Small molecule inhibitors of shared epitope-calreticulin interactions and methods of use

Abstract

The present invention is in the field of medicinal chemistry. In particular, the present invention relates to a new class of small molecules having a triazole-methyl-piperidinyl-pyrrolyl-propenone structure that function as modulators of shared epitope (SE)-calreticulin (CRT) binding and / or interaction, and their use as therapeutic agents for treating immune dysregulation (e.g., autoimmune diseases, inflammatory diseases (e.g., chronic inflammatory diseases), and bone erosive diseases) by selectively inhibiting overactive or dysregulated SE-CRT interactions and / or signaling pathways common in arthritis and / or other diseases or conditions.

Description

Detailed Description of the Invention

[0001] [Technical Field] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No. 62 / 582,584, filed November 7, 2017, which is incorporated herein by reference in its entirety.

[0002] FIELD OF THE INVENTION The present invention is in the field of medicinal chemistry. In particular, the present invention relates to a new class of small molecules having a triazole-methyl-piperidinyl-pyrrolyl-propenone structure that function as modulators of shared epitope (SE)-calreticulin (CRT) binding and / or interaction, and their use as therapeutic agents for treating immune dysregulation (e.g., autoimmune diseases, inflammatory diseases (e.g., chronic inflammatory diseases), and bone erosive diseases) by selectively inhibiting overactive or dysregulated SE-CRT interactions and / or signaling pathways common in arthritis and / or other diseases or conditions.

[0003] Introduction Both rheumatoid arthritis (RA) and periodontal disease are characterized by chronic inflammation and bone erosion (see, e.g., Bromley and Woolley, Arthritis Rheum. August 1984; 27:857-863; Fujikawa et al., Br J Rheumatol. March 1996; 35:213-217; Gravallese et al., Arthritis Rheum. February 2000; 43:250-258; Marotte et al., Ann Rheum Dis. 2006 65:905-909). Both diseases are associated with HLA-DRB1 alleles that encode a five-amino acid sequence motif called a "shared epitope" (SE) in region 70-74 of the DR β chain (see, e.g., Gregersen et al., Arthritis Rheum. 1987; 30:1205-1213). In RA, SE not only confers a higher risk but also increases the likelihood of developing more severe disease. Similarly, in periodontal disease, SE is associated with more severe bone destruction (see, e.g., Marotte et al., Ann Rheum Dis. 2006 65:905-909).

[0004] The underlying mechanism by which SEs affect the susceptibility and severity of bone damage is unknown. A leading hypothesis postulates that SEs enable the presentation of putative self or foreign arthritic antigens (see, e.g., Wucherpfennig and Strominger, J Exp Med. May 1 1995;181:1597-1601), but the identity of such target antigens remains elusive.

[0005] RA is a chronic systemic inflammatory disease that can affect many tissues and organs, but primarily attacks flexible (synovial) joints. If not properly treated, it can be a disabling and painful condition that can lead to substantial loss of function and mobility.

[0006] This process involves swelling of synovial cells (hyperplasia), excess synovial fluid, and an inflammatory response in the capsule surrounding the joint (synovium) secondary to the development of fibrous tissue in the synovium (pannus). The pathology of the disease process often leads to destruction of the articular bone and cartilage, and ankylosis (fusion) of the joint. Rheumatoid arthritis can also result in diffuse inflammation of the lungs, the membrane around the heart (pericardium), the membranes of the lungs (pleura), and the whites of the eyes (sclera), as well as nodular lesions, most commonly in the subcutaneous tissue.

[0007] The cause of RA is unknown, but autoimmunity plays a key role in both its chronicity and progression, and RA is considered a systemic autoimmune disease. Its clinical diagnosis is based on symptoms, physical examination, radiographs (X-rays), and laboratory tests.

[0008] Preventing bone damage in RA, periodontal disease, and other erosive bone diseases remains a challenge. Most current and emerging drugs target common "downstream" immune pathways or inflammatory cytokines. As a result, drug failure and / or side effects are common. Despite their efficacy, peptidomimetics can have drawbacks due to their relatively large molecular weight (approximately 1000 Da), thereby compromising bioavailability and complicating chemical optimization and large-scale synthesis.

[0009] Improved techniques for treating and / or preventing RA and RA-associated bone damage, periodontal disease, and other erosive bone diseases are needed.

[0010] The present invention addresses this need. Summary of the Invention

[0011] Experiments conducted during the development of embodiments of the present invention have demonstrated that RA is a moderately orally available, potent anti-OC small molecule that exhibits potent anti-arthritic and anti-bone erosion effects in vivo when administered orally to mice using a preclinical model of RA. HL840( [ka] )((R,E)-(1-((1-(3-(1-methyl-1H-pyrazol-4-yl)acryloyl)piperidin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)methanaminium) was identified (see, e.g., Examples 1-3).

[0012] Further experiments were conducted to determine whether the enantiomers of HL840 exhibited different pharmacological properties, including potency and metabolic stability. A novel synthetic scheme for synthesizing the racemate and both enantiomers was developed. As shown in Figure 3, the (R)-enantiomer was responsible for all of the activities of racemic HL840 (e.g., inhibition of SE-CRT interaction and signal transduction).

[0013] Further experiments identified additional structurally similar small molecules having the triazole-methyl-piperidinyl-pyrrolyl-propenone structure, which function as modulators of shared epitope (SE)-calreticulin (CRT) binding and / or interaction (see, e.g., Example 4 and Figure 6).

[0014] As such, the present invention provides a new class of small molecules having a triazole-methyl-piperidinyl-pyrrolyl-propenone structure that function as modulators of shared epitope (SE)-calreticulin (CRT) binding and / or interaction and as therapeutic agents for treating immune dysregulation (e.g., autoimmune diseases, inflammatory diseases (e.g., chronic inflammatory diseases), and bone erosive diseases) by selectively inhibiting SE-CRT interactions and / or signaling pathways that are commonly overactive or dysregulated in arthritis and / or other diseases or conditions.

[0015] Thus, the present invention contemplates that exposing an animal (e.g., a human) suffering from an immune dysregulation (e.g., an autoimmune disease, an inflammatory disease (e.g., a chronic inflammatory disease), and a bone erosive disease) to a therapeutically effective amount of a drug(s) (e.g., a small molecule) having a triazole-methyl-piperidinyl-pyrrolyl-propenone structure that selectively inhibits the SE-CRT interaction will prevent and / or ameliorate the effects of such immune dysregulation.

[0016] The present invention contemplates filling an unmet need for the treatment of immune dysregulation (e.g., autoimmune diseases, inflammatory diseases (e.g., chronic inflammatory diseases), and bone erosive diseases) when inhibitors of SE-CRT are administered as monotherapy or when administered in a temporal relationship with additional agent(s), such as other pharmaceutical agents known to be effective in treating such conditions or symptoms associated with such conditions (combination therapy).

[0017] The present applicant has discovered that certain triazolemethyl-piperidinyl-pyrrolyl-propenone compounds function as SE-CRT binding and / or interaction modulators, making them useful as therapeutic agents for the treatment of immune dysregulation (e.g., autoimmune diseases, inflammatory diseases (e.g., chronic inflammatory diseases), and bone erosive diseases) and other diseases. Accordingly, the present invention relates to triazolemethyl-piperidinyl-pyrrolyl-propenone compounds useful for inhibiting SE-CRT binding and / or interaction. Certain triazolemethyl-piperidinyl-pyrrolyl-propenone compounds of the present invention may exist as stereoisomers, including optical isomers. The present invention encompasses all stereoisomers, both as pure and enriched preparations of each individual stereoisomer, as well as racemic mixtures of such stereoisomers and as individual diastereomers and enantiomers that can be separated according to methods well known to those skilled in the art. In one example, the formulation scheme shown in FIG. 4 is used to prepare the compound. However, the present invention is not so limited. Indeed, those skilled in the art will recognize variations of the scheme in Figure 4 that are suitable for preparing compounds of the present invention.

[0018] In certain embodiments, triazole-methyl-piperidinyl-pyrrolyl-propenone compounds and structurally similar compounds encompassed by Formulas I, II, III, and IV are provided: [ka] This includes pharmaceutically acceptable salts, solvates, and / or prodrugs thereof.

[0019] Formulas I, II, III, and IV are not limited to the particular chemical moieties of R1, R2, and R3. In some embodiments, the particular chemical moieties of R1, R2, and R3 independently include any chemical moiety that enables the resulting compound to modulate SE-CRT binding and / or interaction.

[0020] In some embodiments, R1 is [ka] and [ka] is.

[0021] In some embodiments, R2 is CH3, [ka] and [ka] is.

[0022] In some embodiments, R3 is hydrogen or fluorine.

