KR102168006B1 - Cbp/catenin antagonists for enhancing asymmetric division of somatic stem cells - Google Patents

Abstract

Aging, or a method of treating an age-related condition, symptom or disease; Methods of stimulating hair growth, regeneration or pigmentation (or methods of preventing hair loss); Methods of increasing the expression of adenosine receptors in dermal cells (with hair growth); A method of treating a skin condition or disease, or one or more symptoms thereof, including cosmetic treatments (e.g., wrinkles, hyperpigmentation, redness, rosacea, dryness, cracking, loss of firmness, loss of elasticity, skin thinning and loss of vitality) Is provided. The method comprises administering a sufficient amount of a CBP/catenin (e.g., CBP/β-catenin) antagonist as disclosed, in particular the administration relative to or of the symmetric division in the relevant somatic stem cell population. It is done in an amount and manner sufficient to increase the number of asymmetric regenerative disruptions at the expense. In certain aspects, CBP/catenin (eg, CBP/β-catenin) antagonists include alkyl and/or fatty acid ester derivatives thereof disclosed herein.

Description

CBP/catenin antagonist for enhancing asymmetric division of somatic stem cells {CBP/CATENIN ANTAGONISTS FOR ENHANCING ASYMMETRIC DIVISION OF SOMATIC STEM CELLS}

<Field of the present invention>

Certain aspects are generally for treating aging, and more particularly aging and aging-related conditions (e.g., wrinkles, hyperpigmentation, dryness, redness, cracks, rosacea, firmness, elasticity, thickness, scarring, appearance). Of CBP/catenin (e.g., CBP/β-catenin) antagonists (e.g., ICG-001, and alkyl and fatty acid ester derivatives thereof, and other compounds disclosed herein) in the modulation of symmetric vs. asymmetric cleavage It is about the use. Additional aspects generally include treatment of skin-related diseases (e.g. wounds, acne, sun damage, aging effects, latent infections (e.g., HSV, HPV), virus removal (epidermal and mucous tissue), ulcers (diabetic And other ulcers), burns, atopic dermatitis, psoriasis, age-related skin conditions such as wrinkles, hyperpigmentation, redness, rosacea, dryness, cracks, loss of firmness, loss of elasticity, skin thinning and loss of vibrance, etc.) Of the treatment and/or cosmetic (skin and/or hair) purposes, and in certain aspects the promotion of hair growth and/or regeneration and/or pigmentation, and hair loss (e.g., age-related hair loss or loss of pigmentation ) In the prevention or delay of CBP/catenin (eg, CBP/β-catenin) antagonists. A further aspect relates to a method of promoting hair growth by increasing the level of adenosine receptors in dermal cells, preferably dermal papillary cells. Adjuvant and combination therapy embodiments are included.

<Cross reference of related applications>

This application is a U.S. provisional patent application serial number 61/545,033 filed on October 7, 2011, 61/414,334 filed on November 16, 2010, and the same filed on November 16, 2010. It claims the advantage of priority to No. 61/414,348, all of which are incorporated herein by reference in their entirety.

The decision to asymmetric or symmetric division can be a major fundamental intrinsic difference between normal stem cells and cancer stem cells. The use of CBP/catenin or p300/catenin to induce transcription, ie the determination of symmetric or asymmetric division, is believed to be a very basic event as it is already important at the 8-cell stage of embryogenesis. The final decision as to whether a cell will retain its potential or initiate differentiation is the activation of various growth factors, cytokines and hormones, and subsequent activation of various signal transduction complexes and kinase cascades, nutrient levels, oxygen levels, gene mutations, lower layers. It depends on a number of input signals, including the attachment to it. After all, these multipaths must be integrated and funneled down into simple decision points, i.e. yes/no binary decisions. Methods for pharmacologically dealing with the balance of differential catenin co-activator use (i.e., catenin/CBP vs. catenin/p300) in stem/progenitor cell populations are known, but the cell does not have a very complex arrangement of information from its environment. There is still a lack of understanding of how to read and eventually reach a 0/1 binary decision.

US 2005-0250780 A US 2007-0021431 A US 2007-0021425 A US 2010-0120758 A US 2010-0240662 A WO 2007-139346 A US 2004-0072831 A US 2007-0043052 A US 2005-0059628 A WO 2009-051399 A US 2006-0084655 A US 2008-0009500 A US 6,413,963 B US 7,531,320 B US 7,563,825 B WO 2010-128685 A WO 2010-044485 A

<Overview of the invention>

According to certain aspects, as disclosed herein, the equilibrium between CBP-mediated and p300-mediated catenin transcription is determined by the activation of various growth factors, cytokines and hormones, and subsequent activation of various signal transduction complexes and kinase cascades, nutrient levels, It plays an important role in determining asymmetric or symmetric cleavage by integrating numerous input signals, including oxygen levels, gene mutations, and adhesion to the lower layers.

CBP/catenin (eg, beta and gamma) antagonists function by modulating human endogenous stem cell and/or surrounding cell function. Based on animal toxicity studies and as known in the art, these compounds are very safe at effective dose levels. Treating aging and age-related conditions may require long-term administration, so a large safety margin is best for both physicians and patients.

According to certain aspects, CBP/catenin (eg, CBP/β-catenin) antagonists can be used to modulate symmetric vs. asymmetric stem cell division for the treatment of aging and senescence-related conditions.

Certain aspects are CBP/catenin in an amount sufficient to increase the number of asymmetric regenerative divisions at the expense of symmetric division in a stem cell population to a subject in need of treatment of aging or aging disease or one or more conditions or symptoms thereof (e.g. For example, it provides a method of treating aging or aging disease or one or more conditions or symptoms thereof, comprising administering a CBP/β-catenin) antagonist, wherein a method of treating aging or aging disease or one or more symptoms thereof is obtained. Lose.

A further aspect relates to a subject in need of treatment of hair loss (e.g., prevention of hair loss (e.g., in an aging subject) and/or promotion of hair growth or regeneration and/or pigmentation). For example, a CBP/catenin (e.g., CBP/β-catenin) antagonist in an amount sufficient to increase the number of asymmetric regenerative divisions at the expense of symmetric division in hair vesicles or epidermal stem cells (e.g., Topically or otherwise) a method of treating hair loss (e.g., preventing hair loss (e.g., in an aging subject) and/or promoting hair growth or regeneration and/or pigmentation), comprising administering Wherein a method of treating hair loss (eg, preventing hair loss and/or promoting hair growth or regeneration and/or pigmentation in an aging subject) is obtained.

A further aspect is an amount of CBP/catenin (e.g., CBP/β-catenin) sufficient to treat a skin condition or disease or one or more symptoms thereof in a subject in need thereof. A method of treating a skin condition or disease or one or more symptoms thereof comprising administering an antagonist is provided.

Exemplary preferred aspects :

Certain aspects include identifying a mammalian subject having somatic stem cells for one or more tissue compartments or types having an age-related condition, symptom, or disease; And CBP/catenin (e.g., CBP/catenin (e.g., CBP) in a manner and amount sufficient to increase the number of asymmetric regenerative divisions in the subject compared to symmetric division of somatic stem cells for one or more tissue compartments or types or at the expense of the symmetric division. /β-catenin) antagonist, comprising the step of administering an aging, or age-related condition, symptom or disease, wherein the tissue compartment or type of age-related condition, symptom or disease is reduced or Alleviates and results in a method of treating aging, or an age-related condition, symptom or disease. In certain aspects, the somatic stem cells for one or more tissue compartments or types comprise resting somatic stem cells, wherein the administration of the CBP/β-catenin antagonist is compared to symmetric division among the one or more tissue compartments or types of somatic stem cells. Or CBP/β-catenin antagonist-mediated activation of resting somatic stem cells that enhances or accelerates asymmetric regenerative division at the expense of the symmetric division.

In certain aspects, the somatic stem cells are keratinocyte stem cells, epidermis, vesicles, hematopoietic, breast, intestinal epithelium including intestinal gland cells, mesenchymal including muscle satellite cells, melanocyte stem cells, osteoblasts and chondrocyte precursors, endothelium , It includes at least one selected from the group of stem cells constituting the skin including the ventricular membrane or subventricular zone cells, nerves, neural crests, olfactory, testis, and uterus.

In certain aspects of hair growth, the somatic stem cells for one or more tissue compartments or types comprise hair vesicle stem cells of the skin tissue compartment, wherein the increased hair growth or hair pigmentation is the skin tissue compartment or type, preferably the scalp. Provided in tissue compartments or types. In certain embodiments, the CBP/β-catenin antagonist is present in an amount sufficient to modulate or increase the expression of adenosine receptors in dermal cells, preferably dermal derived cells. In certain embodiments, the adenosine receptor is one or more selected from A1, A2A and A2B. In certain aspects of hair growth, the CBP/catenin (e.g., CBP/β-catenin) antagonist is present in an amount sufficient to modulate or increase the expression of sulfonylurea receptor 2B in dermal cells, preferably dermal papillary cells. do.

Certain aspects of hair growth include one or more other hair growth stimulants or hair loss inhibitors (e.g., one or more selected from the group consisting of minoxidil, finasteride, dutasteride, bimatoprost and anti-androgen receptor blockers such as fluridil). Co-administration of or adjuvant treatment using the same.

In certain aspects of maintaining skin repair homeostasis of the methods disclosed herein, the somatic stem cells for one or more tissue compartments or types comprise skin tissue compartments or types of skin stem cells, wherein improved skin recovery and/or maintenance of homeostasis It is provided in compartments or types. In certain aspects, improved skin recovery and/or homeostasis may include wrinkles, hyperpigmentation, redness, rosacea, dryness, cracks, loss of firmness, loss of elasticity, skin thinning, loss of vitality, wounds, scars, acne, sun damage, viruses. One or more aging selected from the group consisting of susceptibility to infection (e.g., HSV, HPV infection), ulcers including diabetic ulcers, burns, atopic dermatitis, psoriasis, and skin conditions including hair loss or loss of hair pigmentation- Related conditions, symptoms or diseases. Certain aspects of maintaining skin repair homeostasis are treatment with CBP/catenin (eg, CBP/β-catenin) antagonists to reduce scarring in wounds to superficial tissue, where scarring is lowered. In certain embodiments, treatment comprises accelerating epidermal or dermal layering and/or increasing cell migration of one or more cell types to a wound (e.g., cell types of cell migration or proliferation are keratinization Cells, fibroblasts, epidermal cells, dermal cells, epithelial cells, mast cells, neutrophils, lymphocytes and macrophages). In certain aspects, treatment accelerates neovascularization of blood vessels or lymphatic vessels and/or increases collagen deposition in the wound. Certain aspects include lacerations, abrasions, ruptures, punctures, chemical-, heat- or radiation-induced burns, amputations, abrasions, incisions, blisters, diabetic ulcers, bedsores or pressure sores, skin grafts, and surgical wounds. And treating a wound to the surface tissue of one or more wound types selected from or a symptom thereof.

In certain aspects, the age-related condition, symptom or disease is wrinkles, hyperpigmentation, redness, rosacea, dryness, cracks, loss of firmness, loss of elasticity, thinning of the skin, loss of vitality, wounds, scars, acne, sun damage, latent Viral infection (e.g., HSV, HPV infection), ulcers including diabetic ulcers, burns, atopic dermatitis, psoriasis, and one or more conditions, symptoms or conditions selected from the group consisting of skin conditions including hair loss or loss of hair pigmentation Includes disease.

In certain embodiments, the CBP/catenin (eg, CBP/β-catenin) antagonist is one or more selected from the group of a compound of Table 1 and a salt thereof, or another compound disclosed herein. In certain aspects, CBP/catenin (eg, CBP/β-catenin) antagonists include alkyl and/or fatty acid ester derivatives thereof disclosed herein. In certain aspects, CBP/β-catenin antagonists include ICG-001 disclosed herein, or an active alkyl and/or fatty acid ester derivative thereof.

In certain aspects, administration of a CBP/catenin (eg, CBP/β-catenin) antagonist includes one or more of topical, gum, buccal, subcutaneous and oral administration.

Certain aspects include co-administration or adjuvant treatment using one or more other therapeutic agents (eg, anti-inflammatory agents; eg, steroids or glucocorticoid steroids). In a particular aspect, the anti-inflammatory agent is a short-acting β ₂ - agonists, persistence, β ₂ - agonists, anticholinergics, corticosteroids, systemic corticosteroids, mast cell stabilizers, leukotriene modifiers, methyl xanthine, β ₂ - agonist, albuterol , Levalbuterol, pirbuterol, arformoterol, formoterol, salmeterol, anticholinergic agents such as ipatropium and tiotropium; Corticosteroids such as beclomethasone, budesonide, flunisolide, fluticasone, mometasone, triamcinolone, methylprednisolone, prednisolone, prednisone; Leukotriene modifiers such as montelukast, zapyrleukast and zileuton; Mast cell stabilizers such as cromoline and nedocromil; Methylxanthine such as theophylline; Combination drugs such as ipatropium and albuterol, fluticasone and salmeterol, glucocorticoid steroids, budesonide and formoterol; Antihistamines such as hydroxyzine, diphenhydramine, loratadine, cetirizine and hydrocortisone; Immune system modulating drugs such as tacrolimus and pimecrolimus; Cyclosporine; Azathioprine; Mycophenolate mofetil; And at least one anti-inflammatory agent selected from the group consisting of a combination thereof.

In certain aspects, one additional therapeutic agent is an antimicrobial agent, antifungal agent and antibiotic (e.g., cyclosporine, hyaluronic acid, carmellose, macrogol(s), dextran and hyprolose, sodium and calcium, sodium and povidone, Hypromellose, carbomer, amikacin, gentamicin, kanamycin, neomycin, netylmycin, streptomycin, tobramycin, paromomycin, geldanamycin, herimycin, loracarbef, ertapenem, imipenem/ Cilastatin, meropenem, cepadroxil, cefazoline, cephalotin/cephalosin, cephalexin, cephachlor, cefamandol, cefoxitin, cefuroxime, cefixime, cephdinir, cephditorene, cephalocin John, Celotaxim, Cephpodoxime, Ceftazidim, Ceftibuten, Ceftizoxim, Ceftriaxone, Cefepime, Teicoplanin, Vancomycin, Azithromycin, Clarithromycin, Dirithromycin, Erythromycin, Oxythromycin, Troleandomycin, Telethromycin, Spectinomycin, Aztreonam, Amoxicillin, Ampicillin, Azlosillin, Carbenicillin, Cloxacillin, Dicloxacillin, Flucloxacillin, Mezlosillin , Naphcillin, penicillin, peperacillin, ticarcillin, bacitracin, colistin, polymyxin B, ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, romefloxacin, moxifloxacin, norfloxacin, oflox Sasin, Trobafloxacin, Mefenide, Protosyl, Sulfacetamide, Sulfamethizol, Sulfanilamide, Sulfasalazine, Sulfisoxazole, Trimethoprim, Trimethoprim-Sulfametoxazole, Demeclocycline , Doxycycline, minocycline, oxytetracycline, tetracycline, arsfenamine, chloramphenicol, clindamycin, lincoamycin, ethambutol, fosfomycin, fusidic acid, furazolidone, isoniazid, linezolide, metronidazole , Mupirosine, nitrofurantoin, platenshimaisin, pyrazinamide, quinupristine/dalfopristine, rifampin/rifampicin, tinidazole, miconazole, ketoconazole, clotrimazole, econazole, biponazole, butoconazole, Penticonazole, isoconazole, oxyconazole, sertaconazole, sulconazole, thioconazole, fluconazole, itraconazole, isabuconazole, La Buconazole, posaconazole, voriconazole, teronazole, terbinapine, amorolpine, naphtipine, butenapine, anidulafungin, caspofungin, micafungin, cyclopyrrox, flucytosine, griseofulvin, Gentian violet, haloprogine, tolnaphtate, undecylenic acid and combinations thereof), antiviral agents (eg, acyclovir, docosanol).

A further aspect is a CBP/catenin (e.g., CBP/β-catenin) antagonist in an amount sufficient to stimulate one or more of hair growth, regeneration and pigmentation in a subject in need of stimulation of hair growth, regeneration or pigmentation. It provides a method of stimulating hair growth, regeneration or pigmentation comprising administering. Certain aspects are the administration of a CBP/catenin (e.g., CBP/β-catenin) antagonist in a manner and amount sufficient to increase the number of asymmetric regenerative divisions compared to symmetric division of somatic vesicle stem cells or at the expense of said symmetric division. Wherein at least one of hair growth, regeneration and pigmentation is obtained. In certain embodiments, the CBP/β-catenin antagonist modulates or increases the expression of adenosine receptors (e.g., one or more selected from A1, A2A and A2B) in dermal cells (e.g., dermal papillary cells). Is present in a sufficient amount. In certain aspects, the CBP/catenin (eg, CBP/β-catenin) antagonist is present in an amount sufficient to modulate or increase the expression of sulfonylurea receptor 2B in dermal papillary cells.

In certain embodiments for stimulation of hair growth, the CBP/catenin (e.g., CBP/β-catenin) antagonist is one or more selected from the group of a compound of Table 1 and a salt thereof, or another compound disclosed herein. . In certain aspects, CBP/catenin (eg, CBP/β-catenin) antagonists include alkyl and/or fatty acid ester derivatives thereof disclosed herein. In certain aspects, CBP/catenin (eg, CBP/β-catenin) antagonists include ICG-001 disclosed herein, or an active alkyl and/or fatty acid ester derivative thereof.

In certain aspects, administration of a CBP/catenin (eg, CBP/β-catenin) antagonist includes one or more of topical, gum, buccal, subcutaneous and oral administration.

Certain embodiments for stimulation of hair growth are from the group consisting of one or more other hair growth stimulators or hair loss inhibitors (e.g. minoxidil, finasteride, dutasteride, bimatoprost and anti-androgen receptor blockers such as fluridil. Co-administration of one or more selected) or adjuvant treatment using the same. In some aspects one or more anti-inflammatory agents (e. G., One or more anti-inflammatory agent is a short-acting β ₂ - agonists, persistence, β ₂ - agonists, anticholinergics, corticosteroids, systemic corticosteroids, mast cell stabilizers, leukotriene modifiers, methyl xanthine, β ₂ -agonists, albuterol, levalbuterol, pirbuterol, arformoterol, formoterol, salmeterol, anticholinergic agents such as ipatropium and tiotropium; corticosteroids such as beclometa Hand, budesonide, flunisolide, fluticasone, mometasone, triamcinolone, methylprednisolone, prednisolone, prednisone; leukotriene modifiers such as montelukast, zapyrlucast and zileuton; mast cell stabilizers such as cromoline and nedocro Wheat; methylxanthine such as theophylline; combination drugs such as ipatropium and albuterol, fluticasone and salmeterol, glucocorticoid steroids, budesonide and formoterol; antihistamines such as hydroxyzine, diphenhydramine, Loratadine, cetirizine and hydrocortisone; immune system modulating drugs such as tacrolimus and pimecrolimus; cyclosporine; azathioprine; mycophenolate mofetil; and combinations thereof) Includes adjuvant therapy.

A further aspect of the invention is the expression of the adenosine receptor (e.g., one or more selected from A1, A2A and A2B) in dermal cells, preferably dermal papillary cells, to a subject in need of increased expression of adenosine receptors in dermal cells. Methods of increasing the expression of adenosine receptors in dermal cells comprising administering an amount of a CBP/catenin (eg, CBP/β-catenin) antagonist sufficient to increase it are provided. In certain aspects of the method, the CBP/catenin (eg, CBP/β-catenin) antagonist is present in an amount sufficient to modulate or increase the expression of sulfonylurea receptor 2B in dermal papillary cells.

In certain embodiments for increasing the expression of adenosine receptor in dermal cells, the CBP/catenin (e.g., CBP/β-catenin) antagonist is selected from the group of a compound of Table 1 and a salt thereof or another compound disclosed herein. Is more than one. In certain aspects, CBP/catenin (eg, CBP/β-catenin) antagonists include alkyl and/or fatty acid ester derivatives thereof disclosed herein. In certain aspects, CBP/catenin (eg, CBP/β-catenin) antagonists include ICG-001 disclosed herein, or an active alkyl and/or fatty acid ester derivative thereof.

In certain aspects, administration of a CBP/catenin (eg, CBP/β-catenin) antagonist includes one or more of topical, gum, buccal, subcutaneous and oral administration.

A further aspect is an amount of CBP/catenin (e.g., CBP/β-catenin) sufficient to treat a skin condition or disease, or one or more symptoms thereof, in a subject in need of treatment of a skin condition or disease, or one or more symptoms thereof. A method of treating a skin condition or disease, or one or more symptoms thereof, comprising administering an antagonist is provided. Certain aspects of the method include a CBP/catenin (e.g., CBP/β-catenin) antagonist sufficient to increase the number of asymmetric regenerative divisions compared to or at the expense of symmetric division of somatic skin stem cells, and Administering in an amount, wherein treatment of a skin condition or disease, or one or more symptoms thereof, is obtained. In certain embodiments, the skin condition or disease is wound, scar, acne, sun damage, latent viral infection (e.g., HSV, HPV infection), ulcer, such as diabetic ulcer, burn (including sunburn, UVB injury), Atopic dermatitis, psoriasis, and aging effects, such as wrinkles, hyperpigmentation, redness, rosacea, dryness, cracking, loss of firmness, loss of elasticity, skin thinning and loss of vitality, and one or more conditions or diseases selected from the group consisting of .

In certain embodiments for the treatment of a skin condition or disease, or one or more symptoms thereof, the CBP/catenin (e.g., CBP/β-catenin) antagonist is a compound of Table 1 and a salt thereof, or another compound disclosed herein. It is at least one selected from the group of. In certain aspects, CBP/catenin (eg, CBP/β-catenin) antagonists include alkyl and/or fatty acid ester derivatives thereof disclosed herein. In certain aspects, CBP/catenin (eg, CBP/β-catenin) antagonists include ICG-001 disclosed herein, or an active alkyl and/or fatty acid ester derivative thereof.

In certain aspects, administration of a CBP/catenin (eg, CBP/β-catenin) antagonist includes one or more of topical, gum, buccal, subcutaneous and oral administration.

Certain aspects of the treatment of a skin condition or disease, or one or more symptoms thereof, include the co-administration or adjuvant treatment using one or more other therapeutic agents (e.g., anti-inflammatory agents; such as steroids or glucocorticoid steroids, etc.). In certain embodiments, one or more anti-inflammatory agent is a short-acting β ₂ - agonists, persistence, β ₂ - agonists, anticholinergics, corticosteroids, systemic corticosteroids, mast cell stabilizers, leukotriene modifiers, methyl xanthine, β ₂ - agonists, Albuterol, levalbuterol, pirbuterol, arformoterol, formoterol, salmeterol, anticholinergic agents such as ipatropium and tiotropium; Corticosteroids such as beclomethasone, budesonide, flunisolide, fluticasone, mometasone, triamcinolone, methylprednisolone, prednisolone, prednisone; Leukotriene modifiers such as montelukast, zapyrleukast and zileuton; Mast cell stabilizers such as cromoline and nedocromil; Methylxanthine such as theophylline; Combination drugs such as ipatropium and albuterol, fluticasone and salmeterol, glucocorticoid steroids, budesonide and formoterol; Antihistamines such as hydroxyzine, diphenhydramine, loratadine, cetirizine and hydrocortisone; Immune system modulating drugs such as tacrolimus and pimecrolimus; Cyclosporine; Azathioprine; Mycophenolate mofetil; And it is selected from the group consisting of a combination thereof.

In a further aspect of the method of treating a skin condition or disease, or one or more symptoms thereof, one additional therapeutic agent is an antimicrobial agent, an antifungal agent and an antibiotic (e.g., cyclosporine, hyaluronic acid, carmellose, macrogol(s), Dextran and hyprolos, sodium and calcium, sodium and povidone, hypromellose, carbomer, amikacin, gentamicin, kanamycin, neomycin, netylmycin, streptomycin, tobramycin, paromomycin, geldana Mycin, Herimicin, Loracarbef, Ertapenem, Imipenem/Cilastatin, Meropenem, Cephadroxil, Cephazoline, Cephalotin/Cepalosine, Cephalexin, Sepachlor, Sepamandol, Sepoxytin, Sephu Loxim, Cefixime, Cephdinir, Cephditoren, Celloperazone, Cellotaxim, Cephpodoxime, Ceftazidim, Ceftibuten, Ceftizom, Cefttriaxone, Cefepime, Teicoplanin, Vancomycin, Azithromycin, clarithromycin, dirithromycin, erythromycin, oxythromycin, troleandomycin, telethromycin, spectinomycin, aztreonam, amoxicillin, ampicillin, azlosillin, carbenicillin, clock fact Lin, dicloxacillin, flucloxacillin, mezlocillin, napsillin, penicillin, peperacillin, ticarcillin, bacitracin, colistin, polymyxin B, ciprofloxacin, enoxacin, gatifloxacin, levofloxacin , Lomefloxacin, Moxifloxacin, Norfloxacin, Ofloxacin, Trobafloxacin, Mefenide, Protosil, Sulfacetamide, Sulfametizol, Sulfanilamide, Sulfasalazine, Sulfisoxazole, Tri Metoprim, trimethoprim-sulfametoxazole, demeclocycline, doxycycline, minocycline, oxytetracycline, tetracycline, arsphenamine, chloramphenicol, clindamycin, lincoamicin, ethambutol, fosfomycin , Fusidic acid, furazolidone, isoniazid, linezolide, metronidazole, free pyrosine, nitrofurantoin, platenshimaisin, pyrazinamide, quinupristine/dalfopristine, rifampin/rifampicin, tinidazole, myconazole, ketoconazole , Clotrimazole, econasol, biponazole, butoconazole, penticonazole, isoconazole, oxyconazole, sertaconazole , Sulconazole, thioconazole, fluconazole, itraconazole, isabuconazole, labuconazole, posaconazole, voriconazole, teronazole, terbinapine, amorolphine, naphtipine, butenapine, anidulafungin, Caspofungin, micafungin, cyclopirox, flucytosine, griseofulvin, gentian violet, haloprogin, tolnaphtate, undecylenic acid, and combinations thereof).

