenyl)sulfanylacetyl]piperazin-1- yl]-4-phenylbutan-1-one ", XP093025459, retrieved from PUBCHEM *
DATABASE PUBCHEM COMPOUND ANONYMOUS : "1-(4-(2-(Benzo[d][1,3]dioxol-5- yl)cyclopropanecarbonyl)piperazin-1-yl)-2-((4- fluorophenyl)thio)ethanone", XP093025454, retrieved from PUBCHEM *
DATABASE PUBCHEM COMPOUND ANONYMOUS : "3-Cyclopentyl-1-[4-[3-(4- fluorophenyl)propanoyl]piperazin-1-yl]propan-1-one ", XP093025456, retrieved from PUBCHEM *

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