[0023] In some embodiments, the following compounds for Formulas I, II, III, and IV are contemplated: [ka] TIFF0007737125000008.tif219169 TIFF0007737125000009.tif198169 TIFF0007737125000010.tif39169 and [ka] or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0024] The present invention further provides processes for preparing any of the compounds of the present invention by following at least some of the techniques cited in the Examples. For example, in some embodiments, the present invention provides processes for preparing compounds having the following formula: [ka] (a) Structure: [ka] starting from piperidin-3-ylmethanol, N-benzyl protecting and converting the alcohol to a mesylate, (b) Intermediates: [ka] Displacing the mesylate with an azide to prepare (c) [ka] cyclization with a substituted alkyne to prepare (d) [ka] debenzylation to prepare (e) [ka] coupling a carboxylic acid analog to prepare (f) [ka] and [ka] and removing the Boc protecting group to prepare

[0025] In another aspect, the present invention provides a method of treating an immune dysregulation in a subject (e.g., a mammalian patient) in need thereof, the method comprising administering to the patient a compound of the present invention in an amount effective to treat the immune dysregulation. The present invention is not limited to a particular immune dysregulation. In one embodiment, the immune dysregulation is an autoimmune disease. In another embodiment, the immune dysregulation is a chronic inflammatory disease. In one embodiment, the autoimmune disease or chronic inflammatory disease is rheumatoid arthritis. In one embodiment, the treatment inhibits and / or reduces bone erosion in the subject.

[0014] Examples of immune dysregulation include autoimmune syndromes including, but not limited to, organ or tissue transplantation, transplant-induced graft-versus-host disease, rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis, inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, and the like. Dermatitis, eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, acne, alopecia areata, keratoconjunctivitis, summer conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, keratoconus, epithelial corneal dystrophy, corneal leukoplakia, ocular pemphigus, Mooren's ulcer, scleritis, Graves' ophthalmopathy, Vog t-Koyanagi-Harada syndrome, sarcoidosis, hay fever, treatable obstructive airway diseases, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or refractory asthma, late-onset asthma and airway hyperresponsiveness, bronchitis, gastric ulcer, vascular damage caused by ischemic disease and thrombosis, ischemic bowel disease, inflammatory bowel disease, necrotizing enterocolitis, intestinal lesions associated with burns, celiac disease, proctitis, eosinophilic gastroenteritis , mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis, Goodpasture's syndrome, hemolytic uremic syndrome, diabetic nephropathy, polymyositis, Guillain-Barre syndrome, Meniere's disease, polyneuritis, polyneuropathy, mononeuritis, radiculopathy, hyperthyroidism, Basedow's disease, pure red cell aplasia, aplastic anemia, aplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia,Agranulocytosis, pernicious anemia, megaloblastic anemia, red blood cell hypoplasia, osteoporosis, sarcoidosis, pulmonary fibrosis, idiopathic interstitial pneumonia, dermatomyositis, albinism, ichthyosis vulgaris, photoallergic hypersensitivity, cutaneous T-cell lymphoma, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, cardiomyopathy, scleroderma, Wegener's granuloma, Sjogren's syndrome, adiposity, eosinophilic fasciitis; gingiva, periodontium, alveolar bone, dental cement Glomerulonephritis, male pattern baldness or senile alopecia by preventing hair loss or providing hair growth and / or promoting hair growth and development, muscular dystrophy, pyoderma and Sezary syndrome, Addison's disease, ischemia-reperfusion injury of organs occurring during storage, transplantation or ischemic disease, endotoxin shock, pseudomembranous colitis, colitis due to drugs or radiation, ischemic acute renal failure, chronic renal failure, pulmonary oxygen or drug intoxication, lung cancer, pneumonia tumors, cataracts, siderosis, retinitis pigmentosa, age-related macular degeneration, vitreous scarring, corneal alkali burns, erythematous dermatitis multiforme, linear IgA bullous dermatitis and cement dermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution, aging, carcinogenesis, metastasis of carcinoma and altitude sickness, diseases caused by histamine or leukotriene-C.sub.4 release, Behcet's disease, autoimmune hepatitis, primary biliary cirrhosis, cirrhosis Other immune dysregulation disorders may also be treated, including inflammatory cholangitis, partial hepatectomy, acute liver necrosis, necrosis caused by toxins, viral hepatitis, shock, or anoxia, B-viral hepatitis, non-A / non-B hepatitis, cirrhosis, alcoholic cirrhosis, liver failure, fulminant liver failure, late-onset liver failure, "chronic acute" liver failure, enhanced chemotherapy effects, cytomegalovirus infection, HCMV infection, AIDS, cancer, senile dementia, trauma, and chronic bacterial infections.

[0026] In yet another embodiment, the present invention provides a method for suppressing the immune system in a subject (e.g., a mammalian patient) in need of immunosuppression, comprising administering to the patient an immunosuppressant-effective amount of a compound of the present invention. In a further embodiment, the compound of the present invention is combined with a pharmaceutically acceptable carrier (e.g., to produce a pharmaceutical composition). The compounds of the present invention and pharmaceutical compositions comprising same find use in methods for treating a disease or condition characterized by bone erosion and / or bone loss in a subject (e.g., a mammalian patient), the method comprising administering to the subject (e.g., patient) a composition (e.g., a pharmaceutical composition) of the present invention in an amount effective to treat the bone erosion and / or bone loss disease or condition. The present invention is not limited by the type of bone loss disease or condition being treated. Indeed, a variety of bone loss diseases or conditions may be treated, including, but not limited to, rheumatoid arthritis, osteoclastic arthritic conditions, periodontal disease, osteoporosis, osteomyelitis, bone metastasis, fracture healing, or other diseases or conditions in which bone loss and / or bone erosion is present.

[0027] In yet another embodiment, the compositions and methods of the present invention can be used in methods of treating a subject (e.g., a mammalian patient) to increase and / or maintain bone density, bone mass, and / or bone structure.

[0028] In another embodiment, the present invention provides therapeutically effective amounts of compounds of the present invention and physiologically acceptable salts, derivatives, prodrugs, and solvates thereof, including mixtures thereof in all ratios, for use in treating or delaying the progression of immune dysregulation in a subject (e.g., a mammalian patient) in need of such treatment. In one embodiment, the compounds exhibit desirable permeability properties (e.g., for oral delivery). In one embodiment, a composition used to treat or delay the progression of an immune dysregulation further comprises one or more anti-inflammatory and / or anti-rheumatic compositions. The present invention is not limited by the type of anti-inflammatory and / or anti-rheumatic composition. Indeed, any anti-inflammatory and / or anti-rheumatic composition known to those skilled in the art may be used in combination with the compounds of the present invention. In one embodiment, the immune dysregulation is a bone-destructive disease or condition (e.g., rheumatoid arthritis). In one embodiment, treatment reduces or eliminates bone erosion and / or bone loss. In another embodiment, treatment enhances and / or maintains bone density, bone mass, and / or bone structure.

[0029] The present invention also provides kits comprising a pharmaceutical agent comprising a compound of the invention (e.g., alone or in combination with a pharmaceutically acceptable carrier) and a package insert containing instructions for administering the pharmaceutical agent to treat or slow the progression of bone erosion and / or bone loss in a mammalian patient. The kit may optionally contain other therapeutic agents, such as anti-inflammatory and / or anti-rheumatic agents. [Brief explanation of the drawings]

[0030] [Figure 1] 1 shows the chemical composition of HL840. [Figure 2] 1 shows various graphs depicting the biological activity of HL840. [Figure 2A] RAW264.7 cells cultured under osteoclast (OC) differentiation conditions in the presence or absence of various compounds, including HL840 (500 pM), and the TRAP enzyme activity measured therein are shown. [Figure 2B]RAW264.7 cells cultured in OC differentiation conditions without or with various concentrations of HL840 are shown. OC differentiation was determined on day 5. [Figure 2C] HL840 administered by oral gavage to DBA / 1 mice and serum levels determined at various time points are shown. [Figure 2D] Collagen-induced arthritis (CIA) was induced in DBA / 1 mice by oral feeding twice a week with either PBS (black line) or HL840 (gray line) at 1.25 g / kg body weight. The incidence of arthritis was recorded. [Figure 2E] The severity of arthritis in the mice shown in Figure 2D is shown. [Figure 2F] Figure 2 shows radiological bone damage in the mice shown in Figure 2D. Two-tailed Student's t-test; **, p<0.005. [Figure 3] Enantiomer specificity of HL840 is shown. RAW264.7 cells were cultured under OC differentiation conditions in the presence or absence of different concentrations of the racemic mixture (left), S-enantiomer (center), or R-enantiomer (right) of HL840, and the inhibitory effect on OC differentiation was determined on day 5. [Figure 4] 1 shows a synthesis scheme of (R)-HL840 in one embodiment of the present invention. [Figure 5] (R)-HL840 and related analogs are shown. [Figure 6] Various graphs depicting the biological activity of HL840 and structurally similar compounds are shown. Specifically, Figure 6 shows RAW264.7 cells cultured under osteoclast (OC) differentiation conditions in the presence or absence of various IC50 values.

[0031] definition For purposes of interpreting this specification, the following definitions shall apply, and whenever appropriate, terms used in the singular shall include the plural and vice versa. In the event that any definition set forth below conflicts with any document incorporated herein by reference, the definition set forth below shall control.