Certain aspects of the method of treating a skin condition or disease, or one or more symptoms thereof, are treating the wound to reduce scarring in wounds to superficial tissue and/or accelerate epidermal or dermal stratification. Includes that. In certain embodiments, the treatment comprises increasing cell migration of one or more cell types to a wound (e.g., wherein the cell type of cell migration or proliferation is keratinocytes, fibroblasts, epidermal cells, dermal cells, Including one or more cells selected from the group consisting of epithelial cells, mast cells, neutrophils, lymphocytes and macrophages). In certain embodiments, the treatment accelerates neovascularization of blood vessels or lymph vessels and/or increases collagen deposition in the wound. Certain aspects are from the group consisting of lacerations, abrasions, ruptures, punctures, chemical-, heat- or radiation-induced burns, amputations, abrasions, incisions, blisters, diabetic ulcers, bedsores or pressure sores, skin grafts and surgical wounds. And treating a wound or symptom thereof to the superficial tissue of one or more wound types selected.

A further aspect is the administration of a CBP/catenin (e.g., CBP/β-catenin) antagonist in an amount sufficient for cosmetic treatment of the skin condition or one or more symptoms thereof to a subject in need of cosmetic treatment of the skin condition or one or more symptoms thereof. And a method of cosmetic treatment of a skin condition or one or more symptoms thereof, comprising: Certain embodiments of the method include a CBP/catenin (e.g., CBP/β-catenin) antagonist in a manner sufficient to increase the number of asymmetric regenerative divisions compared to or at the expense of symmetric division of somatic skin stem cells. And administering in an amount, wherein a cosmetic treatment of a skin condition or one or more symptoms thereof is obtained. Certain aspects include treating one or more conditions or diseases selected from the group consisting of wrinkles, scarring, hyperpigmentation, redness, rosacea, dryness, cracking, loss of firmness, loss of elasticity, skin thinning and loss of vitality.

In certain embodiments for the method of cosmetic treatment of a skin condition or one or more symptoms thereof, the CBP/catenin (e.g., CBP/β-catenin) antagonist is a compound of Table 1 and a salt thereof, or of another compound disclosed herein. It is at least one selected from the group. In certain aspects, CBP/catenin (eg, CBP/β-catenin) antagonists include alkyl and/or fatty acid ester derivatives thereof disclosed herein. In certain aspects, CBP/catenin (eg, CBP/β-catenin) antagonists include ICG-001 disclosed herein, or an active alkyl and/or fatty acid ester derivative thereof. In certain aspects, administration of a CBP/catenin (eg, CBP/β-catenin) antagonist includes one or more of topical, gum, buccal, subcutaneous and oral administration.

1 shows a schematic of balanced asymmetric division of stem cells. Ideally, upon entering mitosis, one of the two daughter cells will remain stem cells in its niche, and the remaining daughter cells will initially amplify temporarily and then differentiate to maintain tissue homeostasis.
Figure 2 shows the structures of catenin co-activator modulators (a) ICG-001 and (b) IQ-1.
3 shows a model of differential coactivation factor use. (a) IQ-1 antagonizes the interaction between p300 and catenin, allowing stem/progenitor cells to utilize CBP/catenin-induced transcription. This increases symmetrical disruption. (b) ICG-001 blocks the interaction between CBP and catenin, allowing cells to utilize p300/catenin-induced transcription. This initiates the transcription of genes involved in the initiation of the differentiation process.
Figure 4 shows a description of the four possible promoter specific results due to differential coactivator recruitment and gene expression. When the CBP/catenin interaction is antagonized by ICG-001, genes that can only use CBP for co-activation (eg, cyclinD1 in colon cancer cells) are downregulated. Accepted genes (eg, c-myc in colon cancer cells) use an additional p300 to compensate for the loss of CBP in its promoter. The p300-dependent gene (eg EpB2 ) exhibits transcriptional activity by mobilizing p300 to its promoter. Some genes (eg, survivin ) further stop gene expression by recruiting an inhibitory complex to its promoter via p300 after removal of CBP and transcription reduction.
5 shows a voice feedback loop. While retention of potential through CBP/catenin-mediated gene transcription may be the default, some CBP/catenin regulatory genes become part of the negative feedback loop that leaves the CBP/catenin arm of this pathway, resulting in the p300/catenin branch. The differentiation process is initiated.
Figure 6 shows a model explaining the mechanistic overlap and difference between vitamins A and D (via their respective receptor complexes) and ICG-001.
7 shows Aβ deposition in a mouse model of Alzheimer's disease. Applicants used a penta-transgenic mouse model of AD, which typically results in large-scale cerebral deposition of Aβ beginning at 6 weeks of age. The mice were treated with (a) ICG-001 (50 mg/kg/day) or (b) saline for 2 months. (b) There was a significant reduction in Aβ staining in the parietal lobe of the (a) ICG-001 treatment group compared to the dark Aβ staining in the saline control-treated group.
8 shows a model explaining the intrinsic differences between normal somatic stem cells and cancer stem cells in relation to symmetric versus asymmetric division.
9 shows the critical equilibrium. It represents a possible impairment that can affect the critical equilibrium between catenin and CBP or p300 use during the aging process.
Figure 10 shows the concentration (Funnel) from stem cells to binary crystals. Regardless of the signaling pathway or receptor used, all input signals received by stem cells are ultimately'lower-focused' as an important binary decision for the use of CBP or p300 as co-activators for catenin.
Figure 11 is a treatment of leukemia mouse model using vincristine/dexamethasone/L-asparginase (VDL) alone or in combination with ICG-001 (CBP/catenin (eg, CBP/β-catenin) antagonist) This photo was taken on the 47th of the year.
12 is a series of photographs taken of 3 exemplary mice over a time course of 8 days (left flank wound was topically treated with mineral oil, right flank wound was 500 uM Laura8 (CBP/catenin antagonist) ) And topically treated with mineral oil).
13 is a photograph demonstrating the effect of a CBP/catenin (eg, CBP/β-catenin) antagonist in a hairless hair loss mouse model. The left mouse was treated with petrolatum alone, whereas the right mouse was treated with Laura8 (the laurate ester of ICG-001) in petrolatum (mineral oil) (CBP/catenin (e.g., CBP/β-catenin) antagonist). .
14 is a series of photographs showing the effect of a CBP/catenin (eg, CBP/β-catenin) antagonist on the skin pathology of mice in the hairless mouse model as shown in FIG. 13. These pictures demonstrate that new hair-vesicles were formed in mice treated with Laura-8 (right), but not in mice treated with petrolatum control (left). In addition, due to the defects of the nuclear co-inhibitors associated with these defects in hair growth, the hair vesicle protrusions symmetrically proliferate to form large cystic products. Treatment with a CBP/catenin antagonist leads to the formation of new hair vesicles by inducing differentiation through increased asymmetric division.
15 is a schematic illustrating the pathway by which CBP/catenin (eg, CBP/β-catenin) antagonists are inhibited.
16 is a schematic illustrating hair vesicles and their formation.
17 shows old mice. The left mouse was a control, while the right mouse received a CBP/catenin (eg, CBP/β-catenin) antagonist (topical laura-8 disclosed herein) for 12 months (from 6 months to 18 months of age). Importantly, this demonstrates that long-term administration of a CBP/catenin antagonist maintains a normal stem cell population by not depleting the normal stem cell niche as would be expected from an agent that induces asymmetric division in the normal stem cell niche. .
18 shows the treatment of human surgical waste skin as described herein. All compounds were shown to increase the expression of both elastin and aquaporin 1, and Me-ICG-001 showed a greater increase than ICG-001 or RA at 5 uM.

Justice. The term “CBP protein” refers to a protein, also known as CREB-binding protein, where CREB is an abbreviation for “cAMP-reactive element binding”. This protein is well known in the art and is described, for example, in Takemaru et al., J. Cell Biol. 149:249-54 (2000)] and US Pat. No. 6,063,583. CBP 1-111 represents the first 111 amino acids of the CBP protein identified from the N-terminus of CBP.

The term “p300 protein” refers to a protein well known in the art. See, eg, Gusterson, R. J. et al., J. Biol. Chem. 2003 Feb. 28;278(9):6838-47]; [An and Roeder, J. Biol. Chem. 2003 Jan. 17;278(3):1504-10]; [Rebel, V. I. et al., Proc Natl Acad Sci USA. 2002 Nov. 12;99(23):14789-94]; And US Patent No. 5,658,784, and also references cited herein. p300 1-111 represents the first 111 amino acids of the p300 protein identified from the p300 N-terminus.

The phrase “Wnt pathway” refers to a signaling cascade that can be initiated by binding of a Wnt protein (a secreted glycoprotein) to a serpentine seven-transmembrane-width receptor. This pathway is known and characterized in the art and is the subject of numerous articles and reports (eg, Huelsken and Behrens, J. Cell Sci. 115: 3977-8, 2002); [Wodarz et al., Annu. Rev. Cell Dev. Biol. 14:59-88 (1998)]; [Morin, PJ, Bioessays 21:1021-30 (1999)]; [Moon et al., Science 296:1644-46 (2002) ]; [Oving et al., Eur. J. Clin. Invest 32:448-57 (2002)]; see Sakanaka et al., Recent Prog. Horm. Res. 55: 225-36, 2000).

The phrase “activity of the Wnt pathway” refers to the activity of one or more components of this pathway. For example, in certain embodiments, the activity of the Wnt pathway may indicate the activity of β-catenin that induces expression of a target gene. Many components of the Wnt pathway are known in the art, and are not limited to, but are not limited to, Cerberus (Cer), FrzB, Dickkopf (DKK), LRP, heterotrimeric G protein, Dsh, casein. Kinase la (CKla), GSK3β, βTrCP, ACP, Axin, CBP, p300, β-catenin, TCF, Graucho, and the like.

A compound "activating the Wnt pathway" refers to a compound that, when present in a system having the Wnt pathway, causes β-catenin induced expression of a target gene. A number of target genes whose expression is induced by β-catenin are known in the art, and are not limited thereto, but are not limited to, Conductin, Myc, Twin, Cyclin D1, Nkd, Ubx, En- 2, PPARd, Xbra, ID2, Siamois, Xnr3, MMP7, TCF-1, Survivin, and the like. Such genes may also be referred to as “genes targeted with the Wnt/β-catenin pathway”.

The phrase “selectively inhibiting the expression of a gene targeted with the Wnt/β-catenin pathway” inhibits the expression of some of the genes targeted with the Wnt/β-catenin pathway, but other genes targeted with the Wnt/β-catenin pathway. It indicates not suppressing the expression of. While not wishing to be bound by any particular mechanism, the inventors of the present invention speculate that selective inhibition of gene expression can be achieved by interfering with the interaction between β-catenin and some (but not all) of its possible binding partners. .

I. Aging and aging-related conditions

Certain aspects of the invention are CBP/catenin for use in treating aging or a condition or disease of aging, or one or more symptoms thereof by increasing the number of asymmetric regenerative divisions at the expense of symmetric division in a stem cell population (e.g. For example, a composition comprising a CBP/β-catenin) antagonist is provided.

According to certain aspects, the determination of symmetric vs. asymmetric differentiation of stem cells is an important cellular determinant process in adults, and the ability to maintain/homeostasis and/or adequately recover tissue (as in wound healing, hematopoiesis, fibrosis and osteoporosis). It is responsible for a variety of conditions and diseases associated with decline, and is the key to causing problems related to aging in general. Interestingly and importantly, the decision to asymmetric or symmetric division can be a major underlying intrinsic difference between normal somatic stem cells and cancer stem cells. Based on the achievements made primarily in Applicants' laboratories over the past decade (both public and unpublished data), the following disclosure describes the critical importance of symmetric vs. asymmetric division and the differential contributions in the Wnt/catenin signaling cascade in stem cells. Support for the role of activator use (eg, CBP vs. p300) and how they can be treated pharmacologically.

Symmetry versus asymmetry in somatic stem cells. For this purpose, stem cells can either remain dormant (i.e. do essentially nothing) or enter the cell cycle and undergo mitosis (i.e., cell division) to produce two daughter cells. It is a cell located in. Ideally, an asymmetric balance is maintained, whereby one of the daughter cells remains in place as stem cells, while the other daughter cells undergo a differentiation process to provide a "transient amplification population" to maintain tissue homeostasis (Fig. One).

According to certain aspects, the asymmetrical balance of fate between these two daughter cells is not always maintained, and in some cases the two daughter cells either become stem cells or both become different and lose their "stem cellity". According to certain aspects, this type of symmetric division is detrimental for a normal population of stem cells.

Symmetry vs. asymmetry is essentially a very simple binary decision process (0/1 determination as in computer logic operations), but stem cells in a niche undergoing mitosis have information from their environment (e.g., oxygen levels, nutrient levels, Very complex arrays of light/dark, i.e. 24-hour cycles, growth factors, adhesion molecules, cell/cell contacts, etc.) have to be read to arrive at the final binary decision. Here, the question is how the stem cells in the right read this excess information to derive a simple molecular 0/1 decision point. Applicants' laboratories have significantly advanced their understanding of the various elements and designs involved in these symmetric vs. asymmetric binary decisions. Using a series of unique pharmacological tools developed through a progressive chemogenetic approach, Applicants can now process and manipulate these binary decisions in both normal stem cell/progenitor populations and also cancer stem cell/progenitor populations.

The results of the study herein indicate that the determination of asymmetric or symmetric division is a fundamental intrinsic difference between normal stem cells and cancer stem cells, and also that the adjustment of the balance between symmetric and asymmetric division provides a method of treating aging. .

Pharmacological tools

Wnt signaling. The Applicant's initial goal was not to develop a pharmacological tool for the study of symmetry versus asymmetry, but to find a way to inhibit abnormal Wnt pathway activation. Approximately 90% of colon cancers have structural activation of the Wnt signaling cascade due to mutations in the gene Adenomatous Polyposis Coli (APC) or beta-catenin. Therefore, the original plan was that if these abnormal Wnt signals could be antagonized, it could provide a novel treatment strategy for colorectal cancer.

The Wnt signaling cascade is very complex. Wnt signaling is a process that occurs throughout development and also on a daily basis, e.g. skin and hair maintenance, intestinal homeostasis, hematopoietic stem cell/progenitor regulation, and also lineage commitment of precursors during hematopoiesis (i.e., generally Blood homeostasis), etc. (1, 2). Other cell replacement activities occurring in the human body, such as liver conversion and neurogenesis, are also involved in Wnt signaling (3-5). While it is generally agreed that Wnt signaling is important in stem cell biology, there is no agreement as to whether Wnt signaling is important for proliferation and maintenance of pluripotency or pluripotency, or on the other hand for differentiation of the same stem/progenitor cells. , There is a lot of controversy. Conventional Wnt/signaling (referred to as canonical Wnt signaling or Wnt/beta-catenin signaling) is characterized by core proteins Axin, APC, GSK3 (glycogen synthase kinase 3) and CK1-alpha (casein kinase 1). It has a soluble pool of cytoplasmic beta-catenin linked to a degradation complex consisting of -alpha). In the absence of the Wnt ligand, beta-catenin is phosphorylated in the complex, thereby being targeted for ubiquitination and subsequent destruction by the proteasome machinery (6). Activation of the Wnt pathway triggers a series of events that disrupt the APC/Axin/GSK3 complex required for targeted destruction of beta-catenin, thereby promoting the stabilization and accumulation of beta-catenin in the cytoplasm. This enhancement in the cytoplasm coincides with the migration of beta-catenin to the nucleus through a mechanism that is still not fully defined. In the nucleus, beta-catenin forms a complex with members of the TCF/LEF family of transcription factors, as conventionally defined in the Wnt signaling cascade. To create a transcriptional activity complex, beta-catenin is a transcriptional co-activator, i.e., cAMP response element-binding protein (CREB)-binding protein (CBP) or a close homologue thereof, p300 (E1A-binding protein, 300-KD ), and also other components of the underlying transcription machinery, which lead to the expression of a number of downstream target genes (7, 8). Applicant's study also demonstrated that cooperation with members of the catenin family of CBP is not limited to beta-catenin. In the absence of beta-catenin, CBP can also cooperate with other catenin-like molecules (eg, gamma-catenin) (9).

CBP and p300. CBP and p300 are large proteins of about 300 kd. They have long been considered to have redundant functions, and have been treated as one and the same protein in the literature. In recent studies, it has been demonstrated that CBP and p300 interact with hundreds of proteins for their role as major regulators of transcription. Despite their high homology, evidence has been gathered indicating that CBP and p300 do not overlap but have a clear and unique role both in vitro and in vivo (10-12). Results of targeted mutagenesis studies in mice demonstrated that mammalian development is highly sensitive to CBP and p300 gene mass. Mice that were heterozygous (CBP +/-) for the targeted mutation of CBP exhibited skeletal abnormalities, some of which were similar to the relatively rare genetic disorder Rubinstein Tayby syndrome (RTS) (13). Analysis of the p300 mutant mice showed that the gene mass of p300 was also important for development (14). Surprisingly, both CBP heterozygous (CBP +/-) and p300 heterozygous (p300 +/-) mouse embryos exhibit a brain exposure phenotype similar to knockout (p300-/- and CBP-/-) mouse embryos (15). . Despite their high homology and similar expression patterns, it has become very clear that CBP and p300 play a unique and completely different role in gene regulation. Applicants recently demonstrated that CBP and p300 play completely different functions in the regulation of TCF/β-catenin-mediated survivin transcription (16, 17). These results are also consistent with other publications demonstrating the non-overlapping role of CBP and p300 in cell growth, differentiation and development (10, 14, 18, 19). Rebel et al. (20) using a hematopoietic stem cell (HSC) model concluded that only CBP, not p300, is essential for HSC self-renewal, whereas p300 is crucial for proper hematopoietic differentiation. The literature [Ugai et al.] (21) found that only p300, not CBP, was absolutely necessary for RA-induced F9 differentiation.

ICG-001. Applicants' pharmacological tools have been identified using a cell-based forward chemical genomic screen of a small molecule secondary structure template chemical library (22). Due to the mutation in gene APC, SW480 colon carcinoma cells exhibit structural migration of beta-catenin to the nucleus, and thus high basal Wnt/catenin transcription (consensus TCF/catenin luciferase receptor construct, TOPFLASH). Evaluated). Using this reporter system, the present applicant previously identified the compound ICG-001 having an IC ₅₀ of 3 μM (FIG. 2A ). Using an affinity chromatographic approach, using an gain/lost function strategy, ICG-001 is unacceptable, despite the fact that the co-activators CBP and p300 are up to 93% identical and have higher homology at the amino acid level. It was determined and subsequently confirmed that it specifically binds to the activator CBP and with high affinity (about 1 nM), but importantly does not bind to its close homologue p300 (22, 23).

Applicants next mapped the binding domain between CBP and beta-catenin and also between p300 and beta-catenin. The C-terminal trans-activation region of beta-catenin (647-781) interacted with the same 1-111 amino acids for both CBP and p300 (23). However, only the interaction between CBP and beta-catenin was destroyed by ICG-001, and the p300/beta-catenin interaction was not destroyed . Subsequent binding and isothermal calorimetry studies have demonstrated that ICG-001 binds selectively and directly to the N-terminus of CBP with high affinity (about 1 nM). In summary, Applicant's data shows that CBP/beta does not affect p300/beta-catenin interactions despite direct association between CBP and ICG-001, and very high homology between the two coactivators. The ability of ICG-001 to selectively destroy only catenin interactions was confirmed.

ICG-001 provides a unique tool that specifically and selectively blocks only the amino terminus of CBP, allowing it to play a role in the interaction between CBP and catenin. Since the region where ICG-001 binds to the CBP is limited only to the amino terminus, the downstream change that this compound affects is not overall, but is limited only to the function controlled by the region of CBP. With a basketball and a golf ball, the following can be inferred-if the golf ball is placed on top of the basketball, the surface area covered by the golf ball on the basketball is not very large, and thus the rest of the basketball remains unaffected. In the same way, ICG-001 blocks a very small region of CBP, so the remaining regions on the coactivator remain unaffected and can interact with its remaining cognate binding partners.

IQ-1. In addition to ICG-001, another compound called IQ-1 was identified as a screen of a large chemical library for maintenance of pluripotency in mES cells (Fig. 2b). IQ-1 maintains the pluripotency of murine embryonic stem cells (mESCs) in long-term culture in a Wnt-dependent manner. Subsequently, Applicants determined that IQ-1 binds to the PR72/130 subunit of serine/threonine phosphatase PP2A. The combination of IQ-1 and PR72/130 reduces the phosphorylation of the co-activator protein p300 in Ser-89 through a mechanism not yet identified. Applicants also demonstrated that phosphorylation of p300 in Ser-89 enhances the binding affinity of beta-catenin to p300. IQ-1 increases the CBP/beta-catenin interaction by reducing the interaction between p300 and beta-catenin (24).

3A and B show a schematic representation of the molecular targets of ICG-001 and IQ-1 and their interaction points in relation to Wnt/catenin signaling. Using the tool under study, the present applicant studied the influence of the use of the differential coactivator CBP or p300 on catenin-mediated transcription. It is difficult, if not impossible, to use conventional "knockout" or "knockdown" techniques as CBP and p300 interact with multiple (more than 400) partners in addition to beta-catenin (25). Gene deletion of CBP or p300 has complex consequences that affect a number of different transcription factors. This highlights the importance of future chemogenetic approaches when used properly (22).

Wnt signaling in proliferation and differentiation

Wnt signaling plays an important role throughout development. While most agree that Wnt/catenin signaling is important in stem cell biology, there is no agreement as to whether Wnt signaling is important for the proliferation of stem/progenitor cells and maintenance of potential (pluripotency or pluripotency) or differentiation. Without. It has been demonstrated that Wnt/catenin signaling maintains pluripotency in ES cells (24, 26), and recently demonstrated an important role of beta-catenin in maintaining the expression of the key pluripotent transcription factor Oct4 in a TCF-independent manner. (27). It has been shown that Wnt/catenin signaling enhances neuronal stem/progenitor cell proliferation.

However, Wnt/catenin signaling is also necessary for neural differentiation of ES cells, that is, fate determination in neural crest stem cells, and Wnt3a inhibits neural stem cell maintenance and promotes differentiation into neural and astrocyte lineages. Reported (28-30). These dramatically varying and different responses, elicited by activation of the Wnt signaling pathway by the same Wnt in essentially the same cell type, fueled much debate about the role of Wnt signaling in the maintenance of potential versus induction of differentiation. have. In addition, questions have been raised about how the Wnt signaling network integrates various input signals received by cells to derive an accurate and equivalent response. To date, the theoretical interpretation of the dichotomous behavior of Wnt/catenin signaling that controls both proliferation and differentiation is unclear.

Non-redundant roles of CBP and p300 in Wnt/catenin signaling

One of Applicants' earlier studies demonstrated that selectively blocking the interaction between the two proteins CBP and beta-catenin using ICG-001 triggered the initiation of the differentiation program. This led to the development of the applicant's differential co-activation factor use model (16, 24). This model highlights completely different roles of the co-activators CBP and p300 in the Wnt/catenin signaling cascade (FIGS. 3A and 3B ). An important feature of this model is that the decision to use CBP or p300 is the first decision to guide cells to initiate a proliferation/potential maintenance or differentiation transcription program, respectively. Other epigenetic modifications after this first step (e.g., histone methylation/demethylation and histone acetylation/deacetylation, etc.), and also of additional transcription factors for both expansion and/or lineage determination of subsequent transient amplification populations. Note that mobilization follows (Wend et al. manuscript under revision Cancer Cell, [Ma et al Oncogene 2005]). In other words, the first step by which catenin cooperates with p300 or CBP is the initiation process rather than the most important, followed by other endogenous proteins, coactivators, enzymes (e.g., histone deacetylase, DNA methyl transferase, etc.) and Transcription factors are involved depending on the level of cellular potential, lineage and environment. The model points out that CBP/catenin-mediated transcription is important for stem cell/progenitor cell maintenance and proliferation, while the use of p300/catenin mediates a transcription program that initiates differentiation, and decreased cellular potential.