[0032] As used herein, the terms "disease" and "pathological condition," unless otherwise indicated herein, are used interchangeably to describe a deviation from what is considered normal or average for members of a species or group (e.g., humans), which is harmful to the affected individual under conditions that are not adverse to the majority of individuals of that species or group. Such deviations may manifest as conditions, signs, and / or symptoms associated with any dysfunction of the normal state of a subject or any of its organs or tissues. A disease or pathological condition may be caused by or result from contact with a microorganism (e.g., a pathogen or other infectious agent (e.g., a virus or bacterium)), may be in response to environmental factors (e.g., malnutrition, industrial accidents, and / or climate), may be in response to an inherent or latent defect in the organism (e.g., a genetic abnormality), or a combination of these and other factors.

[0033] The terms "host," "subject," or "patient" are used interchangeably herein to refer to an individual to be treated (e.g., administered) with the compositions and methods of the present invention. Subjects include, but are not limited to, mammals (e.g., murine, simian, equine, bovine, porcine, canine, feline, etc.), and most preferably, humans. In the context of the present invention, the term "subject" generally refers to an individual to whom one or more compositions of the present invention are or have been administered.

[0034] The term "buffer" or "buffering agent" refers to a substance that, when added to a solution, prevents a change in the pH of the solution.

[0035] The terms "reducing agent" and "electron donor" refer to a material that donates to a second material to reduce the oxidation state of one or more of the atoms of the second material.

[0036] The term "monovalent salt" refers to any salt in which the metal (eg, Na, K, or Li) has a net 1+ charge in solution (ie, one more proton than electron).

[0037] The term "divalent salt" refers to any salt in which the metal (eg, Mg, Ca, or Sr) has a net 2+ charge in solution (ie, two more protons than electrons).

[0038] The term "chelating agent" or "chelating agent" refers to any material that has multiple atoms with lone pairs of electrons available to bond to a metal ion.

[0039] The term "solution" refers to an aqueous or non-aqueous mixture.

[0040] A "disorder" is any condition or disease that would benefit from treatment with the compositions or methods of the present invention. This includes chronic and acute disorders, including pathological conditions that predispose a mammal to the disorder in question. Non-limiting examples of disorders to be treated herein include conditions such as immune dysregulation (e.g., rheumatoid arthritis) and / or bone erosive diseases.

[0041] As used herein, the terms "bone erosion disease," "bone erosion condition," "bone remodeling disorder," "osteopenia," and "bone loss condition" refer to any disease, disorder, and / or condition with symptoms or signs, disorders, or deregulation of bone remodeling. Bone remodeling (or bone metabolism) is a lifelong process in which mature bone tissue is removed from the skeleton (a process called bone resorption) and new bone tissue is formed (a process called ossification or new bone formation). An imbalance in the regulation of the two subprocesses of bone remodeling, bone resorption and bone formation, can lead to or result in a variety of disorders of an inflammatory, metabolic, pharmacological / endocrinological, infectious, neoplastic, mechanical, and idiopathic nature. Specific examples of diseases associated with bone remodeling include, but are not limited to, arthritis (e.g., rheumatoid arthritis), periodontal disease, psoriatic arthritis, reactive arthritis, gout, ankylosing spondylitis, osteoarthritis, osteoporosis, anorexia nervosa, vitamin D deficiency, Cushing's syndrome, hyperparathyroidism, corticosteroid and other drug-induced osteoporosis, osteomyelitis, bone metastases, primary bone tumors, multiple myeloma, fracture healing, post-surgery, prosthesis-related bone injury, disuse, paralysis, bedriddenness, weightlessness, Paget's disease of bone, and osteonecrosis.

[0042] As used herein, "one or more signs or symptoms of rheumatoid arthritis" (RA; rheumatoid arthritis) includes tender, warm, swollen joints, which are usually affected in a symmetrical pattern. Other symptoms of RA include fatigue, occasional fever, or malaise. Pain and stiffness that lasts for more than 30 minutes in the morning or after a long rest are also common symptoms of RA.

[0043] As used herein, "improved" means a reduction in the severity of a sign or symptom of a disease (eg, RA) and a return to normal function.

[0044] As used herein, "treatment," "therapeutic use," or "pharmaceutical use" refers to any and all uses of the compositions and methods of the present invention to treat a disease state or symptom, or otherwise prevent, hinder, inhibit, or reverse the progression of a disease or other undesirable symptoms. A symptom is "reduced" when the severity (e.g., intensity) or frequency of the symptom is reduced. In the case of RA, a symptom is reduced, for example, when a subject experiences less pain in the affected joint, shorter periods of morning joint stiffness, and less swelling. In the case of a disease or disorder characterized by bone erosion and / or bone loss, a symptom is reduced, for example, when bone loss or erosion is reduced (e.g., when bone mass, bone density, and / or bone structure are maintained and / or enhanced). The present disclosure is not intended to be limited only to the elimination of symptoms. The present disclosure specifically contemplates treatments in which symptoms are reduced (thereby "improving" the subject's condition), but not completely eliminated.

[0045] As used herein, a "protecting group" is a group that prevents an undesired reaction (e.g., decomposition) involving an unprotected functional group. Protecting groups can be added to the N-terminus, C-terminus, or both of small molecules and / or compounds. In one embodiment, the present disclosure contemplates that the protecting group is acyl or amide. In one embodiment, acyl is acetate. In another embodiment, the protecting group is a benzyl group. In another embodiment, the protecting group is a benzoyl group. The present disclosure also contemplates combinations of such protecting groups.

[0046] As used herein, the "biological activity" of a small molecule and / or compound refers to the ability of the small molecule and / or compound to modulate a signal transduction pathway or inhibit shared epitope-calreticulin binding, interaction, and / or activity. Activity can be assessed by a number of techniques. For example, biological activity can be assayed in an in vitro cAMP-mediated assay for DNA repair after induction of DNA damage. Biological activity can also be determined by measuring intracellular cAMP levels or protein kinase A activation after application of the small molecule / compound to cells. Biological activity can also be assessed by measuring osteoclast differentiation and / or activity. Biological activity can also be assessed by measuring nitric oxide signaling. Biological activity can also be assessed by measuring the activity and / or activation of T helper 17 (Th17) cells.

[0047] As used herein, "single dose" refers to a pharmaceutical composition in a formulation capable of achieving its intended effect with a single application or administration (e.g., once daily, once weekly, or at other intervals).

[0048] As used herein, the terms "administration" and "administering" refer to the act of providing a composition of the present disclosure to a subject. Exemplary routes of administration to the human body include, but are not limited to, ocular (intracranial), oral (oral), cutaneous (transdermal), nasal (intranasal), pulmonary (inhalation), oral mucosa (buccal), aural, rectal, by injection (e.g., intravenous, subcutaneous, intraperitoneal, intratumoral, etc.), topical, etc.

[0049] As used herein, "oral administration" or "orally" refers to the introduction of a compound and / or pharmaceutical composition containing same to a subject via the oral cavity (e.g., in aqueous liquid or solid form).

[0050] As used herein, "sublingual administration" or "sublingually" refers to the introduction of a compound and / or a pharmaceutical composition containing same to a subject by application to a mucosal surface under the tongue (in the oral cavity) so that the composition is absorbed by the subject.

[0051] As used herein, "buccal administration" or "buccally" refers to the introduction of a compound and / or a pharmaceutical composition containing same into a subject by application to the mucosal surface lining the cheek (intra-oral cavity) so that the composition is absorbed by the subject.

[0052] As used herein, "intranasal administration" or "intranasally" refers to the introduction of a compound and / or pharmaceutical composition containing same into the nasal cavity.

[0053] As used herein, "inhalation" refers to the introduction of a compound and / or pharmaceutical composition containing same into the respiratory tract.

[0054] As used herein, "pulmonary delivery" includes administration to the lungs. Pulmonary delivery of a pharmacological agent to a patient can be achieved by aerosolization. Alternatively, the agent may be administered to the lungs via a bronchoscope.

[0055] As used herein, "transdermal administration" or "transdermally" or "dermally" refers to the introduction of a compound and / or pharmaceutical composition containing same to a subject by application to the surface of the skin so that the composition is absorbed by the subject.

[0056] As used herein, "injection" or "standard injection" refers to the placement of a compound and / or a pharmaceutical composition containing same into a subject (e.g., with a hypodermic needle). For example, such injection can be performed subcutaneously, intravenously, intramuscularly, intracavernosally, etc.

[0057] As used herein, "intra-articular" injection refers to the injection of a compound and / or pharmaceutical composition containing same directly into a joint (eg, in methods of treating RA).

[0058] The term "test compound" refers to any chemical, pharmaceutical, drug, etc. that can be used to treat or prevent a disease, illness, disorder, or impairment of bodily function, or that otherwise alters the physiological or cellular state of a sample. Test compounds include both known and potential therapeutic compounds. Test compounds can be determined to be therapeutic by screening using the screening methods of the present disclosure. A "known therapeutic compound" refers to a therapeutic compound that has been shown (e.g., through animal trials or prior experiments involving administration to humans) to be effective in such treatment or prevention.

[0059] As used herein, the term "effective amount" refers to the amount of a compound and / or pharmaceutical composition containing same (e.g., a compound of the present disclosure) sufficient to produce a beneficial or desired result. An effective amount can be administered in one or more administrations, applications, or dosages, and is not intended to be limited to a particular formulation or route of administration.

[0060] As used herein, the term "therapeutically effective amount" refers to an amount of a therapeutic agent sufficient to improve one or more symptoms of a disorder, inhibit the progression of a disorder, or cause regression of a disorder. For example, with respect to the treatment of immune dysregulation (e.g., autoimmune disease or chronic inflammatory disease (e.g., rheumatoid arthritis)), in one embodiment, a therapeutically effective amount would refer to an amount of a therapeutic agent that inhibits, reduces, decreases, and / or reverses bone erosion, bone loss, bone density loss, and / or bone structure loss in a subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.

[0061] As used herein, the term "co-administration" refers to the administration of at least two agents(s) (e.g., a compound of the present disclosure and another active agent) or therapies to a subject. In some embodiments, the co-administration of two or more agents / therapies is simultaneous. In other embodiments, a first agent / therapy is administered before a second agent / therapy. Those of skill in the art will appreciate that the formulations and / or routes of administration of the various agents / therapy used may vary. Appropriate dosages for co-administration can be readily determined by those of skill in the art. In some embodiments, when agents / therapies are co-administered, each agent / therapy is administered at a lower dosage than would be appropriate for its administration alone. Thus, co-administration is particularly desirable in embodiments where co-administration of agents / therapies reduces the required dosage of known potentially harmful (e.g., toxic) agent(s).

[0062] As used herein, the terms "sensitize" and "sensitizing" refer to making an animal or cells within an animal more susceptible or responsive to the biological effect (e.g., promoting or delaying an aspect of cellular function) of a second agent through administration of a first agent. The sensitizing effect of a first agent on target cells can be measured as the difference in the intended biological effect (e.g., inhibition of bone erosion) observed upon administration of the second agent with and without administration of the first agent. The response of the sensitized cells can be increased by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, at least about 300%, at least about 350%, at least about 400%, at least about 450%, or at least about 500% relative to the response in the absence of the first agent.

[0063] As used herein, the term "toxic" refers to any harmful or adverse effect on a cell or tissue compared to the same cell or tissue prior to administration of the toxic agent.

[0064] As used herein, the term "pharmaceutical composition" refers to a combination of an active agent with an inert or active carrier that makes the composition particularly suitable for diagnostic or therapeutic use in vivo, in vivo, or ex vivo.

[0065] As used herein, the term "pharmaceutically acceptable carrier" refers to any of the standard pharmaceutical carriers, such as phosphate-buffered saline, water, emulsions (e.g., oil / water or water / oil emulsions), and various types of wetting agents. The compositions may also contain stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see, e.g., Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA

[1975] .

[0066] As used herein, the term "purified" or "to purify" refers to the removal of contaminants or undesired compounds from a sample or composition. As used herein, the term "substantially purified" refers to the removal of about 70-90%, and up to 100%, of contaminants or undesired compounds from a sample or composition.

[0067] As used herein, the term "pharmaceutically acceptable salt" refers to any salt of the disclosed compositions (e.g., obtained by reaction with an acid or base) that is physiologically acceptable in the target subject. The "salts" of the disclosed compositions may be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid, benzoic acid, malonic acid, sulfonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like. Other acids, such as oxalic acid, while not themselves pharmaceutically acceptable, may be used in the preparation of salts useful as intermediates in obtaining the compositions of the present invention and their pharmaceutically acceptable acid addition salts. Examples of bases include, but are not limited to, alkali metal (e.g., sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides, ammonia, and compounds of the formula NW4+ (wherein W is C1-4 alkyl, etc.).

[0068] Examples of salts include, but are not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, chloride, bromide, iodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of salts include the anions of the compounds of the present disclosure combined with suitable cations, such as Na, NH, and NW (wherein W is a C alkyl group). For therapeutic use, salts of the compounds of the present disclosure are considered pharmaceutically acceptable. However, salts of pharmaceutically unacceptable acids and bases may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0069] For therapeutic use, salts of the compositions of the present disclosure are considered to be pharmaceutically acceptable, however, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable composition.

[0070] The term "prodrug," as used herein, refers to a pharmacologically inactive derivative of a parent "drug" molecule that requires biotransformation (e.g., either spontaneously or enzymatically) within a target physiological system to release or convert the prodrug (e.g., enzymatically, physiologically, mechanically, electromagnetically) to an active drug. Prodrugs are designed to overcome problems associated with stability, water solubility, toxicity, lack of specificity, or limited bioavailability. Exemplary prodrugs include the active drug molecule itself and a chemical masking group (e.g., a group that reversibly suppresses the activity of the drug). Some prodrugs are variations or derivatives of compounds that have groups cleavable under metabolic conditions.A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard (eds.), Gordon & Breach, 1991, particularly Chapter 5: “Design and Applications of Prodrugs”; Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 1985; Prodrugs: Topical and Ocular Drugs Delivery. Vol.1 and pp.172-178 and They can be readily prepared from the parent compounds using methods known in the art, such as those described in Prodrugs as Novel Delivery Systems, T. Higuchi and V. Stella (eds.), Am. Chem. Soc., 1975, pp. 949-982; Prodrugs as Novel Delivery Systems, T. Higuchi and V. Stella (eds.), Am. Chem. Soc., 1975; and Bioreversible Carriers in Drug Design, EB Broche (ed.), Elsevier, 1987.

[0071] Exemplary prodrugs become pharmaceutically active in vivo or in vitro when they undergo solvolysis under physiological conditions, or undergo enzymatic degradation or other biochemical transformations (e.g., phosphorylation, hydrogenation, dehydrogenation, glycosylation). Prodrugs often offer the advantages of water solubility, tissue compatibility, or delayed release in mammalian organisms. (See, for example, Bundgard, Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam (1985); and Silverman, The Organic Chemistry of Drug Design and Drug Action, pp. 352-401, Academic Press, San Diego, CA (1992)). Common prodrugs include acid derivatives, such as esters prepared by reacting the parent acid with a suitable alcohol (e.g., a lower alkanol) or a suitable carboxylic acid (e.g., an amino acid), amides prepared by reacting the parent acid compound with an amine, a basic group reacted to form an acylated base derivative (e.g., a lower alkyl amide), or phosphorus-containing derivatives, such as phosphate, phosphonate, and phosphoramidate esters, including cyclic phosphates, phosphonates, and phosphoramidates (see, e.g., U.S. Patent Application Publication No. US2007 / 0249564A1, which is incorporated by reference in its entirety).

[0072] As used herein, the term "kit" refers to any delivery system for delivering materials. In the context of the compounds of the present invention, such delivery systems include systems that allow for the storage, transportation, and / or delivery of compounds and / or supporting materials (e.g., instructions for using the materials, etc.) from one location to another. For example, a kit includes one or more enclosures (e.g., boxes) containing related compounds. As used herein, the term "fragmented kit" refers to a delivery system that includes two or more separate containers, each containing a portion of the total kit components. The containers may be delivered to the intended recipient together or separately. For example, a first container may contain a composition including a compound for a particular use, while a second container contains a second drug (e.g., an anti-inflammatory or anti-rheumatic drug). Indeed, any delivery system that includes two or more separate containers, each containing a portion of the total kit components, is included in the term "fragmented kit." In contrast, a "combined kit" refers to a delivery system that contains all of the components necessary for a particular use in a single container (e.g., in a single box housing each of the desired components). The term "kit" includes both fragmentation kits and conjugation kits. [Mode for Carrying Out the Invention]

[0073] Osteoclast (OC)-mediated bone damage is a common and effective outcome in rheumatoid arthritis (RA) (Bromley et al., 1984 Arthritis Rheum. 27:857-863; Gravallese et al., 2000 Arthritis Rheum. 43:250-258). Despite the advent of biologic agents, treating erosive RA remains a challenging endeavor due to a lack of understanding of the mechanisms that specifically trigger and determine the severity of RA disease. Most current and emerging drugs target general immunoregulatory pathways or inflammatory cytokines. As a result, drug failure and / or side effects are common.

[0074] Although the pathogenesis of RA is not fully understood, it has long been observed that the majority of RA patients have HLA-DRB1 alleles that encode a five-amino acid sequence motif called a "shared epitope" (SE) in region 70-74 of the DRβ chain (Gregersen et al., 1987. Arthritis Rheum. 30:1205-1213). SE not only confers a higher risk of RA but also increases the likelihood of developing more severe disease. HLA-DRB1 alleles encoding SE are associated with earlier disease onset and more severe bone erosion (Gonzalez-Gay et al., 2002, Semin. Arthritis Rheum. 31:355-360; Mattey et al., 2001, Arthritis Rheum. 44:1529-1533; Plant et al., 1998, J. Rheumatol. 25:417-426; Weyand et al., 1994, J. Lab. Clin. Med. 124:335-338). Furthermore, there is evidence of a gene dosage effect, with the extent of bone destruction in RA positively correlated with the number of HLA-DRB1 alleles encoding SE (Mattey et al., supra; Plant et al., supra; Weyand et al., supra).