The decision to use CBP/catenin or p300/catenin induced transcription is considered a very basic event, as is already important at the point of determining the first cell potential. The first differentiation events after the first asymmetric division in mammals occur in the 8-cell stage of preimplantation embryos, forming two distinct cell populations: the outer trophoblastic germ (TE) and the inner cell population (ICM). All cell divisions prior to this point are considered symmetric, and all cells remain essentially equal and pluripotent. The cells inside the ICM are believed to be pluripotent to generate a total of three germ layer components, and the cells also contribute to extraembryonic endoderm and mesoderm. On the other hand, the outer layer of TE does not contribute to any embryonic tissue, but generates extra-embryonic ectoderm and can differentiate into multiple trophoblast cell types. Applicants believe that the selection between ICM and TE at these initial and perhaps most important cell determinants is determined by the use of differential co-activators by catenins, i.e., CBP/catenin is the maintenance of ICM and the expression of Oct4. While required for, it was demonstrated that the use of p300/catenin initiates the formation of Cdx2 positive trophoblasts (31). According to a specific aspect of the invention, the basic determining process that occurs in the first symmetric versus asymmetric differentiation is carried out through all somatic stem cell lineages throughout the life of the organism.

Blocking of the interaction between p300 and catenin through the use of IQ-1, for example, allows mouse ES cells to use CBP as its co-activator, promoting CBP/catenin-induced pluripotency maintenance and organ expansion. And prevents spontaneous differentiation even in the absence of leukemia inhibitory factor (LIF). Similarly, knockout of p300 in mES cells prevents spontaneous differentiation upon removal of LIF from the medium (31). Similar results for selective antagonism of the p300/catenin interaction were also obtained using human ES cells (32; Hasegawa K et al accepted Stem Cells Translation Medicine 2011). Blocking the CBP/catenin interaction with ICG-001 can prevent induction of pluripotency, while selectively antagonizing the p300/catenin interaction can improve reprogramming (33; Applicant's non-public data). All of these results are consistent with the Applicant's model, some catenin-transcriptional regulatory genes (e.g., Oct4, survivin) use only CBP as their co-activator, and the rest of the genes (e.g., Cdx2) While p300 is selectively used as a transcriptional co-activator, other catenin-regulated gene promoters are proliferative and can use CBP or p300 for productive transcription (17).

The effect of CBP/catenin antagonism on the Wnt target gene is quite promoter specific. Colorectal cancer cells are treated with ICG-001 to disrupt CBP/catenin interactions, followed by chromatin immuno-precipitation assay (ChIP) (a technique to determine which protein associates with a specific promoter) several Wnt/beta- The occupancy of the coactivator in the promoter region of the catenin-regulated target gene was investigated. In the cyclin D1 promoter, Applicants observed removal of CBP, reduction of message and no recruitment of p300 (23). In the c-myc promoter, Applicants observed a slight increase in messages with the removal of CBP, an increase in p300 occupancy, whereas in the survivin promoter Applicants also observed a decrease in messages with the removal of CBP. Interestingly, in the survivin promoter, Applicants found an increase in recruitment of p300 and a corresponding decrease in survivin message along with additional proteins related to transcriptional inhibition after ICG-001 treatment (17) (FIG. 4 ). In summary, as a result of this, some Wnt/catenin-regulatory genes (e.g., survivin) use only CBP as their transcriptional co-activator, while other gene promoters are proliferative and are CBP or It is confirmed that the p300 can be used. In addition, there are other Wnt/catenin-regulatory genes that selectively use p300 for transcriptional co-activation. An interesting example of the use of this differential co-activator relates to the expression of the gene EphB2 known as the Wnt/TCF/beta-catenin target gene. Since nearly 90% of colon cancers have high abnormal Wnt/TCF/beta-catenin activation, EpHB2 expression will increase with colon cancer disease progression. However, this is not the same case where EphB2 expression is generally lost in end-stage colorectal cancer (34). In addition, destruction of EphB2 in Min mice with a defective APC tumor suppressor gene leads to highly invasive carcinoma in contrast to normal adenoma. The loss of the direct Wnt target gene in colon cancer, a disease characterized by an abnormal increase in Wnt/catenin signaling, so-called "mystery", suggests that the expression of EphB2 is p300/beta-catenin dependent and accompanied by colon cancer disease progression. This is explained relatively easily by the facts, and there is an increased bias regarding the use of the coactivator CBP with respect to Wnt/catenin signaling. In this case, which antagonizes the CBP/catenin interaction through the use of ICG-001, colon cancer cells use p300 as its co-activator for Wnt/catenin signaling to increase the expression of EphB2 (35).

The level of complexity added to the model is in this way, although the subset of gene expression cassettes regulated by CBP/catenin branches is important for the maintenance of potential and proliferation (e.g., Oct4 , survivin, etc.). Other genes that are regulated (eg, hNkd and Axin2) are in fact that they are negative regulators of the CBP/catenin branch of the cascade (36, 37). This type of voice feedback branch is essentially completely understood. If the potential and activation of CBP/catenin branches are the default pathways, one must stop proliferation, exit the cell cycle, asymmetric division, and initiate the differentiation process for developmental progression at several points (Fig. 5). Interestingly, Axin2 expression is frequently silenced through DNA methylation in many tumor types.

Another feature revealed from the applicant's study is that Wnt/CBP/catenin or Wnt/p300/catenin-mediated signaling is not entirely TCF-dependent. Apart from TCF/LEF, beta or gamma catenins are also known to be partners of a number of transcription factors, including members of the nuclear receptor family, Smads, Foxo, etc. (38-40). In this regard, the use of topflash (a reporter construct with multiple TCF binding elements inducing a luciferase reporter gene) as a prerequisite for functional readout for Wnt signaling is not accurate, and also plays a role in the overall transcription of nuclear catenins. Underestimate. Since TCF is clearly not the only transcription-related binding partner for nuclear catenins, even in the absence of any topflash activity, nuclear beta catenins are still transcriptionally active through cooperation with TFs other than members of the TCF family (e.g., FOXO proteins). I can. As a suitable example, Applicants' knowledge of the role of Wnt signaling in breast cancer is by no means complete, but their importance and significance have been the subject of numerous reports over the past five years (41). In human breast cancer, there are many reports of inactivation of negative regulators of the Wnt signaling pathway. The downstream activator, Disheveled (Dsh), is amplified and upregulated in 50% of ductal breast cancer [42]. The serpentine-associated protein 1 ( FRP1/FRZB ), a secreted Wnt inhibitor, is frequently deleted in human breast cancer. Frp1 expression is inhibited or absent in approximately 80% of malignant breast carcinomas, which is one of the most common changes in breast cancer (43). Axin frequently exhibits a loss of heterozygosity (LOH) in breast cancer, which is also downregulated in breast cancer (44, 45). Both of these are negative regulators of the canonical Wnt signaling pathway. Despite the fact that Wnt signaling plays an obviously important role in breast cancer, there is essentially no topflash activity in breast cancer cells.

In essence, another issue that adds to the debate surrounding this field regarding the use of the gene deletion of beta-catenin is the transcriptional image of the loss of beta-catenin of other catenins (e.g., gamma-catenin/flavoglobin). It is at least some offsetting ability. Beta-gamma double knockout mice still show Wnt signaling, which is functional in at least some tissues/organs (9, 46). In addition, beta-catenin plays an important role in cell-cell interactions at the adhesion junction. Thus, loss of beta-catenin can affect both its transcriptional role and its role in cell-cell interactions. Additionally, adding to the complexity associated with Wnt/catenin signaling is a number of growth factors (TGF beta, EGF, HGF, etc.), kinases (e.g., Src, bcr-abl) and adhesion molecules (e.g. E -Cadherin), including the inactivation of beta-catenin, there are several mechanisms/pathways beyond the Wnt signaling cascade that can increase nuclear transfer of beta-catenin (Front Biosci. 2008 May 1;13:3975-85) Microenvironmental regulation of E-cadherin-mediated adherens junctions. Giehl K, Menke A.])

Finally, although nuclear catenins are clearly important for transcription, the absolute level may not. Rather, its choice or balance to the use of the amount and limiting amount of transcriptionally competent catenin between the two coactivators (CBP and p300) is the ultimate determinant in cell determination under symmetric or asymmetric division (35 and Ringing A et al Poster presentation ASCO 2011]).

In summary, the optional pharmacological tools ICG-001 and IQ-1 have proven to be of great importance in the Applicants' study. In accordance with certain aspects of the invention, Applicants use these tools in conjunction with more traditional gene knockout or knockdown, where increased CBP/catenin-mediated transcription is associated with symmetric cleavage, whereas p300/catenin-mediated transcription is associated with rodent and human In all, it has been demonstrated to be important for initiating multiple stem and progenitor cell differentiation.

Selective CBP/catenin antagonists: presence of natural analogs

Acute promyelocytic leukemia (APL) is unique among myelogenous leukemia due to its sensitivity to all-trans retinoic acid (ATRA), a derivative of vitamin A. Treatment with ATRA allows DNA transcription and differentiation of immature leukemia promyelocytes into mature granulocytes by isolating the NCOR-HDACL complex from RAR and targeting tumorigenic transcription factors and their aberrant actions. Unlike most other chemotherapy, ATRA does not kill malignant cells directly, but causes their differentiation. Numerous scientific studies have also investigated the possible role of vitamin D in cancer prevention, including colon, prostate, breast, pancreatic and skin cancer. Interestingly, both ATRA and vitamin D are able to antagonize aberrant Wnt signaling in several settings (eg, colorectal cancer cells) via their respective transcription complexes (RAR/RXR and VDR/RXR). However, there are also records of synergistic effects on the activation of gene expression by ATRA and Wnt (eg (47)). Interestingly, the LXXLL sequence at the amino terminus of both CBP and p300 can recruit these and also other nuclear receptor signaling complexes (eg, ER, AR and PPAR). This is the same region of these coactivator proteins (i.e., CBP and p300) that cooperate with catenin (both beta and gamma), and CBP/catenin antagonist (e.g., ICG-001) also binds to this region. These nuclear receptor ligands have many of the same differentiation effects on the stem cell population observed by the Applicant with a specific CBP/catenin antagonist. Both vitamins A and D are required during development and have several beneficial health effects in adults, but both are high levels of teratogenic substances. Thus, one of the most surprising discoveries in the course of Applicants' research on mouse development is, perhaps, that it appears to be very safe to selectively antagonize the CBP/catenin interaction with ICG-001 at very high levels, and apparently has no detrimental effects. Was not. In essence, mice born from mothers topically treated with high doses of ICG-001 (0.5 M) throughout pregnancy from fertilization (~E0.5) to birth (~E20) at 6 weeks of age had normal weight and weight compared to their control litters. It was sized and was able to give birth to a second generation, demonstrating the absence of deleterious effects on the germ cell population. This contrasts dramatically with the selective antagonism of the intrauterine p300/catenin interaction, which causes severe developmental defects in virtually all organ systems (i.e. vasculature, heart, lungs, CNS, limbs, etc.) that have been studied (Kahn, published Not). Based on the data discussed above, Applicants suggest that agonists such as Vitamin A (ATRA) and Vitamin D are naturally occurring molecules that behave to some extent like Applicants' small molecule CBP/catenin antagonists. They are capable of antagonizing the CBP/catenin interaction by binding to CBP through its nuclear receptor complex (i.e., RAR/RXR and VDR/RXR, respectively). However, very importantly, there are several key differences. CBP/catenin antagonists are direct (ie, bind directly to CBP and do not require any co-receptors, co-receptors are often reduced or silenced/lost in cancer), and are pure CBP antagonists. In addition, they allow probabilistic differentiation (i.e., non-deterministic), but vitamins A or D antagonize the CBP/catenin interactions and are likely to be detrimental to embryogenesis at high doses through their phylogenetic properties. Has an effect (Fig. 6).

CBP/catenin antagonists therapeutic use

cancer. The importance of Wnt signaling in colorectal cancer is clear. Therefore, our research on the therapeutic use of ICG-001 began quite naturally with colon cancer. Applicant showed that the compound down-regulated survivin. Survivin is a transcript number 4, which is commonly upregulated in cancer, is a known inhibitor of caspase activation, and is also important in cytokinesis. Survivin inhibition followed by increased caspase activation exhibits selective cytotoxicity in colorectal cancer cells, but not in normal colon epithelial cells. In vivo ICG-001 is effective in both Min mice with reduced polyps and in nude mouse SW620 xenograft models of colon cancer with reduced tumor growth (23).

According to certain aspects of the invention, the similarity between normal adult somatic/tissue stem cells and cancer stem cells (CSCs) is a signaling pathway involved in the regulation of somatic stem cell maintenance (e.g., Wnt, Hedgehog And Notch) are also involved in the regulation of CSC (48-50). Abnormal regulation of these same pathways leads to neoplastic proliferation in the same tissue. Evidence for the presence of cancer stem cells in leukemia, breast, lung, brain tumors, colon, prostate and pancreatic cancers has increased over the past few years. These cancer stem cells have markers and cellular behavior similar to somatic or tissue stem cells. CSC is believed to be the cause of recurrence and metastasis. Inside the tumor, most of it consists of drug-sensitive/differentiating cells, and CSCs usually appear only in a small fraction inside the tumor. Current therapies are designed to kill most of the drug-sensitive/differentiating cells, but the remaining CSCs, at least partially protected by the multidrug resistance gene, lead to relapse and metastasis. Recently, in various CSC types, the Applicant can differentiate cancer stem cells into those behaving like this while appearing to have the same phenotype as most of the tumor cell population by selectively inhibiting the interaction between CBP and catenin with ICG-001, This could demonstrate that they can be sensitized to current standard therapies. Within the context/categories of this disclosure, Applicants will succinctly highlight some of Applicants' findings.

Breast cancer. Epithelial specific antigen/epithelial cell adhesion molecule (ESA/EpCAM), CD44, exclusion of Hoechst Dye (lateral population (SP)), aldehyde dehydrogenase positive (ALDH) and cell surface antigen CD24 and lineage Breast cancer stem cells identified by various phenotypic markers, including the absence of specific markers, can form tumors in animals with 200 small amounts of cells, then grow and differentiate to reproduce the heterogeneity of the initial tumor. Several developmental pathways, including Wnt, Notch and Hedgehog, are known to regulate the self-renewal of these stem cells. Each change in these pathways can produce breast cancer in animal models and is involved in human breast cancer formation. However, the pharmacological approach to processing these pathways, as evidenced by the initial results due to the inhibition of the Notch pathway, is complicated by the versatility and other properties of the relevant networks, where abnormalities in normal maturation and differentiation emerged. Triple-negative breast cancer (ER, PR and Her2 negative) (TNBC) is a particularly aggressive subtype with a high risk of recurrence and mortality, a higher predisposition to organ metastasis, and also a lack of targeted treatment options for hormones and HER2 receptors. It is a type. TNBCs are biologically distinct, as evidenced by homologous “native” gene expression partners, and most breast cancer cases, including BRCA-1 mutations, are also included in this subset. The TNBC classification approximates a basic subtype of breast cancer defined by a gene expression pattern similar to that of stem cells of the mammary coronary epithelium. In a 190-patient study of primary cases defined by triplicate (ER, PR and HER2)-negative, and also expression of cytokeratin 5/6, EGFR and vimentin, nuclear accumulation of beta-catenin (i.e. Wnt pathway activation Prior readings) were found to be abundant in this basic case. In addition, these cases demonstrating increased beta-catenin levels had a worse prognosis and occurred more frequently in black American patients. Other studies have similarly shown that nuclear localization of beta-catenin is generally more prevalent in triple negative patients.

The triple negative breast cancer cell line MDA-MB-231 exhibits low expression of the Wnt-regulatory cell surface marker CD24, and a relatively high expression of another Wnt-regulatory target gene CD44. These phenotypes CD44 ^hi and CD24 ^lo were associated with a subpopulation of cells behaving like breast cancer stem/tumor initiating cell populations (51). Interestingly, antagonizing the CBP/catenin interaction in MDA-MB-231 cells with ICG-001 decreased CD44 expression while increasing the expression of cell surface CD24 at 24 hours. Essentially, using ICG-001, Applicants reduced the expression of Wnt/CBP/catenin target gene CD44 by allowing catenin to use the co-activator p300, while simultaneously increasing the expression of Wnt/p300/catenin target gene CD24. Can be increased (a situation similar to the EphB2 riddle discussed above) (Ring A et al Poster presentation ASCO 2011). In addition, using ChIP (Identification of unknown target genes of human transcription factors using chromatin immunoprecipitation. Weinmann AS, Farnham PJ. Methods. 2002 Jan;26(1):37-47.]), the applicant of the present invention is ICG-001 It was demonstrated that selective blocking of this CBP/catenin interaction increases the recruitment of p300 to the CD24 promoter. Blocking of CBP/catenin interactions with ICG-001 also dramatically reduced flanking population (SP) and ALDH activity, both of which were more generally associated with stem/progenitor cell populations. Beyond the reduction in survivin message levels, there is a gene expression profile consistent with the occurrence of mesenchymal transition to epithelial (MET) (i.e., reduced expression of twist, vimentin and S100A4 and E-cadherin expression. increase). Recently, a number of documents exist relating epithelial transition to the mesenchymal (EMT) to the CSC phenotype (52). EMT is a normal physiological process that is important in development and in adulthood, for example in wound healing, but pathophysiologically is associated with tumor metastasis and organ fibrosis (see discussion on fibrosis later). Certain CBP/catenin antagonists can reverse this abnormal EMT in vivo (EMT also plays an important role in skin, hair loss, etc. J Dermatol Sci. 2011 Jan;61(1):7-13. Epub) 2010 Dec 5]; The epithelial-mesenchymal transition (EMT) plays an important role not only in morphogenesis, but also in wound healing, tissue fibrosis and cancer progression.. Recently, the regulatory mechanisms of this process have been closely elucidated. May be a new therapeutic target for the treatment of fibrotic alopecia and malignant skin cancer such as squamous cell carcinoma and melanoma).

Interestingly, Applicants also demonstrated that antagonizing the interaction between CBP and catenin using ICG-001 leads to re-expression of the ER alpha receptor, and subsequently sensitivity to the anti-estrogen tamoxifen. These results suggest that the above strategy can be used clinically to eliminate breast cancer stem cell populations through forced differentiation, and that they can be hormone sensitive by inducing the re-expression of estrogen receptors in triple negative breast cancer ( Kahn, not published).

Chronic Myeloid Leukemia (CML). Despite the remarkable clinical success gained today in chronic-stage CML patients treated with the BCR-ABL antagonist Gleevec/Imatinib (IM), responses in advanced-stage patients are often short-lived, and patients still experience disease progression. have. In addition, tolerance to IM occurs in 2% to 4% of patients annually, and escalation of IM doses is usually not sufficient to control the disease. Including low expression of BCR-ABL, and insensitivity to tyrosine kinase inhibitors (TKI) of resting CML stem cells due to the development of drug resistant leukemia clones associated with increased nuclear catenin levels characteristic of increased Wnt/catenin transcription. In addition, several mechanisms have been suggested that contribute to TKI resistance. Interestingly, a number of Wnt signaling-related genes are upregulated in CML, particularly in CML associated with disease progression (53). Epigenetic silencing of negative regulators of the Wnt signaling cascade is also frequently associated with leukemia, including CML. Recently, the Applicant reported that the imatinib-resistant (IR) CML population exhibits properties consistent with the resting leukemia stem cell population, and is a specific small molecule inhibitor ICG-001 that inhibits the interaction between CBP and catenin (both β and γ). It has been demonstrated that it induces differentiation of IR cells both in vitro and in vivo (9). Specifically, the Applicant uses a highly immunocompromised (NOD/SCID/IL2rγ ^-/- ) mouse model of transplanted human CML, specifically using a small molecule ICG-001 to inhibit the interaction between CBP and catenin It has been demonstrated that resistant leukemia stem cells can be eliminated. Importantly, this can be done without adverse effects on normal endogenous hematopoiesis (ie, without damage to normal hematopoietic stem cells (HSC)). Mice treated with one progression of CBP/catenin antagonist and bcr-abl antagonist (28 days from 13 to 41 days after leukemia vaccination) were essentially treated for leukemia and survived as long as litters without leukemia vaccination. (Approximately 2 years).

According to certain aspects of the invention, certain CBP/catenin antagonism can eliminate CSCs through forced differentiation without detrimental effects on the normal endogenous stem cell population.

fibrosis. Idiopathic pulmonary fibrosis (IPF)/common interstitial pneumonia (UIP), i.e., the most common idiopathic interstitial pneumonia, is a destructive progressive disorder characterized by excessive fibroblast proliferation and extracellular matrix remodeling leading to lung destruction. There is currently no effective treatment for these consistently fatal diseases. The recent paradigm suggests an important role in alveolar epithelial cell damage and dysregulated recovery in the pathogenesis of IPF. It is believed that epithelial damage initiates a cascade of fibroblast activation and matrix deposition, preventing the susceptible host from healing as in the course of normal wound healing. Epithelial cells undergo excessive apoptosis, whereas fibroblasts less follow apoptosis, indicating increased survival. A well-characterized model of bleomyosin-induced lung injury was used extensively to investigate possible pathways involved in the pathogenesis of pulmonary fibrosis and to study treatment approaches. Despite some limitations with regard to the repetition of occurrence of human disease, many pathways that are upregulated in IPF (eg, TGF-β and Wnt/β-catenin) are also upregulated with bleomycin. Using transgenic BAT-gal mice, Applicants have demonstrated that abnormal activation of Wnt signaling in the lung is induced after injury. Intranasal administration of bleomycin induces labeled lacZ expression in the airway and alveolar epithelium of BAT-gal transgenic mice, which is significantly reduced by ICG-001, a specific inhibitor of Wnt/beta-catenin/CBP-induced transcription. Became. Bleomycin treatment also includes a number of genes (e.g., S100A4, MMP-7, CTGF, collagen types I and III, fibronectin and TGF-β1) that are particularly related to fibrosis, ECM deposition and EMT (some of which are known Wnt /Beta-catenin target gene) dramatically increased the expression. Treatment with ICG-001 essentially reduced the expression of these genes to control levels. Recent evidence suggests an important role of EMT in fibrosis after treatment with bleomycin. ICG-001 significantly reduced the expression of S100A4/FSP-1 both in the mouse in vivo bleomycin-induced fibrosis model and in fibroblasts from IPF patients in vitro. S100A4/FSP-1 has been suggested to be a characteristic of EMT that can represent a common pathway in diseases marked by airway remodeling. According to certain aspects, the reduction of S100A4/FSP-1 expression through CBP/beta-catenin antagonism is associated with MET. In addition, Applicant demonstrates that using rat type II lung epithelial cells in vitro, ICG-001 prevents TGF-β1-induced upregulation of α-SMA and type I collagen, i.e., a gene that is usually increased in EMT. I did. Importantly, regardless of the mechanism of activation of catenin and migration to the nucleus (ie, Wnt or TGF-beta, etc.), ICG-001 can selectively antagonize EMT-related aberrant transcriptional CBP/catenin activity. ICG-001 pretreatment in vivo significantly reduced the severity of pulmonary fibrosis. In striking contrast, administration of dexamethasone for the same 10-day period (1 mg/kg/day) significantly reduced inflammatory cell infiltration, but did not affect interstitial and alveolar fibrosis, indicating that corticosteroids contributed to pulmonary fibroproliferative disorders. Consistent with previous records of failure to alleviate pulmonary fibrosis in animal models or patients having. More importantly, ICG-001 was able to reverse established fibrosis in a mouse model (54).

Alzheimer's disease. Alzheimer's disease (AD) is the most common form of dementia in the elderly. AD patients exhibit progressive and gradual declines in cognition, learning and memory. These symptoms were associated with the accumulation of extracellular neuritis plaques consisting of fibrillar ß-amyloid (Aß) peptides, intracellular nerve fiber knots containing highly phosphorylated tau, and neurodegeneration. Significant efforts have been made to link these appearance-independent phenomena with the progression of AD, but it is possible that they are distinct signs of a common basic defect in neuronal homeostasis and plasticity. Presenillin-1 (PS-1) (their mutations are associated with early onset familial Alzheimer's disease (FAD)) has been shown to interact with members of the armadillo family of proteins including beta-catenin, which is a Wnt signaling. It provides a possible association between transmission and AD pathology.