[0075] SEs function as signaling ligands that bind to cell surface calreticulin (CRT) in a strictly allele-specific manner and activate nitric oxide (NO)-mediated prooxidant signaling (Ling et al., 2006. Arthritis Rheum. 54:3423-3432; Ling et al., 2007. Arthritis Res Ther 9:R5; Ling et al., 2007. The Journal of Immunology 179:6359-6367; Ling et al., 2012 Arthritis Rheum.; De Almeida et al., 2010. The Journal of Immunology 185:1927-1934; Holoshitz et al., 2010 Ann. N.Y. Acad. Sci. 1209:91-98; U.S. Patent Nos. 7,208,154 and 7,074,893). One of the functional consequences of SE ligand-activated signaling is the proliferation of IL-17-producing T (Th17) cells both in vitro and in vivo (De Almeida et al., supra).

[0076] Th17 cells are central players in the pathogenesis of arthritis (Shahrara et al., 2008 Arthritis Res Ther 10:R93). These cells express high levels of receptor activator of nuclear factor-κB (RANK) ligand (RANKL) and have previously been shown to activate osteoclastogenesis (Sato et al., 2006 J. Exp. Med. 203:2673-2682; Kotake et al., 1999 J. Clin. Invest. 103:1345-1352). Previous studies have shown that SE ligand promotes osteoclast (OC) differentiation in mouse and human cells in vitro and enhances the differentiation of RANKL-expressing Th17 cells. When administered in vivo to mice with collagen-induced arthritis (CIA), SE ligand increased joint swelling, OC abundance in synovial tissue, and erosive bone damage (Holoshitz et al., 2012, J. Immunol).

[0077] Given that SE acts as a signaling ligand that directly contributes to the severity of arthritis, experiments were conducted during the development of embodiments of the present invention to identify and characterize methods of inhibiting this pathway.

[0078] Targeting the SE-CRT pathway offers additional advantages over current treatment paradigms due to the unique role this pathway plays in the upstream pathogenesis of RA. SE is the single most important risk factor for RA. It determines the susceptibility, severity, and even penetrance of the disease in identical twins (Jawaheer et al., 1994 Arthritis Rheum. 37:681-686). Thus, unlike effector cytokines or enzymes involved in lymphocyte activation, this pathway is intimately involved in the pathogenesis and early development of the disease.

[0079] Experiments conducted during the development of embodiments of the present invention have demonstrated that RA is a moderately orally available, potent anti-OC small molecule that exhibits potent anti-arthritic and anti-bone erosion effects in vivo when administered orally to mice using a preclinical model of RA. HL840( [ka] )((R,E)-(1-((1-(3-(1-methyl-1H-pyrazol-4-yl)acryloyl)piperidin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)methanaminium) was identified (see, e.g., Examples 1-3).

[0080] Further experiments were performed to determine whether the enantiomers of HL840 exhibit different pharmacological properties, including potency and metabolic stability. A novel synthetic scheme for synthesizing the racemate and both enantiomers was developed. As shown in Figure 3, the (R)-enantiomer is responsible for all of the activities of racemic HL840 (e.g., inhibition of SE-CRT interaction and signal transduction).

[0081] Further experiments identified additional structurally similar small molecules possessing the triazole-methyl-piperidinyl-pyrrolyl-propenone structure that function as modulators of shared epitope (SE)-calreticulin (CRT) binding and / or interaction (see, e.g., Example 4 and Figure 6).

[0082] Accordingly, the present invention relates to a new class of small molecules having a triazole-methyl-piperidinyl-pyrrolyl-propenone structure that function as modulators of shared epitope (SE)-calreticulin (CRT) binding and / or interaction, and their use as therapeutics for treating immune dysregulation (e.g., autoimmune diseases, inflammatory diseases (e.g., chronic inflammatory diseases), and bone erosive diseases) by selectively inhibiting overactive or dysregulated SE-CRT interactions and / or signaling pathways common in arthritis and / or other diseases or conditions.

[0083] In certain embodiments, triazole-methyl-piperidinyl-pyrrolyl-propenone compounds and structurally similar compounds encompassed by Formulas I, II, III, and IV are provided: [ka] This includes pharmaceutically acceptable salts, solvates, and / or prodrugs thereof.

[0084] Formulas I, II, III, and IV are not limited to the particular chemical moieties of R1, R2, and R3. In some embodiments, the particular chemical moieties of R1, R2, and R3 independently include any chemical moiety that enables the resulting compound to modulate SE-CRT binding and / or interaction.

[0085] In some embodiments, R1 is [ka] and [ka] is.

[0086] In some embodiments, R2 is CH3, [ka] and [ka] is.

[0087] In some embodiments, R3 is hydrogen or fluorine.

[0088] In some embodiments, the following compounds for Formulas I, II, III, and IV are contemplated: [ka] TIFF0007737125000027.tif218169 TIFF0007737125000028.tif198169 TIFF0007737125000029.tif38169 and [ka] or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0089] Thus, the present disclosure provides a compound ((R)-HL840, shown in Figures 1 and 4) and additional compounds (Example 4 and Figure 6) that are highly potent inhibitors of SE-CRT interaction and osteoclast activation. Accordingly, in one embodiment, as described in detail herein, the present invention provides such compounds and compositions (e.g., pharmaceutical compositions) comprising same for use in treating or delaying the progression of immune dysregulation, e.g., caused by SE-CRT signaling and / or osteoclast activation (e.g., rheumatoid arthritis and / or other bone-destructive diseases). Such compounds exhibited acceptable permeation properties and were orally available in vivo (see Examples 1 and 4).

[0090] In one embodiment, the present invention provides pharmaceutically acceptable salts of (R)-HL840 (as well as structurally similar compounds (see Example 4 and Figure 6)) generally derived by dissolving the free acid or lactone, preferably the lactone, in an aqueous or aqueous alcoholic solvent or other suitable solvent containing a suitable base and isolating the salt by evaporating the solution, or by reacting the free acid or lactone, preferably the lactone, with a base in an organic solvent from which the salt can be isolated directly or obtained by concentration of the solution. In practice, use of the salt form is equivalent to use of the acid or lactone form. Suitable pharmaceutically acceptable salts within the scope of the present invention are those derived from bases, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, 1-deoxy-2-(methylamino)-D-glucitol, magnesium hydroxide, zinc hydroxide, aluminum hydroxide, ferrous or ferric hydroxide, ammonium hydroxide, or organic amines such as N-methylglucamine, choline, arginine, etc. Preferably, the lithium, calcium, magnesium, aluminum, and ferrous or ferric salts are prepared from the sodium or potassium salts by adding the appropriate reagent to a solution of the sodium or potassium salt, i.e., adding calcium chloride to a solution of the sodium or potassium salt of (R)-HL840 will give the calcium salt.

[0091] In general, (R)-HL840 and related analogs of the present disclosure can be prepared by synthetic schemes such as those shown in Figure 4. Those of skill in the art will recognize variations of the schemes that are suitable for preparing compounds of the present invention. Thus, in one embodiment, the present disclosure provides pharmaceutical compositions prepared from (R)-HL840 or related analogs (e.g., as shown in Figure 4 or Figure 5, respectively), or pharmaceutically acceptable salts thereof.

[0092] An important aspect of the present invention is that the compounds of the present invention, when administered as monotherapy or in temporal association with additional agent(s), fulfill an unmet need for the treatment of immune dysregulation (e.g., autoimmune diseases, inflammatory diseases (e.g., chronic inflammatory diseases), and bone erosive diseases), where the additional agent(s) are other pharmaceutical agents known to be effective in treating such conditions, or symptoms associated with such conditions, by, for example, inhibiting the binding and / or interaction of SE-CRT (combination therapy).

[0093] In some embodiments, the compositions and methods of the present invention are used to treat diseased cells, tissues, organs, or pathological and / or disease states in animals (e.g., mammalian patients, including but not limited to humans and veterinary animals). In this regard, a variety of diseases and conditions are amenable to treatment or prevention using the present methods and compositions. Indeed, the present invention provides a method of treating an immune dysregulation in a subject (e.g., a mammalian patient) in need thereof, the method comprising administering to the patient an amount of a compound of the present invention effective to treat the immune dysregulation. The present invention is not limited to a particular immune dysregulation. In one embodiment, the immune dysregulation is an autoimmune disease. In another embodiment, the immune dysregulation is a chronic inflammatory disease. In one embodiment, the autoimmune disease or chronic inflammatory disease is rheumatoid arthritis. In one embodiment, the treatment inhibits and / or reduces bone erosion in the subject. Organ or tissue transplantation, graft-versus-host disease caused by transplantation, autoimmune syndromes including, but not limited to, rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type 1 diabetes, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis, inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, acne, alopecia areata, keratoconjunctivitis, summer conjunctivitis, uveitis associated with Behcet's disease, keratitis , herpetic keratitis, keratoconus, epithelial corneal dystrophy, corneal leukoplakia, ocular pemphigus, Mooren's ulcer, scleritis, Graves' ophthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, hay fever, treatable obstructive airway diseases, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or refractory asthma, late-onset asthma and airway hyperresponsiveness, bronchitis, gastric ulcer, vascular damage caused by ischemic disease and thrombosis, ischemic bowel disease, inflammatory bowel disease, necrotizing enterocolitis, intestinal lesions associated with burns, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis,Goodpasture syndrome, hemolytic uremic syndrome, diabetic nephropathy, polymyositis, Guillain-Barre syndrome, Meniere's disease, polyneuritis, polyneuritis, mononeuritis, radiculopathy, hyperthyroidism, Basedow's disease, pure red cell aplasia, aplastic anemia, aplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, red blood cell hypoplasia, osteoporosis, sarcoidosis, pulmonary fibrosis, idiopathic interstitial pneumonia, dermatomyositis, albinism, ichthyosis vulgaris, photoallergic hypersensitivity, cutaneous T-cell lymphoma, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, cardiomyopathy, scleroderma, Wegener's granuloma, Sjogren's syndrome, adiposity, eosinophilic fasciitis; lesions of the gingiva, periodontium, alveolar bone, dental cementum; glomerulonephritis, prevention of hair loss or provision of hair growth and / or promotion of hair growth and hair regrowth in male pattern baldness or age-related alopecia, muscular dystrophy, pyoderma and Sezary syndrome, Addison's disease, ischemia-reperfusion injury of organs occurring during storage, transplantation or Ischemic diseases, endotoxin shock, pseudomembranous colitis, drug- or radiation-induced colitis, ischemic acute renal failure, chronic renal failure, pulmonary oxygen or drug intoxication, lung cancer, emphysema, cataracts, siderosis, retinitis pigmentosa, senile macular degeneration, vitreous scarring, corneal alkali burns, erythematous dermatitis multiforme, linear IgA bullous dermatitis and cement dermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution, aging, carcinogenesis, metastasis of cancer and altitude sickness, and histamine or leukotriene-C.sub.4 release Other immune dysregulation disorders may also be treated, including diseases caused by hepatitis B, Behcet's disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, partial liver resection, acute liver necrosis, necrosis caused by toxins, viral hepatitis, shock, or anoxia, B-viral hepatitis, non-A / non-B hepatitis, cirrhosis, alcoholic cirrhosis, liver failure, fulminant liver failure, late-onset liver failure, "chronic acute" liver failure, enhanced chemotherapy effects, cytomegalovirus infection, HCMV infection, AIDS, cancer, senile dementia, trauma, and chronic bacterial infections.

[0094] In yet another embodiment, the present invention provides a method for suppressing the immune system in a subject (e.g., a mammalian patient) in need of immunosuppression, comprising administering to the patient an immunosuppressant-effective amount of a compound of the present invention. In a further embodiment, the compound of the present invention is combined with a pharmaceutically acceptable carrier (e.g., to produce a pharmaceutical composition). The compounds of the present invention and pharmaceutical compositions comprising same find use in methods for treating a disease or condition characterized by bone erosion and / or bone loss in a subject (e.g., a mammalian patient), the method comprising administering to the subject (e.g., patient) a composition (e.g., a pharmaceutical composition) of the present invention in an amount effective to treat the bone erosion and / or bone loss disease or condition. The present invention is not limited by the type of bone loss disease or condition being treated. Indeed, a variety of bone loss diseases or conditions may be treated, including, but not limited to, rheumatoid arthritis, osteoclastic arthritic conditions, periodontal disease, osteoporosis, osteomyelitis, bone metastasis, fracture healing, or other diseases or conditions in which bone loss and / or bone erosion is present.

[0095] In yet another embodiment, the compositions and methods of the present invention can be used in methods of treating a subject (e.g., a mammalian patient) to increase and / or maintain bone density, bone mass, and / or bone structure.

[0096] Some embodiments of the present invention provide methods for administering an effective amount of a compound of the present invention and at least one additional therapeutic agent, including but not limited to, an anti-inflammatory agent and / or an anti-rheumatic agent. Examples of anti-inflammatory agents and / or anti-rheumatic agents include methotrexate, dexamethasone, dexamethasone alcohol, dexamethasone sodium phosphate, fluromethalone acetate, fluromethalone alcohol, lotoprendol etabonate, medrysone, prednisolone acetate, prednisolone sodium phosphate, difluprednate, rimexolone, hydrocortisone, hydrocortisone acetate, lodoxamate, and the like. Examples of suitable antihistamines include thrombus, aspirin, ibuprofen, suprofen, piroxicam, meloxicam, flurbiprofen, naproxen, ketoprofen, tenoxicam, diclofenac sodium, ketotifen fumarate, diclofenac sodium, nepafenac, bromfenac, flurbiprofen sodium, suprofen, celecoxib, naproxen, rofecoxib, glucocorticoids, diclofenac, and any combination thereof. In one embodiment, an active compound or salt thereof or composition described herein is combined with one or more nonsteroidal anti-inflammatory drugs (NSAIDs) selected from naproxen sodium (Anaprox), celecoxib (Celebrex), sulindac (Clinoril), oxaprozin (Daypro), salsalate (Disalcid), diflunisal (Dolobid), piroxicam (Feldene), indomethacin (Indocin), etodolac (Lodine), meloxicam (Mobic), naproxen (Naprosyn), nabumetone (Relafen), ketorolac tromethamine (Toradol), naproxen / esomeprazole (Vimovo), and diclofenac (Voltaren), and combinations thereof.

[0097] In some embodiments of the invention, a compound of the invention and one or more therapeutic agents (anti-inflammatory and / or anti-rheumatic agents) are administered to an animal under one or more of the following conditions: at different cycles, for different durations, at different concentrations, by different routes of administration, etc. In some embodiments, the compound is administered before the therapeutic agent, e.g., 0.5, 1, 2, 3, 4, 5, 10, 12, or 18 hours, 1, 2, 3, 4, 5, or 6 days, or 1, 2, 3, or 4 weeks before administration of the therapeutic agent. In some embodiments, the compound is administered after the therapeutic agent, e.g., 0.5, 1, 2, 3, 4, 5, 10, 12, or 18 hours, 1, 2, 3, 4, 5, or 6 days, or 1, 2, 3, or 4 weeks after administration of the therapeutic agent. In some embodiments, the compound and therapeutic agent are administered simultaneously but on different schedules, e.g., the compound is administered once daily while the therapeutic agent is administered once weekly, once every two weeks, once every three weeks, or once every four weeks. In other embodiments, the compound is administered once weekly while the therapeutic agent is administered once daily, once weekly, once every two weeks, once every three weeks, or once every four weeks.

[0098] Compounds of the present disclosure (e.g., utilized in the pharmaceutical compositions and methods of using same described herein) can be administered to patients at dosage levels of 70 μg to 500 mg per day, which corresponds to a dosage of 1 μg / kg to 7.1 mg / kg of body weight per day for a normal adult weighing approximately 70 kg. Dosages may preferably be 0.1 to 1.0 mg / kg per day. Any patient who would benefit from inhibition of SE-CRT interaction and / or inhibition of osteoclast activation may benefit from administration of the compounds and compositions described herein. Indeed, immune dysregulation (e.g., caused by SE-CRT interaction and / or signaling or by aberrant osteoclast activation) can be treated with such compounds and compositions.

[0099] The dosage is preferably administered as a unit dosage form. The unit dosage form for oral or parenteral use may vary or be adjusted (e.g., 10 to 500 mg, preferably 20 to 100 mg) depending on the particular application and the potency of the active ingredient(s). The compositions of the present invention may optionally contain other active therapeutic agents (e.g., anti-inflammatory and / or anti-rheumatic drug(s)). Determination of the optimal dosage (e.g., therapeutically effective amount) for a particular situation is within the skill of one of ordinary skill in the art.

[0100] Embodiments of the present disclosure further provide compounds described herein for use in research, screening, and therapeutic applications.

[0101] For example, the present disclosure also provides methods for modifying and derivatizing the compositions of the present disclosure to increase desirable properties (e.g., binding affinity, activity, solubility, etc.) or minimize undesirable properties (e.g., nonspecific reactivity, toxicity, etc.). The principles of chemical derivatization are well understood. In some embodiments, iterative design and chemical synthesis approaches are used to generate libraries of derivatized daughter compounds from parent compounds. In some embodiments, rational design methods are used to predict and model ligand-receptor interactions in silico before confirming results through routine experimentation.

[0102] The present disclosure is not limited by the method of introducing the compounds and compositions (e.g., therapeutic compounds and compositions) into the body. Among other methods, the present disclosure contemplates administration orally, cutaneously, or by standard injection (e.g., intravenously).