However, the effect of the PS-1 mutation on the stability of beta-catenin, TCF/beta-catenin signaling, and thus its possible role in AD, remains controversial. Applicants have found that the introduction of FAD mutant PS-1 (L286V) into PC-12 cells increases TCF/beta-catenin signaling to inhibit neurite production. Treatment of these mutant cells with ICG-001 resolves defects in neuronal differentiation and neurite production in these cells by specifically inhibiting CBP/beta-catenin-mediated transcription. Importantly, the expression of critical markers of neuronal development (ie, GAP43) is dramatically increased in mutant cells treated with ICG-001 during NGF-induced differentiation compared to untreated cells. Importantly, EpB2 expression is again increased by antagonizing the interaction between CBP and catenin with ICG-001, as in colorectal cancer cells. In the CNS, EpB2 expression is associated with axon induction (16). In addition, recent studies have demonstrated that reduced EpB2 expression has been shown to reduce AD disease progression contributing to glutaminergic synaptic deficiency (similar situation to colon cancer described above). Increased expression of EpB2 in a mouse model of AD had a beneficial effect on memory consolidation (55). In the first in vivo study, the Applicants described mutant APP(695) (Swedish (K670N, M671L), Florida (I716V) and London (V717I)) and PS-1 (M146L). And L286V) penta-transgenic mice overexpressing the mutation were treated with ICG-001 for 2 months (months 2-4). These mice generally develop large-scale cerebral deposition of Aβ beginning at 6 weeks of age. As a result of judgment by immunohistochemistry, the formation of amyloid plaques was significantly reduced in the ICG-001-treated group (3 mice, 50 mg/kg/day) compared to the saline-treated control group (FIG. 7).

The effect of antagonizing the CBP/catenin interaction in this highly spreading disease model and other diseases not discussed by the applicant (eg, post-myocardial infarction, multiple sclerosis, etc.) is very interesting. However, questions have been raised as to how one compound would enable it to have beneficial therapeutic effects in these highly diffuse tissue/organ and disease models. Equally important, CBP/catenin antagonists have proven to be very safe in preclinical evaluations in a number of species, and have no apparent adverse effects, particularly on the normal endogenous stem cell population.

Symmetric vs. asymmetric division in somatic and cancer stem cells

Based on some of the results described above, the differential effect of CBP/catenin antagonists on cancer stem cells versus normal somatic stem cells (i.e., forced differentiation and elimination versus recovery of enhanced differentiation without apparent depletion) is clearly cell intrinsic, and CSC versus It has emerged to the applicant that it is not due to the selective targeting of normal somatic stem cells by CBP/catenin antagonists. Thus, according to certain aspects, Applicants utilize the intrinsic tendency of cancer stem cells to increase the number of symmetric divisions at the expense of asymmetric divisions by various mutations (e.g., p53, PTEN) while CBP/catenin antagonists However, it was assumed that normal endogenous stem cells preferentially asymmetrically divide into one daughter cell remaining in place, and the rest become transiently amplified cells necessary to generate new tissues involved in the recovery process. Interestingly, the choice of whether symmetric division is regenerative symmetric division (i.e., retaining the same level of potential) or differential symmetric division (i.e., the two cells are in a less potential state), respectively, depends on the CSC vs. non-CSC stem cell population. Seems to be related to

According to certain aspects, the CBP/catenin antagonists (e.g., ICG-001 and other CBP/beta-catenin antagonists disclosed herein) differentially symmetrically divide a population of tumor stem cells, thus resulting in tumor stem cells from their niches. Deplete In striking contrast, according to certain aspects, for normal somatic stem cells, CBP/catenin antagonists enable asymmetric division, and when it is necessary to increase recovery by activating dormant somatic stem cells, CBP/catenin antagonists can Can be improved or accelerated (Figure 8, top). Since this assumption is not readily tested using inoculated leukemia stem cells, Applicants relied on an exemplary neurogenesis model that was previously used to study symmetric vs. asymmetric cell division.

Using the rapid absorption and penetration of Applicants' small molecule Wnt modulators through the placental barrier, Applicants devised a series of experiments to study symmetric vs. asymmetric division in the ventricular zone (VZ) of the brain during mouse embryogenesis. Pregnant mice were treated topically with DMSO (vehicle control), CBP/catenin antagonist ICG-001 or p300/catenin antagonist IQ-1 for various periods (1-3 days). Using the previously described protocol (56), the localization of polarity related protein 3 (Par3) and DNA was investigated in mitotic cells in VZ. Par3 is symmetrically distributed in symmetric dividing cells and asymmetrically distributed in asymmetric dividing cells, while DNA is distributed symmetrically between two cells. Fluorescence microscopy can be used to quantify the fraction of mitotic cells that divide symmetrically or asymmetrically. For example, after treatment with DMSO for 1 day during the neurogenesis period of development (E13.5 to 14.5), Applicants found that approximately 21% of the cleavage in VZ is asymmetric. Antagonizing the CBP/catenin interaction with ICG-001 did not result in an apparent effect similar to approximately 21% asymmetric cleavage. In striking contrast, treatment with the p300/catenin antagonist IQ-1, and resulting increase in CBP/catenin interactions, significantly reduced the number of asymmetric cleavage by approximately 9%. Importantly, the reduction in asymmetric cleavage after treatment with the IQ-1 could be achieved again at the control level (ie, about 21%) by treatment with essentially a double excess of ICG-001. Additional differences in symmetric versus asymmetric cleavage could be observed with prolonged treatment. For example, treatment with IQ-1 for 3 days (E13.5-16.5) (i.e., increasing the use of CBP by antagonizing the p300/catenin interaction) caused asymmetric cleavage from 31% to 7% compared to the control. Reduced to Interestingly, the increase in symmetric division induced by p300/catenin antagonism by IQ-1 in normal neural stem cells was increased in the subventricular zone (SVZ) at the expense of VZ, and also in transgenic Tis21 reporter mice and neurogenin. 2 (final mitotic marker) It was found to increase the number of symmetric differentiation divisions as judged by the number of neurogenic differentiation divisions judged by the number of positive cells. These reporter mice express EGFP induced by the Tis21 promoter in cells that have undergone neurogenic differentiation division.

Considering that IQ-1 in vitro increases the number of symmetrical non-differentiated divisions in both mES cells and epicardial precursors, this increase in symmetrical differentiation divisions was surprising at first (24, 57). In retrospect, this is the difference previously observed in mouse knockout models (e.g., PTEN in HSC population versus LSC) (58) and how they affect normal stem cell populations, i.e., possibly increased symmetric differentiation division. , And early depletion due to removal of the stem cell population versus the transformed tumor stem cell population (which increases due to increased symmetric non-differentiated division).

Theory of the difference between symmetric regeneration versus symmetric differentiation division in CSC versus normal somatic stem cells

The data described above clearly demonstrated that increased CBP/catenin transcription at the expense of p300/catenin transcription increases the number of symmetric cleavage at the expense of asymmetric cleavage (both in vitro and in vivo). However, the determination of differentiating or non-differentiating symmetric division requires other additional inputs (both intrinsic and extrinsic) to the cells. In addition, in normal somatic stem cells, attempts to symmetric division in vivo often do not preferentially increase the number of regenerative, non-differentiated divisions to increase the stem cell pool, but rather enhance the symmetric differentiation division, thereby enhancing the somatic stem cell population. Seems to lead to premature depletion. A possible theory for this observation goes back to the "Immortal Strand Hypothesis" described more than 35 years ago by Cairns (59). Briefly, upon mitosis, stem cells attempt to retain the first uncopied strand of DNA, and to transfer double strands containing multiple copy errors to daughter cells that will continue in the path toward final differentiation. In this way, the total number of DNA mutations (retained over the lifetime of the organism) in a population of long-lived stem cells in situ is minimized. It is believed to be an inherent defense mechanism that protects the stem cell population, especially in long-lived organisms, and allows long-term accuracy of maintenance and recovery of tissue and organ systems. In striking contrast, transformed stem cells overcome the intrinsic means of protection through a combination of genetic or acquired mutations (e.g., p53, PTEN, KRAS, etc.), and preferentially symmetric non-differentiated divisions to mutate DNA It is believed to increase the stem cell pool, including cells with cells, and decrease the genome stability and accuracy of recovery and maintenance over time.

However, this intrinsic protective mechanism against normal tissue stem cell symmetric regenerative division is by no means fool proof, and a number of factors such as gene mutations (genetic and acquired), various damages (radioactivity, infection, It is destroyed by dietary foreign matter, etc.), chronic inflammation, and the like, making it possible to observe an increase in the number of stem cells in many somatic stem cell populations upon aging. More recently, it has also become clear that the decision process/point for regeneration versus differentiation (ie, maintaining the level of potential or decreasing the level of potential) is also reversible; Induced pluripotent stem (iPS) cells most clearly demonstrate this and also earlier studies of transformation/immortalization of cells. This formation needs to factor into the hypothesis about the origin of cancer stem cells, ie CSCs are derived from mutations to the normal somatic stem cells themselves, or reconstitute the precursors to a more “stem-like” state. It is a mutation that occurs in a more differentiated (transient amplification) precursor. They are not mutually exclusive, and are essentially only semantic debates in terms of treatment strategies targeted at CSCs.

Symmetry vs. asymmetry, and aging

According to certain aspects of the invention, with age, both the accuracy and efficiency of the body homeostasis and recovery process decrease. Although, in principle, this may be due to the reduction in the tissue stem cell population required to drive homeostasis and recovery, according to certain aspects, instead of a decrease in the tissue stem cell population (HSC, skin/hair, etc.), There may be an increase in number. However, according to a further aspect, the “validity” of these stem cells, which function as a regenerative pool during homeostasis and recovery, decreases with age. Interestingly, several mouse models of premature aging, and reduced effectiveness of recovery after injury (ie, increased fibrosis), demonstrated an increase in Wnt signaling (60-62).

According to certain aspects, Applicants believe that this increase in the stem cell pool with a reduced potency in the homeostasis process is the number of symmetric regenerative divisions at the expense of asymmetric divisions in the stem cell population (e.g., somatic stem cell population). Interpret it as arising from increase. According to a further aspect, this results from an increase in CBP/catenin interaction/transcription at the expense of p300/catenin interaction/transcription with aging. In addition, this fits epidemiological data demonstrating that the risk of developing cancer, fibrosis or neurodegeneration is significantly increased with aging after age 50. According to certain aspects, this increase in stem cell symmetry versus asymmetric division with aging can lead to genes, various damages (infection, foreign matter, contaminants, etc.), food/calorie intake/metabolism, and radiation (UV, X-ray). CBP/catenin, which in combination causes an increase in symmetric vs. asymmetric division in the affected somatic stem cell population and an increase in CBP/catenin-driven processes, including And the balance between p300/catenin driven transcription can be biased (Figure 9).

Thus, according to certain aspects, selective small molecule CBP/catenin (e.g., CBP/beta-catenin) antagonists have substantial utility for correcting this bias, whereby more optimal (younger specific) in asymmetric vs. Of) provides balance; That is, it provides an increase in the number of asymmetric regenerative divisions at the expense of symmetric division in a stem cell population (e.g., somatic stem cells), wherein the method of treating aging, or a disease/condition of aging, or one or more symptoms thereof Is obtained.

According to certain aspects, small molecule CBP/catenin (eg, CBP/beta-catenin) antagonists have substantial utility for alleviating the aging process and/or signs thereof.

According to certain aspects, small molecule CBP/beta-catenin antagonists provide prevention against common aging diseases and conditions (e.g., cancer, fibrosis, neurodegeneration, hair loss, skin/tissue degeneration/damage, etc.). Has practical utility for

The final decision for a cell to retain the capacity or to initiate differentiation is the activation of various growth factors, cytokines and hormones, and subsequent activation of various signaling complexes and kinase cascades, nutrient levels, oxygen levels, gene mutations, substratum It follows a lot of information, including attachments. Eventually, these multiple paths must be consolidated and sub-centralized into simple decisions, i.e. 0/1 binary decisions. According to certain aspects, the balance between CBP-mediated and p300-mediated catenin transcription plays a central role in the integration of these signals.

According to certain aspects, cancer, rather than many etiologically different diseases (i.e., breast cancer is different from colorectal cancer and different from leukemia, etc.), between catenin/CBP and catenin/p300, i.e. maintenance of proliferation and ability. , And different mutations (some of which may be tissue specific) that may cause abnormal regulation of the basal equilibrium between the onset of differentiation, or alternatively between symmetric versus asymmetric divisions (e.g., bcr/abl, K-Ras, Her2, etc.) are associated with various combinations of tissue-specific stem cell abnormalities.

Although the present inventors know how to pharmacologically manipulate the balance of differential use of catenin co-activators (i.e., catenin/CBP vs. catenin/p300) in the progenitor/progenitor population, the present inventors believe that the cells are ultimately /1 Reading a very complex collection of information from its environment (e.g., oxygen levels, nutrient levels, light/dark, i.e. biological cycle cycles, growth factors, adhesion molecules, cell/cell contacts, etc.) to arrive at a binary crystal I started to understand only how to do it.

According to a specific aspect, FIG. 10 shows information through various kinase cascades that play an important role in the measurement of binary crystals for symmetrically or asymmetrically distinguishing through control of the balance between CBP/catenin interactions and p300/catenin interactions. Shows Applicant's model for "lower centralization". The fast and reversible (via phosphatase) ability of the kinase cascade to modulate protein/protein interactions provides a very versatile and easy mechanism to modulate this critical binary switch. Interestingly, within the first 111 amino acid residues of CBP and p300, there are 20 serine and threonine residues. It is coupled with an additional point for post-translational modification (e.g., lysine acetylation), and recruitment of differential epigenetic modifiers modulates symmetric versus asymmetric cleavage, and critical expression cassettes associated with self-renewal or differentiation. It provides ample opportunity for the fine tuning required to do so.

Preclinical models for evaluating the role of this critical switch in a series of destructive diseases (e.g. AD, Parkinson, MS, pulmonary hypertension, etc.), pharmacological interventions with small molecule CBP/catenin antagonists, and a more comprehensive With regard to health problems such as metabolic syndrome and aging, these studies provide new treatment options.

References to this section (incorporated herein by reference for its related teachings)

II. Treatment of hair loss: for example promoting hair growth and/or regeneration, and/or preventing or delaying hair loss (and loss of hair pigmentation)

Certain aspects of the invention are CBP/catenins (e.g., CBP/catenins) for use in promoting hair growth and/or regeneration, and/or preventing or delaying hair loss (e.g., aging subjects) ( and loss of hair pigmentation ). For example, a composition comprising a CBP/β-catenin) antagonist is provided.

According to certain aspects, treatment of hair loss; For example, promoting hair growth and/or regeneration, and/or preventing or delaying hair loss ( and loss of hair pigmentation ) at the expense of symmetric division in the relevant stem cell population (e.g., vesicle stem cells). Administering (e.g., topically or otherwise administering) to a subject in need thereof an amount of a CBP/catenin (e.g., CBP/β-catenin) antagonist sufficient to increase the number of symmetric regenerative cleavage, wherein A method of treatment of hair loss (eg, prevention of hair loss and/or promotion of hair growth; eg in aging subjects) ( and loss of hair pigmentation ) is obtained.

The skin is the largest organ in the body. It protects the animal from pathogens and damage from the external environment. It contains nerve endings that respond to hot and cold, tactile and pressure, and various environmental changes. It regulates body temperature and helps control body fluids; It is an important reservoir for lipids and water; It is also important for the synthesis of molecules such as vitamin D. In addition to all the physiological functions mentioned above, skin and hair are important for self-image and self-esteem.

Hair cycle. As briefly reviewed in Thompson & Sisk (Cell Cycle 5:17, 1913-1917, 2006; the full text is incorporated by reference), the hair cycle is the period of vesicle growth (growth phase) followed by degeneration. It is divided into periods of (degenerative phase) and resting (resting phase) During the regression phase, the lower half of the vesicle is completely destroyed by apoptosis After the resting phase, hair vesicle growth resumes, where vesicle stem cells are induced to proliferate. This is because its progeny migrate and differentiate into cell types, including hair follicles.The bulge activation hypothesis, the most widely accepted model for hair vesicle regeneration, suggests that the degeneration of the lower part of the vesicle is in the middle of the dermal papilla (DP). It is specified to move the mesenchymal cells to the side of the stem cell niche (protrusion), so that a diffuse signal from DP reaches the resting stem cells, including Sonic hedgehog, Wnt and TGF-β family members. Several signaling pathways are involved in vesicle regeneration.

Wnt signaling. Wnt signaling, as is well known in the art, is associated with the hair vesicle cycle (possibly through a stem cell mediated process). The hairless (Hr, formerly hr) gene mutation is particularly useful for analyzing the hair cycle, and in these mice, the initial hair growth is normal, but once the hair falls out and the vesicles degenerate, the vesicles fail to regenerate and the hair loss is permanent. This will be. Thomson & Sisque (above) found that hairless protein (HR) (nuclear receptor co-inhibitor) regulates the expression of genes that control Wnt signaling during the hair cycle, and HR in particular regulates the expression of Wise, an inhibitor of Wnt signaling. It is summarized as supporting a model in which HR regulates moderate vesicle regeneration by facilitating Wnt signaling, possibly playing a role in controlling the timing of Wnt signaling required for the hair cycle. Consistent with this model, Beaudoin et al. (PNAS 102:14653-14658, 2005; the full text is incorporated by reference) showed that the transgenic expression of HR in precursor keratinocytes was observed in Hr ^-/- mice. HR in a model that rescues vesicle regeneration, and Wise expression is inhibited by HR in these cells (consistent with vesicle regeneration timing), whereby HR regulates the precise timing of Wnt signaling required for hair vesicle regeneration. And Wnt function linkage. Additionally, Lyubimova et al. (The Journal of Clinical Investigation 120:446-456, 2010; the full text is incorporated by reference) indicates that N-WASP deficiency in mouse skin causes severe hair loss. , Additionally showing a link between N-WASP and Wnt signaling, suggesting that N-WASP acts as a positive modulator of β-catenin-dependent transcription that regulates the differentiation of hair vesicle precursor cells.

The exact mechanism is not known. However, the exact mechanism by which hair growth is resumed is not fully understood and seems to involve the integration of multiple signaling pathways. For example, Botchkareva et al. (Journal of Investigative Dermatology doi:10.1038/sj.jid.5700537, 2006); Survivin is incorporated by reference in its entirety in the hair matrix and external roots of human growing hair vesicles. It is expressed during proliferation of early keratinocytes, and its expression decreases as the degenerative phase progresses, and the expression of survivin in the growing hair vesicle can be controlled by Wnt/β-catenin signaling, Provides evidence that dual functions (promoting proliferation and preventing apoptosis) may be involved in the control of the sophisticated proliferation-apoptotic balance that controls HF cycle behavior. Botscareva et al. showed that in an in vitro microdissected hair vesicle model, the β-catenin antagonist ICG-001 reduced survivin expression and also significantly reduced hair fiber elongation in a dose-dependent manner.

Therefore, as understood in the art, Wnt/β-catenin signaling appears to be required for hair growth and hair vesicle regeneration, and inhibition of Wnt/β-catenin signaling is believed to inhibit hair growth and hair vesicle regeneration. appear.

Surprisingly, certain aspects of the invention include administering to a subject in need an amount of a CBP/catenin (e.g., CBP/β-catenin) antagonist sufficient to stimulate hair growth and/or regeneration, and/or prevent hair loss. It provides a method for stimulating hair growth and/or regeneration, including, and/or preventing hair loss. In certain embodiments, the CBP/β-catenin antagonist is present in an amount sufficient to modulate or increase the expression of adenosine receptors in dermal cells (eg, dermal papillary cells). In certain aspects, the adenosine receptor is one or more selected from A1, A2A and A2B (eg, A1 and/or A2).

In certain embodiments of the method, the CBP/catenin (eg, CBP/β-catenin) antagonist is present in an amount sufficient to modulate or increase the expression of sulfonylurea receptor 2B in dermal papillary cells.

In certain embodiments of the above methods, the CBP/catenin (eg, CBP/β-catenin) antagonist is one or more included in Table 1 or alternatively selected from the group of compounds disclosed herein. In certain aspects, the CBP/catenin (eg, CBP/β-catenin) antagonist is one or more included in Table 1 or otherwise selected from the group of compounds disclosed herein. In certain embodiments, the CBP/catenin (eg, CBP/β-catenin) antagonist comprises active alkyl and/or fatty acid ester derivatives thereof. In certain embodiments, the CBP/catenin (eg, CBP/β-catenin) antagonist comprises ICG-001, or an active alkyl and/or fatty acid ester derivative thereof.

In certain aspects of the method, administration of a CBP/catenin (eg, CBP/β-catenin) antagonist comprises topical administration.

Certain aspects of the method include co-administration of one or more other hair growth stimulants or hair loss inhibitors, or adjuvant treatment using the same. In certain embodiments, the one or more other hair growth stimulants are selected from the group consisting of anti-androgen receptor blockers including minoxidil, finasteride, dutasteride, bimatoprost, and fluridil.

Certain embodiments of the method include co-administration of one or more anti-inflammatory agents or adjuvant treatment using the same. In certain embodiments, one or more anti-inflammatory agent is a short-acting β ₂ - agonists, persistence, β ₂ - agonists, anticholinergics, corticosteroids, systemic corticosteroids, mast cell stabilizers, leukotriene modifiers, methyl xanthine, β ₂ - agonists, Albuterol, levalbuterol, pirbuterol, arformoterol, formoterol, salmeterol, anticholinergic agents such as ipatropium and tiotropium; Corticosteroids such as beclomethasone, budesonide, flunisolide, fluticasone, mometasone, triamcinolone, methylprednisolone, prednisolone, prednisone; Leukotriene modifiers such as montelukast, zapyrleukast and zileuton; Mast cell stabilizers such as cromoline and nedocromil; Methylxanthine such as theophylline; Combination drugs such as ipatropium and albuterol, fluticasone and salmeterol, glucocorticoid steroids, budesonide and formoterol; Antihistamines such as hydroxyzine, diphenhydramine, loratadine, cetirizine and hydrocortisone; Immune system modulating drugs such as tacrolimus and pimecrolimus; Cyclosporine; Azathioprine; Mycophenolate mofetil; And it is selected from the group consisting of a combination thereof.

A further aspect comprises administering to a subject in need an amount of a CBP/catenin (e.g., CBP/β-catenin) antagonist sufficient to increase the expression of adenosine receptors in dermal cells (e.g., dermal papillary cells). A method of increasing the expression of adenosine receptors in dermal cells (eg, dermal papillary cells) comprising. In certain aspects, the adenosine receptor is one or more selected from A1, A2A and A2B. In certain embodiments, the CBP/β-catenin antagonist is present in an amount sufficient to modulate or increase the expression of sulfonylurea receptor 2B in dermal papillary cells.

According to certain aspects, CBP/catenin (e.g., CBP/β), which increases p300/catenin transcription, thereby promoting skin/hair-vesicle stem cell differentiation (e.g., stimulating asymmetric versus symmetric stem cell division). -Catenin) antagonists, essentially Wnt/catenin modulators/modulators, have a wide range of such as accelerating skin healing, delaying skin aging, and surprisingly promoting hair growth and/or regeneration, and/or preventing hair loss or loss of pigmentation. It has a beneficial effect.

According to certain aspects, the CBP/catenin (e.g., CBP/β-catenin) antagonist is by modulating human endogenous stem cell and periphery cell functions (e.g., increasing skin recovery and/or stimulating hair growth. ) Function and is particularly safe at effective dosage levels (an important consideration as many skin/hair conditions may require long-term administration).

In fact, the currently disclosed stimulation of hair growth and/or regeneration is surprising, the demands known in the art for Wnt signaling (β-catenin mediated signaling) for hair vesicle cycles and hair growth as outlined herein above. This is because CBP/β-catenin antagonists (associated with "modulation" of hair growth) will in fact modulate hair growth by inhibiting hair growth by inhibiting the hair vesicle cycle and hair growth. Thus, the method of stimulation of hair growth and/or regeneration (and/or prevention of loss of pigmentation) claimed herein is unexpectedly contrary to the prevalent known dogma.

Applicants unexpectedly discovered the activity claimed herein in the course of treatment of a leukemia mouse model with a CBP/catenin (e.g., CBP/β-catenin) antagonist (ICG-001) (see Working Example 1 below), wherein It was observed that in animals taking ICG-001 within 2 weeks of shaving the mouse (for insertion of a minipump) his hair regrown, whereas the control group did not (due to irradiation and chemotherapy). Became. This allowed Applicants to consider additional possible actions of CBP/catenin (eg, CBP/β-catenin) antagonists in relation to hair growth.

In particular, as disclosed in Working Example 4 herein, Applicants believe that treatment of cells in culture with a CBP/catenin antagonist (e.g., ICG-001) is an adenosine receptor (e.g., colon epithelial adenosine receptor A2B ( ADORA2B)), a gene expression array experiment was performed to demonstrate that it significantly increases (~10X) the expression.

Additionally, Applicants argue that significant inhibition in the increase of intracellular calcium levels by minoxidil or adenosine is not by the adenosine A1 receptor, but by 3,7-dimethyl-1-propargyl-xanthine, an antagonist against the adenosine A2 receptor. It was recognized that it was observed as a result of pre-treatment with 8-cyclopentyl-1,3-dipropylxanthine, an antagonist against the disease (see Li et al., Journal of Investigative Dermatology 117:1594-1600, 2001; full text). Incorporated herein by reference). However, in addition, Li et al. (supra) show that in dermal papillary cells (DPC), adenosine-mediated increase in intracellular Ca (mostly related to A1), and adenosine-mediated VEGF production (both A1 and A2). Related) both indicate that they are important for minoxidil-induced hair growth. Therefore, DPC has a number of adenosine-dependent pathways, and in this regard, Applicants determined that upregulated A2 was reasonably predicted to aid hair growth. Accordingly, Applicants have contemplated that, without being bound by the mechanism, CBP/catenin (e.g., CBP/β-catenin) antagonists can stimulate hair growth, for example by modulating adenosine receptor expression in DPC. Additionally, Applicants have determined that VEGF is also a Wnt regulated target and is known to Applicants as being increased by CBP/catenin (eg, CBP/β-catenin) antagonists.

According to certain aspects, the CBP/β-catenin antagonist having utility in the prevention or alleviation of hair growth and/or regeneration, and/or hair loss is a CBP/catenin antagonist described and disclosed in the patents and patent applications of Table 1 herein below. to be.

Stimulation of hair growth; Combination therapy

As discussed above, the activity of minoxidil, an active ingredient in Rogaine, is mediated through adenosine receptors in dermal papillary cells. Several adenosine receptors are expressed in dermal papillary cells (A1, A2A and A2B; Li M., et al., J. Invest. Dermatol. 117, 1594-1600, 2001).

In gene expression array experiments, Applicants concluded that treatment of cells in culture with a CBP/catenin (e.g., CBP/β-catenin) antagonist (e.g., ICG-001), e.g. colon epithelial adenosine receptor A2B (ADORA2B) ), it was demonstrated herein that the expression of the adenosine receptor was significantly increased (~10X).

Thus, according to certain embodiments, administering a CBP/catenin (e.g., CBP/β-catenin) antagonist together with another hair irritant (e.g., minoxidil) increases the expression of the adenosine receptor, e.g. To treat the scalp locally, for example with a CBP/catenin (e.g., CBP/β-catenin) antagonist and/or modulate the sulfonylurea receptor 2B, which is believed to be a molecular target for minoxidil to act on. It provides a strong additive or synergistic effect in hair growth and/or regeneration.

Treatment method

In general, for the purposes of this application, the term “treating” means and includes reversing, alleviating, inhibiting or preventing progression of a disease, disorder or condition, or one or more symptoms thereof; “Treatment” and “therapeutic” refer to the act of treatment as defined herein.

A “therapeutically effective amount” is any amount of any compound used in the practice of the invention provided herein sufficient to reverse, alleviate, inhibit or prevent progression of a disease, disorder or condition, or one or more symptoms thereof.

Cosmetic and/or therapeutic use, and administration

In certain exemplary embodiments, a CBP/catenin (e.g., CBP/β-catenin) antagonist of the invention, alone or in combination with another cosmetic and/or therapeutic agent, functions as a cosmetic and/or therapeutic composition, This can be done to stimulate hair growth and/or regeneration and/or to prevent hair loss. The composition of the present invention includes a composition that can be administered to a subject in need. As used herein, “subject” can mean any living organism, preferably an animal, more preferably a mammal, and even more preferably a human.

In certain embodiments, the composition formulation may also include one or more additional agents selected from the group consisting of carriers, adjuvants, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfumes, and binders.

In general, as used herein, “pharmaceutically acceptable carrier” and “carrier” generally refer to any form of non-toxic inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation aid (e.g., Creams and lotions, emulsions, jellies, and depot preparations). Some non-limiting examples of substances that can function as pharmaceutically acceptable carriers include sugars such as lactose, glucose and sucrose; Starch, such as corn starch and potato starch; Cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; Tragacanth powder; malt; gelatin; Talc; Excipients such as cocoa butter and suppository wax; Oils such as peanut oil, cottonseed oil; Safflower oil; Sesame oil; Olive oil; Corn oil and soybean oil; Glycol; For example propylene glycol; Esters such as ethyl oleate and ethyl laurate; Agar; Buffering agents such as magnesium hydroxide and aluminum hydroxide; Alginic acid; No-heat source number; Isotonic saline; Ringer's solution; Ethyl alcohol, and phosphate buffered solutions, and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, and also colorants, release agents, coatings, sweeteners, flavoring and flavoring agents, preservatives and antioxidants. It may be present in the composition according to the judgment of the formulator.

Pharmaceutically acceptable carriers described herein, such as vehicles, adjuvants, excipients or diluents, are well known to those of skill in the art. Typically, pharmaceutically acceptable carriers are chemically inert to the therapeutic agent and have no adverse side effects or toxicity under the conditions of use. Pharmaceutically acceptable carriers may include polymers or polymer matrices, nanoparticles, microbubbles, and the like.

In addition to the therapeutic CBP/catenin (e.g., CBP/β-catenin) antagonists of the present invention, the therapeutic composition may contain inert diluents such as additional solvents, solubilizing agents and emulsifying agents such as ethyl alcohol, isopropyl alcohol, ethyl carbo Nate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oil (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame seeds Oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.

Route of administration

The most suitable means of administration for a particular subject will depend on the nature or severity of the disease or condition being treated, or the nature of the therapy used, and also the nature of the therapeutic composition or additional therapeutic agent. In certain embodiments, oral or topical administration is preferred.

Preferably, topical administration is used. In certain aspects, subcutaneous administration, systemic, intravenous (IV) or oral, and the like are used.

Formulations suitable for oral administration include separate units, such as tablets, capsules, cachets, syrups, elixirs, chewing gums, "lollipop" formulations, each containing a pre-measured amount of the active compound, Microemulsions, solutions, suspensions, lozenges or gel-coated ampoules; Powder or granule; Solutions or suspensions in aqueous or non-aqueous liquids; Or as an oil-in-water or water-in-oil emulsion.

As shown in the examples herein, a CBP/catenin (eg, CBP/β-catenin) antagonist was tested in a mouse model and demonstrated the promotion of skin healing and hair growth after accelerated injury.

III. Treatment of skin-related diseases or conditions, including cosmetic purposes

Certain aspects of the invention provide a composition comprising a CBP/beta-catenin antagonist for use in the treatment of skin related diseases or conditions (eg, in aging subjects), including cosmetic purposes. Skin-related disorders include wounds, acne, sun damage, certain skin disorders (there is currently no cure for this; e.g., latent viral infections of epidermal or mucosal tissues (e.g. HSV, HPV)), ulcers (e.g. , Diabetic), burns, atopic dermatitis, any disorders occurring in the skin structure, including but not limited to psoriasis, and aging effects (e.g., wrinkles, hyperpigmentation, dryness, redness, cracks, rosacea, firmness, elasticity, Thickness, appearance). Cosmetic applications include improving and preventing functions that occur in both skin and hair structure. Adjuvant and combination therapy embodiments are included.

According to certain aspects, the treatment of a skin-related disease or condition is a sufficient amount of CBP/catenin (e.g. For example, a CBP/β-catenin) antagonist is administered to a subject in need (eg, topically or otherwise administered), wherein a method of treating a skin related disease or condition is obtained.

The skin is the largest organ in the body. It protects the animal from pathogens and damage from the external environment. It contains nerve endings that respond to hot and cold, tactile and pressure, and various environmental changes. It regulates body temperature and helps control body fluids; It is an important reservoir for lipids and water; It is also important for the synthesis of molecules such as vitamin D. In addition to all the physiological functions mentioned above, skin and hair are important for self-image and self-esteem.

Skin care (including wounds, ulcers and burns management, and treatment of acne, atopic dermatitis, psoriasis, hair loss, and aging effects) is required for the improvement of the external epidermis, and also the health and appearance of the underlying dermis and other tissues. . Injury induced (e.g., amputation, abrasion (one of the treatments such as injury, or laser mediated dermabrasion), blisters, etc.) or surgical induction (e.g., surgical incision, colostomy, etc.) It requires topical treatment to improve the area and prevent further dermal damage.

Currently, most drugs for wounds, ulcers, burns and skin disorders focus on relief of symptoms; Some of these target the cause of the problem and thus do not accelerate the healing process that requires the initial asymmetric division of skin stem cells. A similar situation exists for both skin improvement and hair growth. Accordingly, there is a need for novel therapeutic methods and compositions for skin care and healing of wounds, ulcers, burns and skin diseases.

As discussed herein, CBP/catenin (e.g., CBP/β-catenin) antagonists can be used to promote skin stem cell differentiation and exhibit a wide range of beneficial effects, such as acceleration of skin healing and delay of skin aging. have.

CBP/catenin (eg, CBP/β-catenin) antagonists function by regulation of human endogenous stem cell and/or peripheral cell function. Based on animal toxicity studies and as recognized in the art, these compounds are very safe at effective dosage levels. Since many skin/hair conditions may require long-term administration, a large margin of safety will be very beneficial for both the physician and the patient. According to certain aspects, the CBP/catenin (e.g., CBP/β-catenin) antagonist has no cure for certain skin diseases, ulcers (diabetes), including but not limited to latent viral infections (e.g., HSV, HPV). Sex, etc.), burns, atopic dermatitis, psoriasis, actinic keratosis, and hair loss.

Certain aspects are skin conditions or diseases comprising administering to a subject in need an amount of a CBP/catenin (e.g., CBP/β-catenin) antagonist sufficient to treat a skin condition or disease, or one or more symptoms thereof, Or a method of treating one or more symptoms thereof. In certain aspects, the skin condition or disease is wound, scarring, acne, sun damage, treatment of latent viral infections (e.g., HSV, HPV), ulcers including diabetic ulcers, burns, atopic dermatitis, psoriasis, and wrinkles. , Hyperpigmentation, redness, rosacea, dryness, cracking, loss of firmness, loss of elasticity, skin thinning, and treatment of one or more conditions or diseases selected from the group consisting of aging effects including loss of vitality.

In certain embodiments of the above methods, the CBP/catenin (eg, CBP/β-catenin) antagonist is one or more selected from the group of compounds and salts thereof included in Table 1 or otherwise disclosed herein. In certain aspects, CBP/β-catenin antagonists include alkyl and/or fatty acid ester derivatives thereof as disclosed herein. In certain embodiments, the CBP/β-catenin antagonist comprises ICG-001 disclosed herein, or an active alkyl and/or fatty acid ester derivative thereof.

Preferably, administration of a CBP/catenin (eg, CBP/β-catenin) antagonist comprises topical administration.

Certain aspects of the method include co-administration of one or more other therapeutic agents or adjuvant treatment using the same (eg, joint or adjuvant treatment of a subject with an anti-inflammatory agent). In certain aspects, anti-inflammatory agents include steroids or glucocorticoid steroids. In certain embodiments, one or more anti-inflammatory agent is a short-acting β ₂ - agonists, persistence, β ₂ - agonists, anticholinergics, corticosteroids, systemic corticosteroids, mast cell stabilizers, leukotriene modifiers, methyl xanthine, β ₂ - agonists, Albuterol, levalbuterol, pirbuterol, arformoterol, formoterol, salmeterol, anticholinergic agents such as ipatropium and tiotropium; Corticosteroids such as beclomethasone, budesonide, flunisolide, fluticasone, mometasone, triamcinolone, methylprednisolone, prednisolone, prednisone; Leukotriene modifiers such as montelukast, zapyrleukast and zileuton; Mast cell stabilizers such as cromoline and nedocromil; Methylxanthine such as theophylline; Combination drugs such as ipatropium and albuterol, fluticasone and salmeterol, glucocorticoid steroids, budesonide and formoterol; Antihistamines such as hydroxyzine, diphenhydramine, loratadine, cetirizine and hydrocortisone; Immune system modulating drugs such as tacrolimus and pimecrolimus; Cyclosporine; Azathioprine; Mycophenolate mofetil; And it is selected from the group consisting of a combination thereof.

Antiviral (HSV) combinations may include nucleoside analogs (eg, acyclovir or HSV docosanol (active ingredient in Abreva)).

In certain aspects, the one additional therapeutic agent is selected from the group consisting of antimicrobial agents, antifungal agents and antibiotics. In certain embodiments, the one or more additional therapeutic agents are cyclosporine, hyaluronic acid, carmellose, macrogol(s), dextran and hyprolos, sodium and calcium, sodium and povidone, hypromellose, carbomer, amikacin , Gentamicin, kanamycin, neomycin, netilmycin, streptomycin, tobramycin, paromomycin, geldanamycin, herimycin, loracarbef, ertapenem, imipenem/silastatin, meropenem, cepadroxil, Cefazoline, Cephalotin/Cephalosin, Cephalexin, Cephachlor, Cephamandol, Cephoxytin, Cefuroxime, Cefixime, Cephdinir, Cephditorene, Celloperazone, Cellotaxim, Cephpodoxime, Ceph Tazidim, Ceftibuten, Ceftizoxim, Ceftriaxone, Cefepime, Teicoplanin, Vancomycin, Azithromycin, Clarithromycin, Dirithromycin, Erythromycin, Loxythromycin, Troleandomycin, Teli Tromycin, spectinomycin, aztreonam, amoxicillin, ampicillin, azlosillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, napsillin, penicillin, peperacillin, Ticarcillin, bacitracin, colistin, polymyxin B, ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, romefloxacin, moxifloxacin, norfloxacin, ofloxacin, trobafloxacin, mefenide , Protosyl, Sulfacetamide, Sulfamethizol, Sulfanilamide, Sulfasalazine, Sulfisoxazole, Trimethoprim, Trimethoprim-Sulfametoxazole, Demeclocycline, Doxycycline, Minocyclin, Oxy Tetracycline, Tetracycline, Arsphenamine, Chloramphenicol, Clindamycin, Lincoamicin, Ethambutol, Fosfomycin, Fusidic Acid, Furazolidone, Isoniazid, Linezolide, Metronidazole, Mupirosine, Nitrofurantoin, Pla Tenshimaisin, pyrazinamide, quinupristine/dalfopristine, rifampin/rifampicin, tinidazole, miconazole, ketoconazole, clotrimazole, econasol, biponazole, butoconazole, penticonazole, isoconazole, oxycona Sol, Sertaconazole, Sulconazole, Thioconazole, Fluconazole, Itraconazole, Isabuconazole, Rabuconazole, Posaconazole, voriconazole, Te Ronazole, Terbinapine, Amorolphine, Naphthypine, Butenapine, Anidulafungin, Caspofungin, Micafungin, Cyclopirox, Flucytosine, Griseofulvin, Gentian Violet, Haloprogine, Tolnaphate , Undecylenic acid, and combinations thereof.

Another further aspect is a skin condition, comprising administering to a subject in need an amount of a CBP/catenin (e.g., CBP/β-catenin) antagonist sufficient to cosmetically treat the skin condition or one or more symptoms thereof, or A method of cosmetic treatment of one or more symptoms thereof is provided. In certain aspects, the skin condition includes treatment of one or more conditions or diseases selected from the group consisting of wrinkles, hyperpigmentation, redness, rosacea, dryness, cracking, loss of firmness, loss of elasticity, skin thinning, and loss of vitality. In certain aspects, the CBP/catenin (eg, CBP/β-catenin) antagonist is one or more selected from the group of compounds and salts thereof included in Table 1 or otherwise disclosed herein. In certain embodiments, the CBP/catenin (eg, CBP/β-catenin) antagonist comprises an alkyl and/or fatty acid ester derivative thereof as disclosed herein. In certain aspects, CBP/catenin (eg, CBP/β-catenin) antagonists include ICG-001 as disclosed herein, or an active alkyl and/or fatty acid ester derivative thereof. Preferably, administration of a CBP/catenin (eg, CBP/β-catenin) antagonist comprises topical administration.

Certain aspects are compositions and methods for improving skin care (including wound, ulcer and burn management, and treatment of acne, atopic dermatitis, actinic keratosis, psoriasis, and aging effects), compositions and methods for treating skin disorders, and Compositions and methods for cosmetic use are provided, which are desired to improve the health and appearance of the outer epidermis and also the underlying dermis and other tissues. Skin-related disorders include wounds, acne, sun damage, certain skin disorders (which currently have no cure; for example viral infections (HSV, HPV)), ulcers (e.g. diabetic), burns, atopic dermatitis, psoriasis , And any disorder arising in the structure of the skin including, but not limited to, aging effects (eg, wrinkles, hyperpigmentation, dryness, redness, cracking, rosacea, firmness, elasticity, thickness, appearance).

As recognized in the art, Wnt signaling is required during wound healing. For example, Fatke et al. (BMC Cell Biology 7:4 doi 10.1186/1471-2121-7-4) show that Wnt signaling induces epithelial differentiation during cutaneous wound healing. Similarly, Gudjonsson et al. (The Journal of Investigative Dermatology 130:1849-1859, 2010), for example, show that standard Wnt signaling is reduced in psoriatic skin lesions.

According to certain aspects, CBP/catenin (e.g., CBP/β-catenin) antagonists promote skin/hair-vesicle stem cell differentiation, thereby providing a wide range of beneficial effects, such as accelerating skin healing and delaying skin aging. .

According to certain aspects, CBP/catenin (e.g., CBP/β-catenin) antagonists function by regulation of human endogenous stem cell and/or peripheral cell function and are very safe at effective dose levels (many skin/hair This is an important consideration as the condition may require long-term administration).

Applicants unexpectedly discovered the activity claimed herein in the course of treatment of a leukemia mouse model with a CBP/catenin (e.g., CBP/β-catenin) antagonist (ICG-001) (see Working Example 1 below), wherein It was observed that within 2 weeks of shaving the mice and inserting the mini pump, the wounds of the animals taking ICG-001 were substantially improved, but the control group did not. This allowed Applicants to consider the additional possible actions of CBP/catenin (eg, CBP/β-catenin) antagonists with regard to wound management.

According to certain aspects, CBP/catenin (e.g., CBP/β-catenin) antagonists having utility in the treatment and cosmetic use of skin disorders as disclosed herein are described and disclosed in the patents and patent applications in Table 1 below. /It is a catenin antagonist.

Certain aspects provide formulations for topical application of CBP/catenin (eg, CBP/β-catenin) antagonists, such as the compounds of Table 1.

Treatment method

The term "treating" means and includes the reversal, alleviation, inhibition or prevention of progression of a disease, disorder or condition, or one or more symptoms thereof; “Treatment” and “therapeutic” refer to the act of treatment as defined herein.

A “therapeutically effective amount” is any amount of any compound used in the practice of the invention provided herein sufficient to reverse, alleviate, inhibit or prevent progression of a disease, disorder or condition, or one or more symptoms thereof.

Cosmetic and/or therapeutic use, and administration

In certain exemplary embodiments, the CBP/β-catenin antagonist of the invention, alone or in combination with another cosmetic and/or therapeutic agent, functions as a cosmetic and/or therapeutic composition, such that the therapeutic composition is one of a wound-related disease or condition. It can prevent or alleviate the above symptoms or increase adequate wound healing. The therapeutic composition of the present invention includes a composition that can be administered to a subject in need. As used herein, “subject” can mean any living organism, preferably an animal, more preferably a mammal, even more preferably a human.

In certain embodiments, the composition formulation may also include one or more additional agents selected from the group consisting of carriers, adjuvants, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfumes, and binders.

“Pharmaceutically acceptable carrier” and “carrier” as used herein generally refer to any type of non-toxic inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation aid (e.g., cream and Lotion, emulsion, jelly, depot preparation). Some non-limiting examples of substances that can function as pharmaceutically acceptable carriers include sugars such as lactose, glucose and sucrose; Starch, such as corn starch and potato starch; Cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; Tragacanth powder; malt; gelatin; Talc; Excipients such as cocoa butter and suppository wax; Oils such as peanut oil, cottonseed oil; Safflower oil; Sesame oil; Olive oil; Corn oil and soybean oil; Glycol; For example propylene glycol; Esters such as ethyl oleate and ethyl laurate; Agar; Buffering agents such as magnesium hydroxide and aluminum hydroxide; Alginic acid; No-heat source number; Isotonic saline; Ringer's solution; Ethyl alcohol, and phosphate buffered solutions, and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, and also colorants, release agents, coatings, sweeteners, flavoring and flavoring agents, preservatives and antioxidants. It can be included in the composition according to the judgment of the formulator.

Pharmaceutically acceptable carriers described herein, such as vehicles, adjuvants, excipients or diluents, are well known to those of skill in the art. Typically, pharmaceutically acceptable carriers are chemically inert to the therapeutic agent and have no adverse side effects or toxicity under the conditions of use. Pharmaceutically acceptable carriers may include polymers and polymer matrices, nanoparticles, microbubbles, and the like.

In addition to the therapeutic CBP/catenin (e.g., CBP/β-catenin) antagonists of the present invention, the therapeutic composition may contain inert diluents such as additional solvents, solubilizing agents and emulsifying agents such as ethyl alcohol, isopropyl alcohol, ethyl carbo Nate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oil (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame seeds Oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.

Route of administration

The most suitable means of administration for a particular subject will depend on the nature or severity of the disease or condition being treated, or the nature of the therapy used, and also the nature of the therapeutic composition or additional therapeutic agent. In certain embodiments, oral or topical administration is preferred.

Preferably, topical administration is used.

Formulations suitable for oral administration include separate units, such as tablets, capsules, cachets, syrups, elixirs, chewing gums, "lollipop" formulations, microemulsions, solutions, each containing a pre-measured amount of the active compound, Suspensions, lozenges, or gel-coated ampoules; Powder or granule; Solutions or suspensions in aqueous or non-aqueous liquids; Or as an oil-in-water or water-in-oil emulsion.

As shown in the examples herein, a CBP/catenin (eg, CBP/β-catenin) antagonist was tested in a mouse model and demonstrated the promotion of skin healing and hair growth after accelerated injury.

IV. Exemplary CBP/catenin (e.g., CBP/β-catenin) antagonists having utility in the methods disclosed herein

In certain embodiments of the methods described herein (treatment of aging, aging-related conditions or diseases, prevention of hair growth or hair loss, and treatment of skin conditions), CBP/catenin (e.g., CBP/β-catenin ) The antagonist is one or more selected from the group of compounds and salts thereof included in Table 1 or alternatively disclosed herein. In certain aspects, CBP/catenin (eg, CBP/β-catenin) antagonists include alkyl and/or fatty acid ester derivatives thereof as disclosed herein. In certain embodiments, the CBP/catenin (eg, CBP/β-catenin) antagonist comprises ICG-001 as disclosed herein, or an active alkyl and/or fatty acid ester derivative thereof.

Preferably, administration of a CBP/catenin (eg, CBP/β-catenin) antagonist includes administration such as topical and/or oral and/or IV and/or intramuscularly.

Certain aspects of the method include co-administration of one or more other therapeutic agents or adjuvant treatment using the same (eg, joint or adjuvant treatment of a subject with an anti-inflammatory agent). In certain aspects, anti-inflammatory agents include steroids or glucocorticoid steroids. In certain embodiments, one or more anti-inflammatory agent is a short-acting β ₂ - agonists, persistence, β ₂ - agonists, anticholinergics, corticosteroids, systemic corticosteroids, mast cell stabilizers, leukotriene modifiers, methyl xanthine, β ₂ - agonists, Albuterol, levalbuterol, pirbuterol, arformoterol, formoterol, salmeterol, anticholinergic agents such as ipatropium and tiotropium; Corticosteroids such as beclomethasone, budesonide, flunisolide, fluticasone, mometasone, triamcinolone, methylprednisolone, prednisolone, prednisone; Leukotriene modifiers such as montelukast, zapyrleukast and zileuton; Mast cell stabilizers such as cromoline and nedocromil; Methylxanthine such as theophylline; Combination drugs such as ipatropium and albuterol, fluticasone and salmeterol, glucocorticoid steroids, budesonide and formoterol; Antihistamines such as hydroxyzine, diphenhydramine, loratadine, cetirizine and hydrocortisone; Immune system modulating drugs such as tacrolimus and pimecrolimus; Cyclosporine; Azathioprine; Mycophenolate mofetil; And it is selected from the group consisting of a combination thereof.

In certain aspects, the one additional therapeutic agent is selected from the group consisting of antimicrobial agents, antifungal agents and antibiotics. In certain embodiments, the one or more additional therapeutic agents are cyclosporine, hyaluronic acid, carmellose, macrogol(s), dextran and hyprolos, sodium and calcium, sodium and povidone, hypromellose, carbomer, amikacin , Gentamicin, kanamycin, neomycin, netilmycin, streptomycin, tobramycin, paromomycin, geldanamycin, herimycin, loracarbef, ertapenem, imipenem/silastatin, meropenem, cepadroxil, Cefazoline, Cephalotin/Cephalosin, Cephalexin, Cephachlor, Cephamandol, Cephoxytin, Cefuroxime, Cefixime, Cephdinir, Cephditorene, Celloperazone, Cellotaxim, Cephpodoxime, Ceph Tazidim, Ceftibuten, Ceftizoxim, Ceftriaxone, Cefepime, Teicoplanin, Vancomycin, Azithromycin, Clarithromycin, Dirithromycin, Erythromycin, Loxythromycin, Troleandomycin, Teli Tromycin, spectinomycin, aztreonam, amoxicillin, ampicillin, azlosillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, napsillin, penicillin, peperacillin, Ticarcillin, bacitracin, colistin, polymyxin B, ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, romefloxacin, moxifloxacin, norfloxacin, ofloxacin, trobafloxacin, mefenide , Protosyl, Sulfacetamide, Sulfamethizol, Sulfanilamide, Sulfasalazine, Sulfisoxazole, Trimethoprim, Trimethoprim-Sulfametoxazole, Demeclocycline, Doxycycline, Minocyclin, Oxy Tetracycline, Tetracycline, Arsphenamine, Chloramphenicol, Clindamycin, Lincoamicin, Ethambutol, Fosfomycin, Fusidic Acid, Furazolidone, Isoniazid, Linezolide, Metronidazole, Mupirosine, Nitrofurantoin, Pla Tenshimaisin, pyrazinamide, quinupristine/dalfopristine, rifampin/rifampicin, tinidazole, miconazole, ketoconazole, clotrimazole, econasol, biponazole, butoconazole, penticonazole, isoconazole, oxycona Sol, Sertaconazole, Sulconazole, Thioconazole, Fluconazole, Itraconazole, Isabuconazole, Rabuconazole, Posaconazole, voriconazole, Te Ronazole, Terbinapine, Amorolphine, Naphthypine, Butenapine, Anidulafungin, Caspofungin, Micafungin, Cyclopirox, Flucytosine, Griseofulvin, Gentian Violet, Haloprogine, Tolnaphate , Undecylenic acid, and combinations thereof.