[0103] The present disclosure also contemplates administering the compounds described herein to patients intranasally or via respiratory inhalation. Formulations suitable for intranasal administration include ointments, creams, lotions, pastes, gels, sprays, aerosols, oils, and other pharmaceutical carriers that achieve direct contact between the compounds of the present disclosure or pharmaceutical compositions comprising the compounds of the present disclosure and the nasal cavity. Examples of pharmaceutical compositions that can be administered intranasally are described in U.S. Patent Nos. 5,393,773 and 5,554,639 to Craig et al. and U.S. Patent No. 5,801,161 to Merkus, all of which are incorporated herein by reference. Formulations suitable for respiratory inhalation include ointments, creams, lotions, pastes, gels, sprays, aerosols, oils, and other pharmaceutical carriers that achieve direct contact between the compounds of the present disclosure or pharmaceutical compositions comprising the compounds of the present disclosure and the respiratory tract. Examples of pharmaceutical compositions administered by respiratory inhalation are described in U.S. Pat. Nos. 4,552,891 to Hu et al.; 5,869,479 to Kreutner et al.; and 5,864,037 to Chasis et al., all of which are incorporated herein by reference.

[0104] In some embodiments, intranasal administration and inhalation are used for ease of administration and faster onset of therapeutic activity. It is believed that intranasal administration and inhalation may be advantageous because they may allow for smaller effective dosages to be administered than are possible with oral administration. Another mode of administration includes pulmonary administration. Pulmonary delivery of pharmacological agents to patients can be achieved by aerosolization. Alternatively, the agent may be administered to the lungs via a bronchoscope.

[0105] The present disclosure is not limited by the oral administration form of the aqueous and / or organic solutions of the compounds described herein. Similarly, the compounds of the present disclosure can be combined with solid pharmaceutical carriers for solid oral administration (e.g., in pill form). Those skilled in the art can prepare such solid formulations; in one non-limiting embodiment, the inactive ingredients include croscarmellose sodium, hydroxypropyl methylcellulose, lactose, magnesium stearate, methocel E5, microcrystalline cellulose, povidine, propylene glycol, and / or titanium dioxide.

[0106] The compounds described herein may also be administered to the skin in a carrier suitable for topical administration. Such carriers include creams, ointments, lotions, pastes, jellies, sprays, aerosols, bath oils, or other pharmaceutical carriers that achieve direct contact between the compounds of the present disclosure and the pores of the skin. Generally, pharmaceutical preparations may contain about 0.001% to about 10%, preferably about 0.01 to 5% w / w, of the active compound. In some cases, it may be useful to dissolve the active compound in a suitable solvent such as ethanol or DMSO (dimethyl sulfoxide) to facilitate incorporation into the pharmaceutical preparation.

[0107] Although the present disclosure is not limited by a particular method of introducing the compounds of the present disclosure by injection, injection of the compounds of the present disclosure can be performed by any conventional injection means (e.g., using a hypodermic syringe and needle or similar device, e.g., the NovolinPen sold by Squibb-Novo, Inc., Princeton, NJ, USA). The injection can be by the subject injecting themselves or by another person injecting the patient.

[0108] The compounds described herein can be introduced by injection into physiologically acceptable compositions.Such compositions are physiologically acceptable aqueous solutions for injection administration.Physiologically acceptable carriers are selected so that they are painless or non-irritating when injected.Physiologically acceptable compositions are preferably sterile when administered by injection.

[0109] Physiologically acceptable compositions used in the compositions and methods of the present invention are physiological saline or phosphate buffered saline in which the compounds of the disclosed embodiments are dissolved or suspended, such that the resulting composition is suitable for injection. Such physiologically acceptable compositions may also contain a non-irritating preservative, such as 0.05% (w / v) to 0.2% (w / v) benzalkonium chloride.

[0110] The present disclosure is not limited to the method of injecting the compounds, but in some embodiments, they are injected with a standard syringe. One skilled in the art can inject the compounds of the present disclosure with carriers such as those described above.

[0111] In some embodiments (e.g., in methods of treating a subject with symptoms of RA), it is desirable for the compositions of the present disclosure to reach the affected joint. In some embodiments, this may be achieved by dermal or transdermal application of a pharmaceutical composition comprising a compound described herein directly to the skin of the affected joint. In other embodiments, delivery of the compound to the affected joint may be by direct injection into the joint. The present disclosure specifically contemplates intra-articular injection (e.g., into the specific joint to be treated (e.g., knee, shoulder, acromioclavicular, sternoclavicular, ankle, subtalar ankle, wrist, first carpometacarpal, metacarpophalangeal, interphalangeal, metatarsophalangeal, and interphalangeal toe joints, elbow, hip, temporomandibular joint, and / or other joints that would benefit from treatment)).

[0112] As described herein, embodiments of the present disclosure provide compositions and methods for treating various autoimmune diseases, including, but not limited to, rheumatoid arthritis (RA). In some embodiments, a compound (e.g., a compound described herein and / or a pharmaceutical composition comprising same) is administered to a subject diagnosed with RA. In some embodiments, administration reduces or eliminates one or more symptoms of RA. In some embodiments, administration prevents or reverses bone damage caused by RA.

[0113] In some embodiments, a compound (e.g., a compound described herein and / or a pharmaceutical composition comprising same) is administered once to a subject in need thereof. In other embodiments, the composition is administered continuously, recurrently, or repeatedly (e.g., multiple times per day, once per day, once every 2, 3, 4, 5, or 6 days, once per week, etc.) for a period of time (e.g., days, weeks, months, or years). Suitable dosages and administration schedules can be determined by one of skill in the art using suitable methods (e.g., those described in the Experimental Section below or known to those of skill in the art).

[0114] In some embodiments, the present disclosure provides methods of treating diseases and / or disorders characterized as involving bone erosion, bone loss, and / or unregulated bone remodeling. Examples include, but are not limited to, inflammatory diseases or disorders (e.g., arthritis (e.g., rheumatoid arthritis), periodontal disease, psoriatic arthritis, reactive arthritis, gout, SLE, ankylosing spondylitis, osteoarthritis), metabolic diseases or disorders (e.g., osteoporosis, anorexia nervosa), pharmacological diseases or disorders (e.g., corticosteroid, other drug-induced osteoporosis), endocrine diseases or disorders (e.g., vitamin D deficiency, Cushing's syndrome, hyperparathyroidism), infectious diseases (e.g., osteomyelitis), neoplastic diseases or disorders (e.g., bone metastases, primary bone tumors, multiple myeloma), mechanical disorders (e.g., fracture healing, post-operative, prosthesis-related bone injury, disuse, paralysis, bedridden), and idiopathic diseases or disorders (e.g., Paget's disease of bone, osteonecrosis).

[0115] The present invention also provides kits comprising a pharmaceutical agent comprising a compound of the invention (e.g., alone or in combination with a pharmaceutically acceptable carrier) and a package insert containing instructions for administering the pharmaceutical agent to treat or slow the progression of bone erosion and / or bone loss in a mammalian patient. The kit may optionally contain other therapeutic agents, such as anti-inflammatory and / or anti-rheumatic agents.

[0116] Those skilled in the art will readily recognize that the foregoing represents merely a detailed description of certain preferred embodiments of the present invention. Various modifications and variations of the compositions and methods described above can be readily accomplished using the expertise available in the art and are within the scope of the present invention. [Example]

[0117] The following examples are illustrative, but not limiting, of the compounds, compositions, and methods of the present invention. Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered in clinical therapy that are obvious to those skilled in the art are within the spirit and scope of the present invention.

[0118] Example 1 HL840 inhibits SE-CRT interaction and signaling. As described in detail herein, shared epitope (SE) ligands bind to calreticulin (CRT) and activate aberrant immune system signaling / regulation.

[0119] Experiments were conducted during the development of embodiments of the present invention to identify and characterize compounds capable of inhibiting SE-CRT binding and / or immune signaling activation. HL840 (see FIG. 1) was identified and exhibited potent competitive inhibition of SE-CRT interaction. HL840 was tested in vitro for anti-osteoclast (OC) activity using an in vitro OC differentiation assay, as shown in FIG. 2. HL840 exhibited potent (IC 50 =1.99x10 -11 M) exhibits anti-osteoclast (OC) activity and has desirable permeability properties (permeability of Caco-2 cell layers (PappA-B =5.6x10 -6 Further experiments demonstrated that HL840 is orally available in vivo.

[0120] Specifically, experiments were conducted in an animal model of collagen-induced arthritis (CIA). When orally administered to CIA mice (at a low dose of 1.25 μg / kg body weight twice weekly), HL840 strongly inhibited disease onset, reduced the severity of arthritis, and prevented bone destruction (see Figure 2). Significant therapeutic effects were also observed in another preclinical model of RA in SKG mice.

[0121] Example 2 HL840 enantiomer-specific effects, HL840 is commercially available as a racemate. Experiments were conducted to determine whether the enantiomers of HL840 exhibit different pharmacological properties, including potency and metabolic stability. Therefore, the racemate and both enantiomers were synthesized via a novel synthetic route (see Example 3 below and Figure 4). As shown in Figure 3, the (R)-enantiomer is responsible for all of the activities of racemic HL840 (e.g., inhibition of SE-CRT interaction and signal transduction).