Another further aspect is a skin condition, comprising administering to a subject in need an amount of a CBP/catenin (e.g., CBP/β-catenin) antagonist sufficient to cosmetically treat the skin condition or one or more symptoms thereof, or A method of cosmetic treatment of one or more symptoms thereof is provided. In certain aspects, the skin condition includes treatment of one or more conditions or diseases selected from the group consisting of wrinkles, hyperpigmentation, redness, rosacea, dryness, cracking, loss of firmness, loss of elasticity, skin thinning, and loss of vitality. In certain aspects, the CBP/catenin (eg, CBP/β-catenin) antagonist is one or more selected from the group of compounds and salts thereof included in Table 1 or otherwise disclosed herein. In certain embodiments, the CBP/catenin (eg, CBP/β-catenin) antagonist comprises an alkyl and/or fatty acid ester derivative thereof as disclosed herein. In certain aspects, CBP/catenin (eg, CBP/β-catenin) antagonists include ICG-001 as disclosed herein, or an active alkyl and/or fatty acid ester derivative thereof. Preferably, administration of a CBP/catenin (eg, CBP/β-catenin) antagonist comprises topical administration.

Certain aspects provide compositions and methods for treating aging.

Certain aspects provide compositions and methods for treating aging effects (eg, wrinkles, hyperpigmentation, dryness, redness, cracks, rosacea, firmness, elasticity, thickness, appearance).

As recognized in the art, Wnt signaling is required during wound healing. For example, Patke et al. (BMC Cell Biology 7:4 doi 10.1186/1471-2121-7-4) show that Wnt signaling induces epithelial differentiation during cutaneous wound healing. Similarly, Gudjonson et al (The Journal of Investigative Dermatology 130:1849-1859, 2010), for example, show that standard Wnt signaling is reduced in psoriatic skin lesions.

According to certain aspects, CBP/catenin (e.g., CBP/β-catenin) antagonists promote skin/hair-vesicle stem cell differentiation, thereby preventing a wide range of beneficial effects, such as acceleration of skin healing, delay of skin aging. to provide.

According to certain aspects, the CBP/catenin (e.g., CBP/β-catenin) antagonist functions by modulating human endogenous stem cell and/or peripheral cell function (e.g., enhancing the recovery of the skin). It is very safe at the effective dose level (this is an important consideration as many skin/hair conditions may require long-term administration).

Applicants unexpectedly discovered the activity claimed herein in the course of treatment of a leukemia mouse model with a CBP/catenin (e.g., CBP/β-catenin) antagonist (ICG-001) (see Working Example 1 below), wherein It was observed that the wounds of the animals taking ICG-001 within 2 weeks of shaving the mouse and inserting the minipump were substantially improved, but the control group did not. This allowed Applicants to consider the additional possible actions of CBP/catenin (eg, CBP/β-catenin) antagonists with regard to wound management.

According to certain aspects, the CBP/catenin (e.g., CBP/β-catenin) antagonist having utility in the treatment and cosmetic use of skin disorders is described and disclosed in the patents and patent applications in Table 1 below. For example, CBP/β-catenin) antagonists.

Certain aspects provide formulations for topical application of CBP/catenin (eg, CBP/β-catenin) antagonists, such as the compounds of Table 1.

<Table 1>

Of aging and related skin disorders, which have utility in the prevention or alleviation of hair growth and/or regeneration, and/or hair loss by stimulating adenosine receptor expression, and having utility in the treatment and cosmetic use of skin disorders as disclosed herein. Exemplary CBP/β-catenin antagonists having utility in therapeutic and cosmetic applications. All compound genus, species and conformational forms thereof, and their composites in the patent applications and patents in this table are all incorporated herein by reference as exemplary compounds having utility in the methods claimed herein.

Exemplary compound genus (continued)

US 2005/0250780 . All compound genera, species and conformational forms thereof of US 2005/0250780, including the exemplary compounds of Tables 2 to 6 of US 2005/0250780, the claimed compounds and each of the disclosed compounds are for use in the methods claimed herein by Applicants. As exemplary compounds, all are incorporated herein by reference.

Specific exemplary embodiments include a compound having Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof.

<Formula I>

In the above formula,

R1 is -X-R5, where X is -C(=O)-, -C(=O)O-, -C(=O)NH- or -SO2-, and R5 is an amino acid side chain residue or an amino acid side chain Is a derivative;

R2 is hydrogen or -Y-R6, where Y is a direct bond, -NH-, -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH- or -NHSO2- , R6 is an amino acid side chain residue or an amino acid side chain derivative;

R3 is -Z-R7, where Z is a direct bond, -(CH2)mC(=O)NR8-, -(CH2)kNHC(=O) or -(CH2)kNHC(=O)NR8-, and R7 And R8 is independently an amino acid side chain residue or an amino acid side chain derivative, m is an integer from 1 to 4, and k is 1 or 2;

R4 represents the remainder of the compound;

Wherein any two adjacent CH groups or adjacent NH and CH groups of the fused bicyclic compound optionally form a double bond.

In further specific exemplary embodiments, X is -C(C-0)0- and R2 is H, C1-C6 alkyl or C7-C11 arylalkyl; R3 is ---(CH ₂ ) _1-6 -N(R')(R"), wherein R'and R" are independently H or -C(NH)(NH2); R4 is C7-C11 arylalkyl; R5 is C7-C11 arylalkyl, wherein R4 and R5 are independently optionally substituted with 1 to 3 halogens, 1 to 3 C1-C3 haloalkyl, or 1 to 3 C1-C3 alkyl. Compound is included.

이며, 여기서 Rx는 H, OH 또는 할로이고; R4가 C7-C11 아릴알킬이고; R5가 C7-C11 아릴알킬이며, 여기서 R2, R4 및 R5는 독립적으로 1 내지 3개의 할로겐, 1 내지 3개의 C1-C3 할로알킬 또는 1 내지 3개의 C1-C3 알킬로 임의로 치환된 것인 화학식 I의 화합물이 포함된다.In further specific exemplary embodiments, in the compound, X is -C(CO)NH- and R2 is H, C1-C6 alkyl or C7-C11 arylalkyl; R3 is

Wherein Rx is H, OH or halo; R4 is C7-C11 arylalkyl; R5 is C7-C11 arylalkyl, wherein R2, R4 and R5 are independently optionally substituted with 1-3 halogens, 1-3 C1-C3 haloalkyl or 1-3 C1-C3 alkyl. Compounds of are included.

US 2007/0021431 . All compound genera, species and conformations of US 2007/0021431, including the exemplary compounds of Tables 1 to 5 of US 2007/0021431, the claimed compounds and each of the disclosed compounds, are examples for use in the methods claimed herein by the applicants. All of these compounds are incorporated herein by reference.

Specific exemplary embodiments include a compound having Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof.

<Formula I>

In the above formula, A is -(CHR3)- or -(C=O)-, B is -(CHR4)-, -(C=O)-, and D is -(CHR5)- or -(C=O )-, E is -(ZR6)-, -(C=O)-, and G is -(XR7)n-, -(CHR7)-(NR8)-, -(C=O)-(XR9) -Or -(C=O)-, W is -Y(C=O)-, -(C=O)NH-, -(SO2)- or absent, and Y is oxygen, sulfur or -NH- And X and Z are independently nitrogen or CH, and n is 0 or 1; R1, R2, R3, R4, R5, R6, R7, R8 and R9 are the same or different and are independently selected from amino acid side chain residues or derivatives thereof, the remainder of the molecule, linkers and solid supports, and stereoisomers thereof. (As defined in US 2007/0021431).

US 2007/0021425. All compound genera, species and conformations thereof of US 2007/0021425, including the exemplary compounds of Tables 1 to 5 of US 2007/0021425, the claimed compounds, and each of the disclosed compounds are used in the methods claimed herein by the applicant. As exemplary compounds for, all are incorporated herein by reference.

Specific exemplary embodiments include compounds having the structure of formula I

<Formula I>

In the above formula, A is -(CHR ₃ )- or -(C=O)-, B is -(CHR ₄ )- or -(C=O)-, and D is -(CHR ₅ )- or -( C=O)-, E is -(ZR ₆ )- or -(C=O)-, and G is -(XR ₇ ) _n -, -(CHR ₇ )-(NR ₈ )-, -(C =O)-(XR ₉ )- or -(C=O)-, W is -Y(C=O)-, -(C=O)NH-, -(S0 ₂ )- or absent, Y is oxygen, sulfur or -NH-, X and Z are independently nitrogen or CH, and n is 0 or 1; R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are the same or different, and amino acid side chain residues or derivatives thereof, the rest of the molecule, linkers and solid supports, and It is independently selected from their stereoisomers (as defined in US 2007/0021425).

A is -(CHR ₃ )-, B is -(C=O)-, D is -(CHR ₅ )-, E is -(C=O)-, and G is -(XR ₇ ) _n In an exemplary embodiment, the compound of the present invention has the formula II

<Formula II>

In the above formula, W, X, Y and n are as defined above, and R ₁ , R ₂ , R ₃ , R ₅ and R ₇ are as defined in US 2007/0021425.

A is -(C=O)-, B is -(CHR ₄ )-, D is -(C=O)-, E is -(ZR ₆ )-, and G is -(C=O) In an exemplary embodiment where -(XR ₉ )-, the compounds of the present invention have Formula III

<Formula III>

In the above formula, W, X and Y are as defined above, Z is nitrogen or CH (however, when Z is CH, X is nitrogen), R ₁ , R ₂ , R ₄ , R ₆ and R ₉ is as defined in US 2007/0021425.

A is -(C=O)-, B is -(CHR ₄ )-, D is -(C=O)-, E is -(ZR ₆ )-, and G is (XR ₇ ) _n- In an exemplary embodiment, the compounds of the present invention have Formula IV

<Formula IV>

In the above formula, W, Y and n are as defined above, Z is nitrogen or CH (when Z is nitrogen, n is 0, when Z is CH, X is nitrogen and n is not 0 ), R ₁ , R ₂ , R ₄ , R ₆ and R ₇ are as defined in US 2007/0021425.

In certain embodiments, the compounds of this invention have Formula VI

<Formula VI>

In the above formula, R _a is a phenyl group; Amino, amidino, guanidino, hydrazino, amidazonyl, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _{1 -3} a substituted phenyl group having at least one substituent independently selected from at least one of alkoxy, nitro, carboxy, cyano, sulfuryl and hydroxyl groups; Benzyl group; Amino, amidino, guanidino, hydrazino, amidazonyl, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-3 alkoxy, nitro, A substituted benzyl group having one or more substituents independently selected from one or more of carboxy, cyano, sulfuryl and hydroxyl groups; Or a bicyclic aryl group having 8 to 11 ring members which may have 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur; R _b is a monocyclic aryl group having 5 to 7 ring members which may have 1 to 2 heteroatoms selected from nitrogen, oxygen or sulfur, and the aryl ring in the compound is halide, hydroxy, cyano, May have one or more substituents selected from the group consisting of lower alkyl and lower alkoxy groups; R _c is a saturated or unsaturated C _1-6 alkyl, C _1-6 alkoxy, perfluoro C _1-6 alkyl group; X ₁ , X ₂ and X ₃ may be the same or different and may be independently selected from hydrogen, hydroxyl and halides.

In addition, the invention relates to prodrugs using libraries containing one or more compounds of formula (I). Typically, prodrugs are designed to release the active drug from the body during or after absorption by enzymatic and/or chemical hydrolysis. The prodrug method involves the oral bioavailability or i.v. of poorly water-soluble drugs by chemical derivatization with more water-soluble compounds. It is an effective means to improve administration. The most commonly used prodrug method for increasing the water solubility of a drug containing a hydroxyl group is to produce an ester containing an ionizable group such as a phosphate group, a carboxylate group, an alkylamino group (literature [Fleisher et al., Advanced Drug Delivery Reviews, 115-130, 1996]; [Davis et al., Cancer Res., 7247-7253, 2002], [Golik et al., Bioorg. Med. Chem. Lett., 1837-1842, 1996]).

In certain embodiments, prodrugs of the invention have Formula VII:

<Formula VII>

-YR ₁₀ (VI)

Wherein VI is formula VI as described above; Y is oxygen, sulfur or nitrogen of a group selected from R _a , R _b , R _c , X ₁ , X ₂ and X ₃ ;

R ₁₀ is phosphate, hemisuccinate, phosphoryloxymethyloxycarbonyl, dimethylaminoacetate, amino acid, or salts thereof; Here, the prodrug can act as a substrate for a phosphatase or carboxylase, thus converting to a compound having formula VI.

US 2010/0120758 . All compound genera, species and conformations of US 2010/0120758, including the exemplary compounds of Tables 1 to 5 of US 2010/0120758, the claimed compounds, and each of the disclosed compounds are examples for use in the methods claimed herein by Applicants. All of these compounds are incorporated herein by reference.

Specific exemplary embodiments include a compound having Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof.

<Formula I>

In the above formula, A is -(CHR3)- or -(C=O)-, B is -(CHR4)-, -(C=O)-, and D is -(CHR5)- or -(C=O )-, E is -(ZR6)-, -(C=O)-, and G is -(XR7)n-, -(CHR7)-(NR8)-, -(C=O)-(XR9) -Or -(C=O)-, W is -Y(C=O)-, -(C=O)NH-, -(SO2)- or absent, and Y is oxygen, sulfur or -NH- And X and Z are independently nitrogen or CH, and n is 0 or 1; R1, R2, R3, R4, R5, R6, R7, R8 and R9 are the same or different and are independently selected from amino acid side chain residues or derivatives thereof, the remainder of the molecule, linkers and solid supports, and stereoisomers thereof. (As defined in US 2010/0120758).

Specific exemplary embodiments include compounds of Formula VI below as isolated stereoisomers, or mixtures of stereoisomers, or as pharmaceutically acceptable salts.

<Formula VI>

In the above formula, Ra is a bicyclic aryl group having 8 to 11 ring members which may have 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur;

Rb is a monocyclic aryl group having 5 to 7 ring members which may have 1 to 2 heteroatoms selected from nitrogen, oxygen, or sulfur, and the aryl ring in the compound is halide, hydroxy, cyano, lower May have one or more substituents selected from the group consisting of alkyl and lower alkoxy groups;

Rc is a saturated or unsaturated C1-6 alkyl, C1-6 alkoxy, perfluoro C1-6 alkyl group;

X1, X2 and X3 are the same or different and may be independently selected from hydrogen, hydroxyl and halide.

US 2010/0240662 . All compound genera, species and conformational forms thereof of US 2010/0240662, including the exemplary compounds of Tables 1 to 5 of US 2010/0240662, the claimed compounds and each of the disclosed compounds are for use in the methods claimed herein by the applicant. As exemplary compounds, all are incorporated herein by reference.

Specific exemplary embodiments include a compound having Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof.

<Formula I>

In the above formula, A is -(CHR3)- or -(C=O)-, B is -(CHR4)-, -(C=O)-, and D is -(CHR5)- or -(C=O )-, E is -(ZR6)-, -(C=O)-, and G is -(XR7)n-, -(CHR7)-(NR8)-, -(C=O)-(XR9) -Or -(C=O)-, W is -Y(C=O)-, -(C=O)NH-, -(SO2)- or absent, and Y is oxygen, sulfur or -NH- And X and Z are independently nitrogen or CH, and n is 0 or 1; R1, R2, R3, R4, R5, R6, R7, R8 and R9 are the same or different and are independently selected from amino acid side chain residues or derivatives thereof, the remainder of the molecule, linkers and solid supports, and stereoisomers thereof. (As defined in US 2010/0240662).

A is -(CHR ₃ )- or -(C=O)-; B is -(CHR ₄ )- or -(C=O)-; D is -(CHR ₅ )- or -(C=O)-; E is -ZR ₆ -or -(C=O)-, wherein Z is CH or N; G is -XR ₇ -or -(C=O)-, where X is CH or N; W is -(C=O)NH-, -(C=O)S-, -S(O) ₂ -or absent; In an exemplary embodiment, wherein each of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are the same or different, and are independently amino acid side chain residues or amino acid side chain derivatives, the compounds of the invention are It has the formula IA.

<Formula IA>

Specific examples of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are as defined in US 2010/0240662.

WO 2007/139346 . All compound genera, species and conformations thereof of US 2010/0240662, including the exemplary compounds of Tables 1 to 2 of US 2010/0240662, the claimed compounds, and each of the disclosed compounds, are used in the methods claimed herein by the applicant. As exemplary compounds for, all are incorporated herein by reference.

Specific exemplary embodiments include compounds having Formula I

<Formula I>

In the above formula,

E is -(ZR ₄ )- or -(C=O)-; G is absent or -(XR ₅ )- or -(C=O)-; W is -Y(C=O)-, -(C=O)NH-, -(SO ₂ )- or absent; Y is oxygen or sulfur; X or Z is independently nitrogen or CH; R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are the same or different and are amino acid side chain residues; C _1-12 alkyl, or an amino, guanidino, C _1-4 alkyl, guanidino, di-C _1-4 alkyl, guanidino, amidino, C _1-4 alkyl, amidino, di-C _1-4 alkyl amino Substituted C _1-12 alkyl having one or more substituents independently selected from dino, C _1-5 alkylamino, diC _1-5 alkylamino, sulfide, carboxyl, hydroxyl;

C _1-6 alkoxy;

C _6-12 aryl, or amino, amidino, guanidino, hydrazino, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl Substituted C _6-12 aryl having one or more substituents independently selected from C _1-3 alkoxy, nitro, carboxyl, cyano, sulfuryl and hydroxyl;

Monocyclic aryl-alkyl having 5 to 7 ring members which may have 1 to 2 heteroatoms selected from nitrogen, oxygen or sulfur, or amino, amidino, guanidino, hydrazino, C _1-4 alkyl Independently selected from amino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-6 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, sulfuryl and hydroxyl Substituted monocyclic aryl-alkyl having one or more substituents;

Bicyclic aryl-alkyl having 8 to 10 ring members which may have 1 to 2 heteroatoms selected from nitrogen, oxygen or sulfur, or halogen, C _1-6 alkyl, C _1-6 alkoxy, cyano, Substituted bicyclic aryl-alkyl having one or more substituents independently selected from hydroxyl;

Tricyclic aryl-alkyl having 5 to 14 ring members which may have 1 to 2 heteroatoms selected from nitrogen, oxygen or sulfur, or halogen, C _1-6 alkyl, C _1-6 alkoxy, cyano, hydr Substituted bicyclic aryl-alkyl having one or more substituents independently selected from hydroxyl;

ArylC _1-4 alkyl, or amino, amidino, guanidino, hydrazino, C _1-4 alkylamino, C _1-4 dialkylamino, C _3-6 cycloalkyl, halogen, perfluoroC _{1- 4} alkyl, C _1-6 alkyl, C _1-3 alkoxy, nitro, carboxyl, cyano, sulfuryl, hydroxyl, amide, C _1-6 alkyloxy C _1-6 acyl and morpholinyl C _1-6 Substituted _{arylC 1-4} alkyl having one or more substituents independently selected from alkyl;

Cycloalkylalkyl, or amino, amidino, guanidino, hydrazino, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C Substituted cycloalkylalkyl having one or more substituents independently selected from _1-3 alkoxy, nitro, carboxyl, cyano, sulfuryl and hydroxyl; And

Cycloalkyl, or amino, amidino, guanidino, hydrazino, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoroC _1-4 alkyl, C _1-4 alkyl, C _{1 -3} substituted cycloalkyl with one or more substituents independently selected from alkoxy, nitro, carboxyl, cyano, sulfuryl and hydroxyl

It is independently selected from the group consisting of.

In certain embodiments, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are the same or different,

C _1-12 alkyl, or an amino, guanidino, C _1-4 alkyl, guanidino, di-C _1-4 alkyl, guanidino, amidino, C _1-4 alkyl, amidino, di-C _1-4 alkyl amino Substituted C _1-12 alkyl having one or more substituents independently selected from dino, C _1-5 alkylamino, diC _1-5 alkylamino, sulfide, carboxyl, hydroxyl;

C _1-6 alkoxy; CycloalkylC _1-3 alkyl; Cycloalkyl;

Phenyl, or amino, amidino, guanidino, hydrazino, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoroC _1-4 alkyl, C _1-6 alkyl, C _{1- 3} substituted phenyl having one or more substituents independently selected from alkoxy, nitro, carboxyl, cyano, sulfuryl, hydroxyl;

PhenylC _2-4 alkyl, or amino, amidino, guanidino, hydrazino, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoroC _1-4 alkyl, C _1-6 PhenylC _2-4 alkyl having one or more substituents independently selected from alkyl, C _1-3 alkoxy, nitro, carboxyl, cyano, sulfuryl, sulfide, hydroxyl;

Naphthyl, or amino, amidino, guanidino, hydrazino, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoroC _1-4 alkyl, C _1-6 alkyl, C _{1 -3} substituted naphthyl having one or more substituents independently selected from alkoxy, nitro, carboxyl, cyano, sulfuryl, hydroxyl;

NaphthylC _1-4 alkyl, or amino, amidino, guanidino, hydrazino, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoroC _1-4 alkyl, C _1- NaphthylC _1-4 alkyl having one or more substituents independently selected from ₆ alkyl, C _1-3 alkoxy, nitro, carboxyl, cyano, sulfuryl, hydroxyl;

Benzyl, or amino, amidino, guanidino, hydrazino, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, trifluoro C _1-4 alkyl, Substituted benzyl having one or more substituents independently selected from C _1-6 alkyl, C _1-3 alkoxy, nitro, carboxyl, cyano, sulfuryl and hydroxyl;

Bisphenylmethyl, or amino, amidino, guanidino, hydrazino, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-6 alkyl, C Substituted bisphenylmethyl having one or more substituents independently selected from _1-3 alkoxy, nitro, carboxyl, cyano, sulfuryl and hydroxyl;

Benzylphenyl amide, or amino, amidino, guanidino, hydrazino, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-6 alkyl, C Substituted benzylphenyl amide having one or more substituents independently selected from _1-3 alkoxy, nitro, carboxyl, cyano, sulfuryl and hydroxyl;

Pyridyl, or amino, amidino, guanidino, hydrazino, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-6 alkyl, C _{1 -3} substituted pyridyl having one or more substituents independently selected from alkoxy, nitro, carboxyl, cyano, sulfuryl and hydroxyl;

[50] pyridylC _1-4 alkyl, or amino, amidino, guanidino, hydrazino, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, Substituted pyridylC _1-4 alkyl having one or more substituents independently selected from C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxyl, cyano, sulfuryl and hydroxyl;

PyrimidylC _1-4 alkyl, or amino, amidino, guanidino, hydrazino, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1- Substituted pyrimidylC _1-4 alkyl having one or more substituents independently selected from ₆ alkyl, C _1-3 alkoxy, nitro, carboxyl, cyano, sulfuryl and hydroxyl;

Triazin-2-ylC _1-4 alkyl, or amino, amidino, guanidino, hydrazino, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl Substituted triazin-2-ylC _1-4 alkyl having one or more substituents independently selected from C _1-6 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, sulfuryl and hydroxyl;

Imidazolyl C _1-4 alkyl, or amino, amidino, guanidino, hydrazino, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C ₁ Substituted imidazolylC _1-4 alkyl having one or more substituents independently selected from _-6 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, sulfuryl and hydroxyl;

Benzothiazoline C _1-4 alkyl, or amino, amidino, guanidino, hydrazino, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C ₁ Substituted benzothiazoline C _1-4 alkyl having one or more substituents independently selected from _-6 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, sulfuryl and hydroxyl;

Phenoxazine C _1-4 alkyl; Benzyl p-tolyl ether; Phenoxybenzyl; N-amidinopiperazinyl-NC _1-4 alkyl; Quinoline C _1-4 alkyl; N-amidinopiperazinyl; N-amidinopiperidinylC _1-4 alkyl; 4-aminocyclohexylC _1-2 alkyl; And 4-aminocyclohexyl

It is independently selected from the group consisting of.

In certain embodiments, E is -(ZR ₄ )-, G is -(XR ₅ )-, wherein Z is CH, X is nitrogen, and the compound has Formula II

<Formula II>

In the above formula, R ₂ , R ₃ and R ₅ are as defined in Formula I.

In certain embodiments, the compound has Formula III

<Formula III>

In certain embodiments, E is -(ZR ₄ )-, G is absent, wherein Z is nitrogen and the compound has Formula IV

<Formula IV>

In the above formula, R ₁ , R ₂ , R ₃ , R ₄ and W are as defined in Formula I.

In certain embodiments, E is -(ZR ₄ )-, G is -(XR ₅ )-, wherein Z and X are independently CH, and the compound has the structure of Formula V

<Formula V>

In the above formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and W are as defined in Formula I.

In certain embodiments, the compound has Formula VI

<Formula VI>

US 2004/0072831 . All compound genera, species and conformations of US 2004/0072831, including the exemplary compounds of Tables 1 to 5 of US 2004/0072831, the claimed compounds, and each of the disclosed compounds are examples for use in the methods claimed by the applicants herein. All of these compounds are incorporated herein by reference.

Specific exemplary embodiments include compounds having Formula I

<Formula I>

In the above formula, A is -(CHR ₃ )- or -(C=O)-, B is -(CHR ₄ )- or -(C=O)-, and D is -(CHR ₅ )- or -( C=O)-, E is -(ZR ₆ )- or -(C=O)-, and G is -(XR ₇ ) _n -, -(CHR ₇ )-(NR ₈ )-, -(C =O)-(XR ₉ )- or -(C=O)-, W is -Y(C=O)-, -(C=O)NH-, -(SO ₂ )- or absent, Y is oxygen or sulfur, X and Z are independently nitrogen or CH, and n is 0 or 1; R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are the same or different, and amino acid side chain residues or derivatives thereof, the rest of the molecule, linkers and solid supports, and It is independently selected from their stereoisomers (as defined in US 2004/0072831).

A is -(CHR ₃ )-, B is -(C=O)-, D is -(CHR ₅ )-, E is -(C=O)-, and G is -(XR ₇ ) _n In an embodiment where -, the compounds of the invention have the formula II

<Formula II>

In the above formula, W, X, Y and n are as defined above, and R ₁ , R ₂ , R ₃ , R ₅ and R ₇ are as defined in US 2004/0072831.

A is -(C=O)-, B is -(CHR ₄ )-, D is -(C=O)-, E is -(ZR ₆ )-, and G is -(C=O) In an embodiment wherein -(XR ₉ )-, the compounds of the present invention have formula III

<Formula III>

In the above formula, W, X and Y are as defined above, Z is nitrogen or CH (however, when Z is CH, X is nitrogen), R ₁ , R ₂ , R ₄ , R ₆ and R ₉ is as defined in US 2004/0072831.

A is -(C=O)-, B is -(CHR ₄ )-, D is -(C=O)-, E is -(ZR ₆ )-, and G is (XR ₇ ) _n- In a phosphorus embodiment, the compounds of the invention have Formula IV

<Formula IV>

In the above formula, W, Y and n are as defined above, Z is nitrogen or CH (when Z is nitrogen, n is 0, when Z is CH, X is nitrogen and n is not 0 ), R ₁ , R ₂ , R ₄ , R ₆ and R ₇ are as defined in US 2004/0072831.

In certain embodiments, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are aminoC _2-5 alkyl, guanidinoC _2-5 alkyl, C _{1 -4} alkylguanidinoC _2-5 alkyl, diC _1-4 alkylguanidino-C _2-5 alkyl, amidinoC _2-5 alkyl, C _1-4 alkylamidinoC _2-5 alkyl, di C _1-4 alkylamidino C _2-5 alkyl, C _1-3 alkoxy, phenyl, substituted phenyl (wherein the substituent is amino, amidino, guanidino, hydrazino, amidazonyl, C _1-4 alkyl Independent from one or more of amino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl Selected), benzyl, substituted benzyl (wherein the substituents on benzyl are amino, amidino, guanidino, hydrazino, amidazonyl, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, purple Luoro C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, sulfuryl, independently selected from one or more of hydroxyl), naphthyl, substituted naphthyl (wherein the substituent is amidino, Guanidino, hydrazino, amidazonyl, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro , Carboxy, cyano, sulfuryl or hydroxyl independently selected from one or more of), bis-phenyl methyl, substituted bis-phenyl methyl (wherein the substituents are amino, amidino, guanidino, hydrazino, amida Zonyl, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, sulfuryl or Independently selected from one or more of hydroxyl), pyridyl, substituted pyridyl (wherein the substituents are amino, amidino, guanidino, hydrazino, amidazonyl, C _1-4 alkylamino, C _1-4 Dialkylamino, halogen Rogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl independently selected from one or more of), pyridyl C _1-4 Alkyl, substituted pyridylC _1-4 alkyl (wherein the pyridine substituent is amino, amidino, guanidine, hydrazino, amidazonyl, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, Independently selected from one or more of perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl), pyrimidylC _1-4 alkyl, Substituted pyrimidylC _1-4 alkyl (wherein the pyrimidine substituent is amino, amidino, guanidino, hydrazino, amidazonyl, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, purple Luoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy or independently selected from one or more of nitro, carboxy, cyano, sulfuryl or hydroxyl), triazin-2-yl-C _{1 -4} alkyl, substituted triazin-2-yl-C _1-4 alkyl (wherein the triazine substituent is amino, amidino, guanidino, hydrazino, amidazonyl, C _1-4 alkylamino, C ₁ Independently selected from at least one of _-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl), ImidazoC _1-4 alkyl, substituted imidazole C _1-4 alkyl (wherein the imidazole substituents are amino, amidino, guanidino, hydrazino, amidazonyl, C _1-4 alkylamino, C _{1- 4} dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl independently selected from one or more of), already DazolinylC _1-4 alkyl, N-amidinopiperazinyl-NC _0-4 alkyl, hydroxyC _2-5 alkyl, C _1-5 alkylaminoC _2-5 alkyl, hydroxyC _2-5 alkyl , C _1-5 alkyla Independently selected from the group consisting of mino-C _2-5 alkyl, C _1-5 dialkylaminoC _2-5 alkyl, N-amidinopiperidinylC _1-4 alkyl and 4-aminocyclohexylC _0-2 alkyl do.

US 2007/0043052. All compound genera, species and conformational forms thereof of US 2007/0043052, including exemplary compounds of Tables 1 to 5 of US 2007/0043052, the claimed compounds and each of the disclosed compounds, are intended for use by the applicant in the methods claimed herein. As exemplary compounds, all are incorporated herein by reference.

Specific exemplary embodiments include compounds having Formula (I):

<Formula I>

In the above formula, A is -(CHR ₃ )- or -(C=O)-, B is -(CHR ₄ )- or -(C=O)-, and D is -(CHR ₅ )- or -( C=O)-, E is -(ZR ₆ )- or -(C=O)-, and G is -(XR ₇ ) _n -, -(CHR ₇ )-(NR ₈ )-, -(C =O)-(XR ₉ )- or -(C=O)-, W is -Y(C=O)-, -(C=O)NH-, -(SO ₂ )- or absent, Y is oxygen or sulfur, X and Z are independently nitrogen or CH, and n is 0 or 1; R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are the same or different, and amino acid side chain residues or derivatives thereof, the rest of the molecule, linkers and solid supports, and It is independently selected from their stereoisomers (as defined in US 2007/0043052).

A is -(CHR ₃ )-, B is -(C=O)-, D is -(CHR ₅ )-, E is -(C=O)-, and G is -(XR ₇ ) _n -In an embodiment, the compounds of the invention have the formula II:

<Formula II>

In the above formula, W, X, Y and n are as defined above, and R ₁ , R ₂ , R ₃ , R ₅ and R ₇ are as defined in US 2007/0043052.

A is -(C=O)-, B is -(CHR ₄ )-, D is -(C=O)-, E is -(ZR ₆ )-, and G is -(C=O) In an embodiment where -(XR ₉ )-, the compounds of the invention have Formula III:

<Formula III>

In the above formula, W, X and Y are as defined above, Z is nitrogen or CH (however, when Z is CH, X is nitrogen), R ₁ , R ₂ , R ₄ , R ₆ and R ₉ Is as defined in US 2007/0043052.

A is -(C=O)-, B is -(CHR ₄ )-, D is -(C=O)-, E is -(ZR ₆ )-, and G is (XR ₇ ) _n- In a phosphorus embodiment, the compounds of the invention have Formula IV:

<Formula IV>

In the above formula, W, Y and n are as defined above, Z is nitrogen or CH (when Z is nitrogen, n is 0, when Z is CH, X is nitrogen and n is not 0), R ₁ , R ₂ , R ₄ , R ₆ and R ₇ are as defined in US 2007/0043052.

In certain embodiments, the compounds of the invention have Formula VI:

<Formula VI>

In the above formula, R _a is a phenyl group; Amino, amidino, guanidino, hydrazino, amidazonyl, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _{1 -3} a substituted phenyl group having one or more substituents independently selected from one or more of alkoxy, nitro, carboxy, cyano, sulfuryl and hydroxyl groups; Benzyl group; Amino, amidino, guanidino, hydrazino, amidazonyl, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-3 alkoxy, nitro, A substituted benzyl group having one or more substituents independently selected from one or more of carboxy, cyano, sulfuryl and hydroxyl groups; Or a bicyclic aryl group having 8 to 11 ring members which may have 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur; R _b is a monocyclic aryl group having 5 to 7 ring members which may have 1 to 2 heteroatoms selected from nitrogen, oxygen or sulfur, and the aryl ring in the compound is halide, hydroxy, cyano, lower May have one or more substituents selected from the group consisting of alkyl and lower alkoxy groups; R _c is a saturated or unsaturated C _1-6 alkyl, C _1-6 alkoxy, perfluoro C _1-6 alkyl group; X ₁ , X ₂ and X ₃ may be the same or different and may be independently selected from hydrogen, hydroxyl and halides.

In certain embodiments, the prodrug has Formula VII, and the prodrug can act as a substrate for a phosphatase or carboxylase, thus converting to a compound having Formula VI:

<Formula VII>

(VI)-YR ₁₀

Wherein (VI) is formula VI as described above; Y is oxygen, sulfur or nitrogen of a group selected from R _a , R _b , R _c , X ₁ , X ₂ and X ₃ ;

R ₁₀ is phosphate, hemisuccinate, hemimalate, phosphoryloxymethyloxycarbonyl, dimethylaminoacetate, dimethylaminoalkylcarbamate, hydroxyalkyl, amino acid, glycosyl, substituted or unsubstituted piperidine Oxycarbonyl, or a salt thereof.

In some embodiments, R ₁₀ of Formula VII is not an amino acid group or a phospho-amino acid group.

US 2005/0059628. All compound genera, species and conformations thereof of US 2005/0059628, including the exemplary compounds of Tables 1 to 5 of US 2005/0059628, the claimed compounds and each of the disclosed compounds, are intended for use by the applicants in the methods claimed herein. As exemplary compounds, all are incorporated herein by reference.

Specific exemplary embodiments include compounds having Formula (I):

<Formula I>

In the above formula, A is -(CHR ₃ )- or -(C=O)-, B is -(CHR ₄ )- or -(C=O)-, and D is -(CHR ₅ )- or -( C=O)-, E is -(ZR ₆ )- or -(C=O)-, and G is -(XR ₇ ) _n -, -(CHR ₇ )-(NR ₈ )-, -(C =O)-(XR ₉ )- or -(C=O)-, W is -Y(C=O)-, -(C=O)NH-, -(SO ₂ )- or absent, Y is oxygen or sulfur, X and Z are independently nitrogen or CH, and n is 0 or 1; R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are the same or different, and amino acid side chain residues or derivatives thereof, the rest of the molecule, linkers and solid supports, and It is independently selected from their stereoisomers (as defined in US 2005/0059628).

In certain embodiments, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and R ₉ of formula I are _{aminoC 2-5} alkyl, guanidinoC _2-5 Alkyl, C _1-4 alkylguanidino C _2-5 alkyl, diC _1-4 alkylguanidino-C _2-5 alkyl, amidino C _2-5 alkyl, C _1-4 alkylamidino C _{2- 5} alkyl, diC _1-4 alkylamidinoC _2-5 alkyl, C _1-3 alkoxy, phenyl, substituted phenyl (wherein the substituent is amino, amidino, guanidino, hydrazino, amidazonyl, C _{Among 1-4} alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl Independently selected from one or more), benzyl, substituted benzyl, wherein the substituents on the benzyl are amino, amidino, guanidino, hydrazino, amidazonyl, C _1-4 alkylamino, C _1-4 dialkylamino , Halogen, perfluoro C _1-4 alkyl, C _1-3 alkoxy, independently selected from one or more of nitro, carboxy, cyano, sulfuryl or hydroxyl), naphthyl, substituted naphthyl (wherein the substituent Is amino, amidino, guanidino, hydrazino, amidazonyl, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 independently selected from one or more of alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl), bis-phenyl methyl, substituted bis-phenyl methyl, wherein the substituent is amino, amidino, guanidino , Hydrazino, amidazonyl, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy, Independently selected from one or more of cyano, sulfuryl or hydroxyl), pyridyl, substituted pyridyl, wherein the substituent is amino, amidino, guanidino, hydrazino, amidazonyl, C _1-4 alkyl Amino, C _1-4 D are independently selected from alkyl, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, sulfuryl or one or more hydroxyl) , PyridylC _1-4 alkyl, substituted pyridylC _1-4 alkyl (wherein the pyridine substituent is amino, amidino, guanidino, hydrazino, amidazonyl, C _1-4 alkylamino, C _{1- 4} dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, sulfuryl, independently selected from one or more of hydroxyl), pyri MidylC _1-4 alkyl, substituted pyrimidylC _1-4 alkyl (wherein the pyrimidine substituent is amino, amidino, guanidino, hydrazino, amidazonyl, C _1-4 alkylamino, C _1-4 Dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, or independently selected from one or more of nitro, carboxy, cyano, sulfuryl or hydroxyl), triazine -2-yl-C _1-4 alkyl, substituted triazin-2-yl-C _1-4 alkyl (wherein the triazine substituent is amino, amidino, guanidino, hydrazino, amidazonyl, C _{1 -4} alkylamino, one of C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl Independently selected from the above), imidazo C _1-4 alkyl, substituted imidazole C _1-4 alkyl (wherein the imidazole substituents are amino, amidino, guanidino, hydrazino, amidazonyl, C _{1- 4} alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, at least one of sulfuryl or hydroxyl Independently selected from), imidazolinylC _1-4 alkyl, N-amidinopiperazinyl-NC _0-4 alkyl, hydroxyC _2-5 alkyl, C _1-5 alkylaminoC _2-5 alkyl, Hydroxy C _2-5 Alkyl, C _1-5 alkylaminoC _2-5 alkyl, C _1-5 dialkylaminoC _2-5 alkyl, N-amidinopiperidinylC _1-4 alkyl and 4-aminocyclohexylC _0-2 alkyl It is independently selected from the group consisting of.

In certain embodiments, A is -(CHR ₃ )-, B is -(C=O)-, D is -(CHR ₅ )-, E is -(C=O)-, and G is- (XR ₇ ) _n -and the compound has the formula II:

<Formula II>

In the above formula, R ₁ , R ₂ , R ₃ , R ₅ , R ₇ , W, X and n are as defined in Formula I.

In certain embodiments, A is -(C=O)-, B is -(CHR ₄ )-, D is -(C=O)-, E is -(ZR ₆ )-, and G is- (C=O)-(XR ₉ )-, and the compound has the formula III:

<Formula III>

In the above formula, R ₁ , R ₂ , R ₄ , R ₆ , R ₉ , W and X are as defined in Formula I, and Z is nitrogen or CH (when Z is CH, X is nitrogen).

In certain embodiments, A is -(C=O)-, B is -(CHR ₄ )-, D is -(C=O)-, E is -(ZR ₆ )-, and G is- (XR ₇ ) _n -and the compound has the formula IV:

<Formula IV>

In the above formula, R ₁ , R ₂ , R ₄ , R ₆ , R ₇ , W, X and n are as defined in Formula I, Z is nitrogen or CH, but when Z is nitrogen n is 0, When Z is CH, X is nitrogen and n is not zero.

In certain embodiments, the compound has Formula VI:

<Formula VI>

In the above formula, R _a is a bicyclic aryl group having 8 to 11 ring members which may have 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur, and R _b is 1 to 1 selected from nitrogen, oxygen or sulfur. It is a monocyclic aryl group having 5 to 7 ring members which may have 2 heteroatoms, and the aryl ring in the compound is at least one substituent selected from the group consisting of halide, hydroxy, cyano, lower alkyl and lower alkoxy group. Can have Optionally, R _a is a naphthyl, quinolinyl or isoquinolinyl group, and R _b is phenyl, pyridyl or piperidyl, all of which consist of halide, hydroxy, cyano, lower alkyl and lower alkoxy groups. It may be substituted with one or more substituents selected from the group. In certain embodiments, R _a is naphthyl and R _b is phenyl, which may be substituted with one or more substituents selected from the group consisting of halide, hydroxy, cyano, lower alkyl and lower alkoxy groups.

In certain embodiments, the compound is selected from compounds 1, 3, 4 and 5 as defined in US 2005/0059628.

WO 2009/051399. All compound genus, species and conformational forms thereof of WO 2009/051399, including exemplary compounds of Tables 1 to 5 of WO 2009/051399, the claimed compounds and each of the disclosed compounds are for use in the methods claimed herein by the applicant. As exemplary compounds, all are incorporated herein by reference.

Specific exemplary embodiments include compounds having Formula (I):

<Formula I>

Wherein E is -ZR ₃ -or -(C=O)-, where Z is CH or N; W is -(C=O)-, -(C=O)NH-, -(C=O)O-, -(C=O)S-, -S(O)z- or a bond; Each of R ₁ , R ₂ , R ₃ , R ₄ and R ₅ is the same or different, and is independently an amino acid side chain residue or an amino acid side chain derivative. The reverse turn mimetic compounds may exist as isolated stereoisomers or mixtures of stereoisomers or as pharmaceutically acceptable salts thereof. In certain embodiments, R ₁ of the compound of formula I is indazolyl or substituted indazolyl. Specific examples for R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are as defined in WO 2009/051399.

In an embodiment wherein E is CHR ₃ , the compounds of the invention have formula II:

<Formula II>

In the above formula, W is as defined above, and R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are as defined in WO 2009/051399.

In certain embodiments, the compounds of the invention have formula III:

<Formula III>

In the above formula, R ₁ , R ₄ , R ₆ , X ₁ , X ₂ and X ₃ are as defined in WO 2009/051399.

In certain embodiments, prodrugs of the invention have Formula IV:

<Formula IV>

(III)-R ₇

Wherein (III) is formula III as described above; One of R ₁ , R ₄ , R ₆ , X ₁ , X ₂ and X ₃ is connected to R ₇ through Y; Y is oxygen, sulfur or nitrogen in R ₁ , R ₄ or R ₆ , or oxygen in X ₁ , X ₂ or X ₃ ; R ₇ is hydroxyalkyl, glycosyl, phosphoryloxymethyloxycarbonyl, substituted or unsubstituted piperidine carbonyloxy, or a salt thereof; Or YR ₇ is an amino acid residue, a combination of amino acid residues, phosphate, hemimalate, hemisuccinate, dimethylaminoalkylcarbamate, dimethylaminoacetate, or a salt thereof; When not linked to R ₇ R ₁ , R ₄ , R ₆ , X ₁ , X ₂ and X ₃ are as defined in WO 2009/051399.

US 2006/0084655. All compound genera, species and conformational forms thereof of US 2006/0084655, including the exemplary compounds of Tables 1 to 5 of US 2006/0084655, the claimed compounds and each of the disclosed compounds, are intended for use by the applicants in the methods claimed herein. As exemplary compounds, all are incorporated herein by reference.

Specific exemplary embodiments include compounds having Formula (I):

<Formula I>

In the above formula, A is -(CHR ₃ )- or -(C=O)-, B is -(CHR ₄ )- or -(C=O)-, and D is -(CHR ₅ )- or -( C=O)-, E is -(ZR ₆ )- or -(C=O)-, and G is -(XR ₇ ) _n -, -(CHR ₇ )-(NR ₈ )-, -(C =O)-(XR ₉ )- or -(C=O)-, W is -Y(C=O)-, -(C=O)NH-, -(SO ₂ )- or absent, Y is oxygen, sulfur or -NH-, X and Z are independently nitrogen or CH, and n is 0 or 1; R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are the same or different, and amino acid side chain residues or derivatives thereof, the rest of the molecule, linkers and solid supports, and It is independently selected from their stereoisomers (as defined in US 2006/0084655).

A is -(CHR ₃ )-, B is -(C=O)-, D is -(CHR ₅ )-, E is -(C=O)-, and G is -(XR ₇ ) _n In one embodiment, the compounds of the present invention have the formula II:

<Formula II>

In the above formula, W, X, Y and n are as defined above, and R ₁ , R ₂ , R ₃ , R ₅ and R ₇ are as defined in US 2006/0084655.

A is -(C=O)-, B is -(CHR ₄ )-, D is -(C=O)-, E is -(ZR ₆ )-, and G is -(C=O) In one embodiment where -(XR ₉ )-, the compounds of the invention have Formula III:

<Formula III>

In the above formula, W, X and Y are as defined above, Z is nitrogen or CH (however, when Z is CH, X is nitrogen), R ₁ , R ₂ , R ₄ , R ₆ and R ₉ Is as defined in US 2006/0084655.

A is -(C=O)-, B is -(CHR ₄ )-, D is -(C=O)-, E is -(ZR ₆ )-, and G is -(XR ₇ ) _n In one embodiment, the compounds of the invention have the formula IV:

<Formula IV>

In the above formula, W, Y and n are as defined above, Z is nitrogen or CH (when Z is nitrogen, n is 0, when Z is CH, X is nitrogen and n is not 0), R ₁ , R ₂ , R ₄ , R ₆ and R ₇ are as defined in US 2006/0084655.

US 2008/0009500. All compound genera, species and conformations thereof of US 2008/0009500, including the exemplary compounds of Tables 1 to 5 of US 2008/0009500, the claimed compounds and each of the disclosed compounds, are intended for use by the applicants in the methods claimed herein. As exemplary compounds, all are incorporated herein by reference.

Specific exemplary embodiments include compounds having Formula I and a pharmaceutically acceptable carrier:

<Formula I>

In the above formula, A is -(C=O)-CHR ₃ -or -(C=O), B is -NR ₅ -or -CHR ₆ -, and D is -(C=O)-(CHR ₇ ) -Or -(C=O)-, E is -(ZR ₈ )- or (C=O), and G is -(XR ₉ ) _n -, -(CHR ₁₀ )-(NR ₆ )-,- (C=O)-(XR ₁₂ )-, -(or absent)-, -(C=O)-, X-(C=O)-R ₁₃ , X-(C=O)-NR ₁₃ R ₁₄ , X-(SO ₂ )-R ₁₃ or X-(C=O)-OR ₁₃ , and W is -Y(C=O)-, -(C=O)NH-, -(SO ₂ )- , -CHR ₁₄ , (C=O)-(NR ₁₅ )-, substituted or unsubstituted oxidazole, substituted or unsubstituted triazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted 4,5 Dihydrooxazole, substituted or unsubstituted 4,5 dihydrothiazole, substituted or unsubstituted 4,5 dihydroimidazole or absent, Y is oxygen or sulfur, and X and Z are independently nitrogen or CH, n is 0 or 1; R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ and R ₁₅ are the same or different, Amino acid side chain residues or derivatives thereof, the remainder of the molecule, linkers and solid supports, and stereoisomers, salts and prodrugs thereof.