[0122] Example 3 Chiral synthesis of (R)-HL840 and related analogues The synthesis of (R)-HL840 (R1 = Me, R2 = H) is shown in Figure 4. This route is highly amenable to analog synthesis. Coupling of commercially available chiral piperidin-3-ylmethanol 2 with pyrazole acrylic acid 1 gave amide 3. Many heterocyclic equivalents for pyrazoles (e.g., isoxazole, oxazole) are commercially available as the appropriate acrylic acid regioisomer (e.g., 1a in Figure 4). Various substituted acrylic acids can also be synthesized from commercially available aldehydes R1HETCHO. Mesylation of alcohol 3 gave 4, which was then displaced with azide to give crude 5. Azide 5 can then undergo 3+2 cyclization with commercially available Boc-protected substituted alkynes to give 1,2,3 triazole 6. Removal of Boc under standard conditions affords analog 7. Subsequent sequential reductive amination with an aldehyde affords analogs 8 and 9, respectively.

[0123] Additional analogs may be synthesized using the same or similar schemes. For example, in addition to (R)-HL840 shown in Figure 4, additional R groups and heterocyclic equivalents to the left (e.g., many of which are commercially available) may be used to generate related analogs (see, for example, the analogs shown in Figure 5).

[0124] Example 4 Structurally similar small molecules with a triazole-methyl-piperidinyl-pyrrolyl-propenone structure inhibit osteoclast formation. Experiments have identified additional structurally similar small molecules with a triazole-methyl-piperidinyl-pyrrolyl-propenone structure that function as modulators of shared epitope (SE)-calreticulin (CRT) binding and / or interaction.

[0125] To differentiate osteoclasts (OCs) from RAW264.7 mouse macrophages, the same method was used (2 x 10 cells per well) except that RANKL was added at 20 ng / ml for 5-6 days in the presence or absence of different concentrations of various compounds. 4Cells were cultured in 10% CO₂ at 27°C (10% CO₂). To quantify the number of OCs, cultures were fixed and stained for tartrate-resistant acid phosphatase (TRAP) activity using an acid phosphatase kit (Kamiya Biomedical Company, Seattle, WA) according to the manufacturer's instructions. TRAP-positive multinuclear OCs (>3 nuclei) were counted using an inverted tissue culture microscope. All experiments were performed in triplicate and repeated four times (C&D, N = 12) or three times (EL; N = 9). The percent inhibition of OC formation was calculated compared to cultures containing PBS and presented as a dose-response curve. IC50 values ​​were calculated using GraphPad-Prism software.

[0126] [Figure 6] Various graphs depicting the biological activity of HL840 and structurally similar compounds are shown. Specifically, Figure 6 shows RAW264.7 cells cultured under osteoclast (OC) differentiation conditions in the presence or absence of various IC50 values.

[0127] Although the present invention has now been fully described, it will be understood by those skilled in the art that the same can be practiced within a wide and equivalent range of conditions, formulations, and other parameters without affecting the scope of the invention or any embodiment thereof. All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety.

[0128] Incorporation by Reference The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes.

[0129] equivalent The present invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The above-described embodiments, therefore, are to be considered in all respects as illustrative and not limiting of the invention described herein. The scope of the invention is, therefore, indicated by the appended claims, rather than the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

1. A compound selected from the group consisting of: 【Chemical 1】 or a pharmaceutically acceptable salt or solvate thereof.

2. 10. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof.

3. A method for treating or ameliorating immune dysregulation in a mammalian patient (excluding humans), the method comprising administering a therapeutically effective amount of the pharmaceutical composition described in claim 2 to the mammalian patient (excluding humans).

4. 4. The method of claim 3, wherein the immune dysregulation is an autoimmune disease or a chronic inflammatory disease.

5. 5. The method of claim 4, wherein the autoimmune disease or chronic inflammatory disease is rheumatoid arthritis.

6. 6. The method of claim 5, wherein said treating or ameliorating inhibits and / or reduces bone erosion in said mammalian subject (excluding humans).

7. The immune dysregulation is systemic lupus erythematosus, rheumatoid arthritis, type I diabetes, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves' ophthalmopathy, asthma, organ or tissue transplantation, transplant-induced graft-versus-host disease, autoimmune syndromes including rheumatoid arthritis, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, rheumatic fever, and post-infectious diseases including post-infectious glomerulonephritis. Autoimmune diseases, inflammatory and hyperproliferative skin diseases, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, acne, alopecia areata, keratoconjunctivitis, summer conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, keratoconus, epithelial corneal dystrophy, corneal leukoplakia, ocular pemphigus, Mooren's ulcer, scleritis, Graves' ophthalmopathy, Vogt-Koyanagi-Harada syndrome, hay fever, treatable obstructive airways Diseases, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or refractory asthma, late-onset asthma and airway hyperresponsiveness, bronchitis, gastric ulcer, vascular damage caused by ischemic disease and thrombosis, ischemic bowel disease, inflammatory bowel disease, necrotizing enterocolitis, intestinal lesions associated with burns, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, migraine, rhinitis, eczema, interstitial nephritis, Goodpasture syndrome, hemolytic uremic syndrome, diabetic nephropathy, polymyositis, Guillain-Barre syndrome, Meniere's disease, polyneuritis, polyneuritis, mononeuritis, Radiculopathy, hyperthyroidism, Basew's disease, pure red cell aplasia, aplastic anemia, aplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, red blood cell hypoplasia, pulmonary fibrosis, idiopathic interstitial pneumonia, dermatomyositis, albinism, ichthyosis vulgaris, photoallergic hypersensitivity, cutaneous T-cell lymphoma, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, cardiomyopathy, scleroderma, Wegener's granuloma, Sjogren's syndrome, adiposity, eosinophilic fasciitis; lesions of the gingiva, periodontium, alveolar bone, and dental cementum;Glomerulonephritis, male pattern baldness or senile alopecia by preventing hair loss or providing hair growth and / or promoting hair growth and development, muscular dystrophy, pyoderma and Sezary's syndrome, Addison's disease, ischemia-reperfusion injury of organs occurring during storage, transplantation or ischemic disease, endotoxin shock, pseudomembranous colitis, colitis due to drugs or radiation, ischemic acute renal failure, chronic renal failure, pulmonary oxygen or drug intoxication, lung cancer, emphysema, cataracts, siderosis, retinitis pigmentosa, senile macular degeneration, vitreous scarring, corneal alkali burns, erythema multiforme exudative dermatitis, linear IgA bullous dermatitis and cement dermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution, aging, carcinogenesis, metastasis of carcinoma and altitude sickness, histamine or leukotriene-C. sub.

4. The method of claim 3, wherein the disease is selected from the group consisting of diseases caused by erythropoietin-4 release, Behcet's disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, partial hepatectomy, acute liver necrosis, necrosis caused by toxins, viral hepatitis, shock or anoxia, B-viral hepatitis, non-A / non-B hepatitis, cirrhosis, alcoholic cirrhosis, liver failure, fulminant liver failure, late-onset liver failure, "chronic acute" liver failure, enhanced chemotherapy effects, cytomegalovirus infection, HCMV infection, AIDS, cancer, senile dementia, trauma, and chronic bacterial infection.

8. 4. The method of claim 3, further comprising administering to said mammalian subject (excluding humans) one or more anti-inflammatory and / or anti-rheumatic compositions.

9. 4. The method of claim 3, wherein the immune dysregulation is selected from the group consisting of: 1) rheumatoid arthritis, 2) multiple sclerosis, 3) systemic lupus erythematosus, 4) psoriasis, 5) transplanted organ or tissue rejection, 6) inflammatory bowel disease, and 7) insulin and non-insulin dependent diabetes mellitus.

10. A method for suppressing the immune system of a mammalian patient (excluding humans) in need of an immunosuppressant, comprising administering to said mammalian patient (excluding humans) an immunosuppressively effective amount of the pharmaceutical composition of claim 2.

11. A method for treating or ameliorating a disease or condition characterized by bone erosion and / or bone loss in a mammalian patient (excluding humans), the method comprising administering to the mammalian patient (excluding humans) an amount of the pharmaceutical composition described in claim 2 effective to treat or ameliorate the disease or condition of bone erosion and / or bone loss.

12. 12. The method of claim 11, wherein the disease or condition is one or more of rheumatoid arthritis, bone-destructive arthritic conditions, periodontal disease, osteoporosis, osteomyelitis, bone metastasis, and fracture healing.

13. 12. The method of claim 11, wherein said treatment or improvement increases and / or maintains bone density, bone mass, and / or bone structure in said mammalian subject (excluding humans).

14. 12. The method of claim 11, further comprising administering to said mammalian subject (excluding humans) one or more anti-inflammatory and / or anti-rheumatic compositions.

15. 10. A kit comprising a pharmaceutical agent comprising the compound of claim 1, a pharmaceutically acceptable salt, and / or solvate thereof, and an optional pharmaceutically acceptable carrier, and a package insert containing instructions for administering the pharmaceutical agent to treat or slow the progression of bone erosion and / or bone loss in a mammalian patient.

16. The compound of claim 1, wherein: 【Chemistry 2】 2. The compound of claim 1, wherein:

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