In certain embodiments, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ and R ₁₅ are , AminoC _2-5 alkyl, guanidino C _2-5 alkyl, C _1-4 alkylguanidino C _2-5 alkyl, diC _1-4 alkylguanidino-C _2-5 alkyl, amidino C _2-5 alkyl, C _1-4 alkylamidinoC _2-5 alkyl, diC _1-4 alkylamidinoC _2-5 alkyl, C _1-3 alkoxy, phenyl, substituted phenyl (wherein the substituent is amino, Amidino, guanidino, hydrazino, amidrazonyl, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 Independently selected from one or more of alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl), benzyl, substituted benzyl (wherein the substituent on benzyl is amino, amidino, guanidino, hydrazino, amidrazonyl , C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, sulfuryl or hydrogen Independently selected from one or more of hydroxyl), naphthyl, substituted naphthyl (wherein the substituent is amino, amidino, guanidino, hydrazino, amidrazonyl, C _1-4 alkylamino, C _1-4 di Independently selected from one or more of alkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl), bis-phenyl Methyl, substituted bis-phenyl methyl (wherein the substituents are amino, amidino, guanidino, hydrazino, amidrazonyl, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl independently selected from one or more of), pyridyl, substituted pyridyl (wherein the substituent Is amino, amidino, guanidino, hydrazino, amidrazonyl, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl independently selected from one or more of), pyridylC _1-4 alkyl, substituted pyridylC _1-4 alkyl (wherein the pyridine substituent is amino , Amidino, guanidino, hydrazino, amidrazonyl, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _{1- 3} Independently selected from one or more of alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl), pyrimidylC _1-4 alkyl, substituted pyrimidylC _1-4 alkyl (wherein the pyrimidine substituent is amino, Amidino, guanidino, hydrazino, amidrazonyl, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 Independently selected from one or more of alkoxy or nitro, carboxy, cyano, sulfuryl or hydroxyl), triazin-2-yl-C _1-4 alkyl, substituted triazin-2-yl-C _1-4 alkyl (Wherein, the triazine substituent is amino, amidino, guanidino, hydrazino, amidrazonyl, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, sulfuryl, independently selected from one or more of hydroxyl), imidazoC _1-4 alkyl, substituted imidazole C _1-4 alkyl ( Here, the imidazole substituent is amino, amidino, guanidino, hydrazino, amidrazonyl, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _{1 -4} alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, sulfuryl, hydroxyl or methyl independently selected from at least one), imidazolinyl C _1-4 alkyl, N-amidinopiperazi Nyl-NC _0-4 alkyl, hydroxyC _2-5 alkyl, C _1-5 alkylaminoC _2-5 alkyl, hydroxyC _2-5 alkyl, C _1-5 alkylaminoC _2-5 alkyl, C _{1 -5} dialkylaminoC _2-5 alkyl, N-amidinopiperidinylC _1-4 alkyl and 4-aminocyclohexylC _0-2 alkyl are independently selected from the group consisting of.

In certain aspects, A is -(CHR ₃ )-(C=O)-, B is -(NR ₄ )-, D is (C=O)-, and E is -(ZR ₆ )-, G is -(C=O)-(XR ₉ )-, and the compound has the formula III:

<Formula III>

In the above formula, Z is nitrogen or CH, and when Z is CH, X is nitrogen.

In certain aspects, A is -O-CHR ₃ -, B is -NR ₄ -, D is -(C=O)-, E is -(ZR ₆ )-, and G is -(XR ₇ ) _n -and the compound has the formula IV:

<Formula IV>

In the above formula, R ₁ , R ₂ , R ₄ , R ₆ , R ₇ , R ₈ , W, X and n are as defined above, and Y is -C=O, -(C=O)-O-, -(C=O)-NR ₈ , -SO ₂ -or absent, Z is nitrogen or CH (when Z is nitrogen, n is 0, when Z is CH, X is nitrogen and n is 0 Not).

A is -(C=O), B is -(CHR ₆ )-, D is -(C=O)-, E is -(ZR ₈ )-, and G is -(NH)- or- (CH ₂ )-, W is substituted or unsubstituted oxidazole, substituted or unsubstituted triazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted 4,5 dihydrooxazole, substituted or unsubstituted In certain embodiments, which is a substituted 4,5 dihydrothiazole, substituted or unsubstituted 4,5 dihydroimidazole, the compound has Formula V:

<Formula V>

Wherein K is nitrogen, oxygen or sulfur, L is nitrogen, oxygen, -(CH)- or -(CH ₂ )-, J is nitrogen, oxygen or sulfur, Z is nitrogen or CH, and R ₁ , R ₂ , R ₆ , R ₈ and R ₁₃ are selected from amino acid side chain residues.

Certain embodiments provide compounds having Formula VI:

<Formula VI>

In the above formula, B is -(CHR ₂ )-, -(NR ₂ )-, E is -(CHR ₃ )-, V is -(XR ₄ )- or absent, and W is -(C=O )-(XR ₅ R ₆ ), -(SO ₂ )-, substituted or unsubstituted oxidazole, substituted or unsubstituted triazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted 4,5 di Hydrooxazole, substituted or unsubstituted 4,5 dihydrothiazole, substituted or unsubstituted 4,5 dihydroimidazole, X is independently nitrogen, oxygen or CH, and R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are selected from amino acid side chain residues or derivatives thereof, the remainder of the molecule, linkers and solid supports, and stereoisomers, salts and prodrugs thereof. In certain aspects, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ and R ₁₅ are, AminoC _2-5 alkyl, guanidino C _2-5 alkyl, C _1-4 alkylguanidino C _2-5 alkyl, diC _1-4 alkylguanidino-C _2-5 alkyl, amidino C _{2 -5} alkyl, C _1-4 alkylamidinoC _2-5 alkyl, diC _1-4 alkylamidinoC _2-5 alkyl, C _1-3 alkoxy, phenyl, substituted phenyl (wherein the substituents are amino, amino Dino, guanidino, hydrazino, amidrazonyl, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy , Nitro, carboxy, cyano, sulfuryl or hydroxyl independently selected from one or more of), benzyl, substituted benzyl (wherein the substituent on benzyl is amino, amidino, guanidino, hydrazino, amidrazonyl, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl Independently selected from one or more of), naphthyl, substituted naphthyl, wherein the substituent is amino, amidino, guanidino, hydrazino, amidrazonyl, C _1-4 alkylamino, C _1-4 dialkyl Independently selected from one or more of amino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl), naphthyl, substituted Naphthyl (wherein the substituent is amino, amidino, guanidine, hydrazino, amidrazonyl, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _{1 -4} alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, sulfuryl, independently selected from one or more of hydroxyl), bis-phenyl methyl, substituted bis-phenyl methyl (wherein the substituent is a Mino, amidino, guanidino, hydrazino, amidrazonyl, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _{1 -3} independently selected from at least one of alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl), pyridyl, substituted pyridyl (wherein the substituent is amino, amidino, guanidino, hydrazino, ami Drazonyl, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, sulfuryl Or independently selected from one or more of hydroxyl), pyridylC _1-4 alkyl, substituted pyridylC _1-4 alkyl (wherein the pyridine substituent is amino, amidino, guanidino, hydrazino, amidrazonyl , C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, sulfuryl or hydrogen Independently selected from one or more of the hydroxyls), pyrimidylC _1-4 alkyl, substituted pyrimidylC _1-4 alkyl (wherein the pyrimidine substituent is amino, amidino, guanidino, hydrazino, amidrazonyl, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy or nitro, carboxy, cyano, sulfuryl or hydroxyl Independently selected from one or more of), triazin-2-yl-C _1-4 alkyl, substituted triazin-2-yl-C _1-4 alkyl, wherein the triazine substituent is amino, amidino, guani Dino, hydrazino, amidrazonyl, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy , Cyano, sulfuryl or hydroxyl, independently selected from one or more of), imidazoC _1-4 alkyl, substituted imidazole C _1-4 alkyl (wherein the imidazole substituent is amino, amidino , Guanidino, hydrazino, amidrazonyl, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, Independently selected from one or more of nitro, carboxy, cyano, sulfuryl, hydroxyl or methyl), imidazolinylC _1-4 alkyl, N-amidinopiperazinyl-NC _0-4 alkyl, hydroxyC _2-5 alkyl, C _1-5 alkylaminoC _2-5 alkyl, hydroxyC _2-5 alkyl, C _1-5 alkylaminoC _2-5 alkyl, C _1-5 dialkylaminoC _2-5 alkyl, It is independently selected from the group consisting of N-amidinopiperidinylC _1-4 alkyl and 4-aminocyclohexylC _0-2 alkyl.

B is -(CH)-(CH ₃ ), E is -(CH)-(CH ₃ ), V is -(XR ₄ )- or absent, W is a substituted or unsubstituted oxidazole, substituted Or unsubstituted triazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted 4,5 dihydrooxazole, substituted or unsubstituted 4,5 dihydrothiazole, substituted or unsubstituted 4,5 In certain aspects, wherein being dihydroimidazole and X is independently nitrogen or CH, the compound has formula VII:

<Formula VII>

In the above formula, K is nitrogen, oxygen or sulfur, L is nitrogen, oxygen, -(CH)- or -(CH ₂ )-, J is nitrogen, oxygen or sulfur, and R ₅ is amino C _2-5 Alkyl, guanidinoC _2-5 alkyl, C _1-4 alkylguanidinoC _2-5 alkyl, diC _1-4 alkylguanidino-C _2-5 alkyl, amidinoC _2-5 alkyl, C _1-4 alkylamidinoC _2-5 alkyl, diC _1-4 alkylamidinoC _2-5 alkyl, C _1-3 alkoxy, phenyl, substituted phenyl (wherein the substituent is amino, amidino, guanidino , Hydrazino, amidrazonyl, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy, Independently selected from one or more of cyano, sulfuryl or hydroxyl), benzyl, substituted benzyl (wherein the substituents on benzyl are amino, amidino, guanidino, hydrazino, amidrazonyl, C _1-4 alkyl Independent from one or more of amino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl Selected from), naphthyl, substituted naphthyl (wherein the substituent is amino, amidino, guanidino, hydrazino, amidrazonyl, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, purple Luoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl independently selected from one or more), bis-phenyl methyl, substituted bis- Phenyl methyl (wherein the substituent is amino, amidino, guanidino, hydrazino, amidrazonyl, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, sulfuryl, independently selected from one or more of hydroxyl), pyridyl, substituted pyridyl (wherein the substituent is amino, amidino, or Anidino, Hydra Zino, amidrazonyl, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano , Sulfuryl or hydroxyl independently selected from at least one of), pyridylC _1-4 alkyl, substituted pyridylC _1-4 alkyl (wherein the pyridine substituent is amino, amidino, guanidino, hydrazino, Amidrazonyl, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, alcohol Independently selected from one or more of furyl or hydroxyl), pyrimidylC _1-4 alkyl, substituted pyrimidylC _1-4 alkyl (wherein the pyrimidine substituent is amino, amidino, guanidino, hydrazino, ami Drazonyl, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy or nitro, carboxy, cyano, sulfuryl Or independently selected from one or more of hydroxyl), triazin-2-yl-C _1-4 alkyl, substituted triazin-2-yl-C _1-4 alkyl (wherein the triazine substituent is amino, amidino , Guanidino, hydrazino, amidrazonyl, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, Independently selected from one or more of nitro, carboxy, cyano, sulfuryl or hydroxyl), imidazoC _1-4 alkyl, substituted imidazole C _1-4 alkyl (wherein the imidazole substituent is amino, amidino, Guanidino, hydrazino, amidrazonyl, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro , Carboxy, cyano, sulfuryl, hydroxyl or methyl independently selected from one or more), imidazolinyl C _1-4 alkyl, N-amidinopiperazinyl-NC _0-4 alkyl, hydroxy C _{2 -5} Alkyl, C _1-5 alkylaminoC _2-5 alkyl, hydroxyC _2-5 alkyl, C _1-5 alkylaminoC _2-5 alkyl, C _1-5 dialkylaminoC _2-5 alkyl, N-ami It is independently selected from the group consisting of _{dinopiperidinylC 1-4} alkyl and 4-aminocyclohexylC _0-2 alkyl.

Additional compounds include those selected from the group consisting of compounds 1 to 2217 of 2008/0009500.

US 2010/0222303. All compound genera, species and conformational forms thereof of US 2010/0222303, including the exemplary compounds of Tables 3 to 5 of US 2010/0222303, the claimed compounds and each of the disclosed compounds, are intended for use by the applicants in the methods claimed herein. As exemplary compounds, all are incorporated herein by reference.

Specific exemplary embodiments include a compound having the following structural formula, or a pharmaceutically acceptable salt or stereoisomer thereof:

In the above formula, A is -(CHR ₃ )- or -(C=O)-, B is -(CHR ₄ )- or -(C=O)-, and D is -(CHR ₅ )- or -( C=O)-, E is -(ZR ₆ )- or -(C=O)-, and G is -(XR ₇ ) _n -, -(CHR ₇ )-(NR ₈ )-, -(C =O)-(XR ₉ )- or -(C=O)-, W is -Y(C=O)-, -(C=O)NH-, -(SO ₂ )- or absent, Y is oxygen, sulfur or -NH-, X and Z are independently nitrogen or CH, and n is 0 or 1; R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are the same or different, and amino acid side chain residues or derivatives thereof, the rest of the molecule, linkers and solid supports, and It is independently selected from their stereoisomers (as defined in US 2010/0222303).

A is -(CHR ₃ )- or -(C=O)-; B is -(CHR ₄ )- or -(C=O)-; D is -(CHR ₅ )- or -(C=O)-; E is -ZR ₆ -or -(C=O)-, wherein Z is CH or N; G is -XR ₇ -or -(C=O)-, where X is CH or N; W is -(C=O)NH-, -(C=O)O-, -(C=O)S-, -S(O) ₂ -or absent; In an embodiment wherein each of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ is the same or different, and independently an amino acid side chain residue or an amino acid side chain derivative, the compound of the present invention is represented by the following formula (IA) Has:

<Formula IA>

In the above formula, specific examples for R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are as defined in US 2010/0222303.

A is -(CHR ₃ )-, B is -(C=O)-, D is -(CHR ₅ )-, E is -(C=O)-, and G is -(XR ₇ ) _n -In an embodiment, the compounds of the invention have the formula II:

<Formula II>

In the above formula, W, X, Y and n are as defined above, and R ₁ , R ₂ , R ₃ , R ₅ and R ₇ are as defined in US 2010/0222303.

A is -(C=O)-, B is -(CHR ₄ )-, D is -(C=O)-, E is -(ZR ₆ )-, and G is -(C=O) In an embodiment where -(XR ₉ )-, the compounds of the invention have Formula III:

<Formula III>

In the above formula, W, X and Y are as defined above, Z is nitrogen or CH (however, when Z is CH, X is nitrogen), R ₁ , R ₂ , R ₄ , R ₆ and R ₉ Is as defined in US 2010/0222303.

A is -(C=O)-, B is -(CHR ₄ )-, D is -(C=O)-, E is -(ZR ₆ )-, and G is -(XR ₇ ) _n -In an embodiment, the compounds of the invention have the formula IV:

<Formula IV>

In the above formula, W, Y and n are as defined above, Z is nitrogen or CH (when Z is nitrogen, n is 0, when Z is CH, X is nitrogen and n is not 0), R ₁ , R ₂ , R ₄ , R ₆ and R ₇ are as defined in US 2010/0222303.

A is -(C=O)-, B is -(CHR ₄ )-, D is -(C=O)-, E is -CHR ₆ -, and G is -XR _7- (where X Is CH or N), the compound has the structural formula IVA:

<Formula IVA>

In the above formula, R ₁ , R ₂ , R ₄ , R ₆ and R ₇ are as defined in US 2010/0222303.

In one embodiment for a compound of formula IVA, wherein X is N, the compound has the structure of formula IVA ₁

<Formula IVA ₁ >

In the above formula, R ₁ , R ₂ , R ₄ , R ₆ , R ₇ are as defined in US 2010/0222303.

In certain embodiments, the compounds of the invention have Formula VI:

<Formula VI>

In the above formula, R _a , R _b and R _c are as defined in US 2010/0222303, X ₁ , X ₂ and X ₃ may be the same or different, and may be independently selected from hydrogen, hydroxyl and halide. have.

US 6,413,963. All compound genus, species and conformational forms thereof of US 6,413,963, including exemplary compounds of Tables 1 to 5 of US 6,413,963, claimed compounds and each of the disclosed compounds, are exemplary compounds for use in the methods claimed herein by Applicants. All are incorporated herein by reference.

Specific exemplary embodiments include compounds having Formula (I):

<Formula I>

In the above formula, Y is -CH(R ₅ )-AN(R ₁ )-, -AN(R ₁ )-CH(R')-, -AN(R ₁ )-C(=O)-, -AC( =O)-N(R ₁ )-, -A-CH(R ₁ )-O- and -A-CH(R ₁ )-N(R')-; A is -(CHR') _n -; B is -(CHR") _m -; n is 0, 1 or 2; m is 1, 2 or 3; Any two adjacent CH groups or adjacent NH and CH groups on the bicyclic ring are optionally Can form double bonds; wherein R', R", R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are as defined in US 6,413,963.

In embodiments wherein Y is -CH(R ₅ )-AN(R ₁ )-, the compounds of the invention have the following structure I':

<Formula I'>

In the above formula, A and B are as defined above, and R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are as defined in US 6,413,963.

In embodiments where Y is -AN(R ₁ )-CH(R')-, the compounds of the invention have the following structure I”:

<Formula I">

In the above formula, A and B are as defined above, and R', R ₁ , R ₂ , R ₃ and R ₄ are as defined in US 6,413,963.

In embodiments where Y is -AN(R ₁ )-C(=O)-, the compounds of the invention have the following structure I"':

<Formula I"'>

In the above formula, A and B are as defined above, and R ₁ , R ₂ , R ₃ and R ₄ are as defined in US 6,413,963.

In embodiments where Y is -AC(=O)-N(R ₁ )-, the compounds of the invention have the following structure I"":

<Formula I"">

In the above formula, A and B are as defined above, and R ₁ , R ₂ , R ₃ and R ₄ are as defined in US 6,413,963.

In embodiments where Y is -A-CH(R ₁ )-O-, the compounds of the invention have the following structural formula I""':

<Formula I""'>

In the above formula, A and B are as defined above, and R ₁ , R ₂ , R ₃ and R ₄ are as defined in US 6,413,963.

In embodiments wherein Y is -A-CH(R ₁ )-N(R')-, the compounds of the invention have the following structure I""":

<Formula I""">

In the above formula, A and B are as defined above, and R', R ₁ , R ₂ , R ₃ and R ₄ are as defined in US 6,413,963.

US 7,531,320. All compound genera, species and conformations thereof of US 7,531,320, including the exemplary compounds of Tables 1 to 5 of US 7,531,320, the claimed compounds and each of the disclosed compounds, are exemplary compounds for use in the methods claimed herein by Applicants. All are incorporated herein by reference.

Specific exemplary embodiments include compounds having Formula (I):

<Formula I>

In the above formula, A is -(CHR ₃ )- or -(C=O)-, B is -(CHR ₄ )- or -(C=O)-, and D is -(CHR ₅ )- or -( C=O)-, E is -(ZR ₆ )- or -(C=O)-, G is -(XR ₇ ) _n -, and -(CHR ₇ )-(NR ₈ )-, -( C=O)-(XR ₉ )- or -(C=O)-, W is -Y(C=O)-, -(C=O)NH-, -(SO ₂ )- or absent , Y is oxygen or sulfur, X and Z are independently nitrogen or CH, and n is 0 or 1; R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are the same or different, and each amino acid side chain residue, a derivative of an amino acid side chain residue or the rest of the molecule, and Are independently selected from stereoisomers of

In certain embodiments, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and R ₉ of formula I are _{aminoC 2-5} alkyl, guanidinoC _2-5 Alkyl, C _1-4 alkylguanidino C _2-5 alkyl, diC _1-4 alkylguanidino-C _2-5 alkyl, amidino C _2-5 alkyl, C _1-4 alkylamidino C _{2- 5} alkyl, diC _1-4 alkylamidinoC _2-5 alkyl, C _1-3 alkoxy, phenyl, substituted phenyl (wherein the substituent is amino, amidino, guanidino, hydrazino, amidazonyl, C _{Among 1-4} alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl Independently selected from one or more), benzyl, substituted benzyl, wherein the substituents on the benzyl are amino, amidino, guanidino, hydrazino, amidazonyl, C _1-4 alkylamino, C _1-4 dialkylamino , Halogen, perfluoro C _1-4 alkyl, C _1-3 alkoxy, independently selected from one or more of nitro, carboxy, cyano, sulfuryl or hydroxyl), naphthyl, substituted naphthyl (wherein the substituent Is amino, amidino, guanidino, hydrazino, amidazonyl, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 independently selected from one or more of alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl), bis-phenyl methyl, substituted bis-phenyl methyl, wherein the substituent is amino, amidino, guanidino , Hydrazino, amidazonyl, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy, Independently selected from one or more of cyano, sulfuryl or hydroxyl), pyridyl, substituted pyridyl, wherein the substituent is amino, amidino, guanidino, hydrazino, amidazonyl, C _1-4 alkyl Amino, C _1-4 D are independently selected from alkyl, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, sulfuryl or one or more hydroxyl) , PyridylC _1-4 alkyl, substituted pyridylC _1-4 alkyl (wherein the pyridine substituent is amino, amidino, guanidino, hydrazino, amidazonyl, C _1-4 alkylamino, C _{1- 4} dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, sulfuryl, independently selected from one or more of hydroxyl), pyri MidylC _1-4 alkyl, substituted pyrimidylC _1-4 alkyl (wherein the pyrimidine substituent is amino, amidino, guanidino, hydrazino, amidazonyl, C _1-4 alkylamino, C _1-4 Dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, or independently selected from one or more of nitro, carboxy, cyano, sulfuryl or hydroxyl), triazine -2-yl-C _1-4 alkyl, substituted triazin-2-yl-C _1-4 alkyl (wherein the triazine substituent is amino, amidino, guanidino, hydrazino, amidazonyl, C _{1 -4} alkylamino, one of C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl Independently selected from the above), imidazo C _1-4 alkyl, substituted imidazole C _1-4 alkyl (wherein the imidazole substituents are amino, amidino, guanidino, hydrazino, amidazonyl, C _{1- 4} alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, at least one of sulfuryl or hydroxyl Independently selected from), imidazolinylC _1-4 alkyl, N-amidinopiperazinyl-NC _0-4 alkyl, hydroxyC _2-5 alkyl, C _1-5 alkylaminoC _2-5 alkyl, Hydroxy C _2-5 Alkyl, C _1-5 alkylaminoC _2-5 alkyl, C _1-5 dialkylaminoC _2-5 alkyl, N-amidinopiperidinylC _1-4 alkyl and 4-aminocyclohexylC _0-2 alkyl It is independently selected from the group consisting of.

In certain embodiments, A is -(CHR ₃ )-, B is -(C=O)-, D is -(CHR ₅ )-, E is -(C=O)-, and G is- (XR ₇ ) _n -and the compound has the formula II:

<Formula II>

In the above formula, R ₁ , R ₂ , R ₃ , R ₅ , R ₇ , W, X and n are as defined in Formula I.

In certain embodiments, A is -(C=O)-, B is -(CHR ₄ )-, D is -(C=O)-, E is -(ZR ₆ )-, and G is- (C=O)-(XR ₉ )-, and the compound has the formula III:

<Formula III>

In the above formula, R ₁ , R ₂ , R ₄ , R ₆ , R ₉ , W and X are as defined in formula I, and Z is nitrogen or CH (when Z is CH, X is nitrogen).

In certain embodiments, A is -(C=O)-, B is -(CHR ₄ )-, D is -(C=O)-, E is -(ZR ₆ )-, and G is- (XR ₇ ) _n -and the compound has the formula IV:

<Formula IV>

In the above formula, R ₁ , R ₂ , R ₄ , R ₆ , R ₇ , W, X and n are as defined in Formula I, Z is nitrogen or CH, but when Z is nitrogen, n is 0, When Z is CH, X is nitrogen and n is not zero.

In certain embodiments, the compound has Formula VI:

<Formula VI>

In the above formula, R _a is a bicyclic aryl group having 8 to 11 ring members which may have 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur, and R _b is 1 to 1 selected from nitrogen, oxygen or sulfur. It is a monocyclic aryl group having 5 to 7 ring members that may have 2 heteroatoms, and the aryl ring in the compound is at least one substituent selected from the group consisting of halide, hydroxy, cyano, lower alkyl and lower alkoxy group Can have Optionally, R _a is a naphthyl, quinolinyl or isoquinolinyl group, and R _b is phenyl, pyridyl or piperidyl, all of which consist of halide, hydroxy, cyano, lower alkyl and lower alkoxy groups. It may be substituted with one or more substituents selected from the group. In certain embodiments, R _a is naphthyl and R _b is phenyl, which may be substituted with one or more substituents selected from the group consisting of halide, hydroxy, cyano, lower alkyl and lower alkoxy groups.

In certain embodiments, the compound is selected from compounds 1, 3, 4 and 5 as defined in US 6,413,963.

US 7,563,825. All compound genera, species and conformational forms thereof of US 7,563,825, including the exemplary compounds of Tables 1 to 5 of US 7,563,825, the claimed compounds and each of the disclosed compounds, are exemplary compounds for use in the methods claimed herein by Applicants. All are incorporated herein by reference.

Specific exemplary embodiments include compounds having Formula (I):

<Formula I>

In the above formula, A is -(C=O)-(CHR ₃ )-, B is -NR ₄ -, D is -(CHR ₅ )- or -(C=O)-, and E is -(ZR ₆ )- or -(C=O)-, and G is -(XR ₇ ) _n -, -(CHR ₇ )-(NR ₈ )-, -(C=O)-(XR ₉ )- or -( C=O)-, W is -Y(C=O)-, -(C=O)NH-, -(SO ₂ )- or absent, Y is oxygen or sulfur, and X and Z are independently As nitrogen or CH, n is 0 or 1; R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are the same or different, and amino acid side chain residues or derivatives thereof, the rest of the molecule, linkers and solid supports, and It is independently selected from their stereoisomers. More specifically, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are amino C _2-5 alkyl, guanidine C _2-5 alkyl, C _1-4 AlkylguanidinoC _2-5 alkyl, diC _1-4 alkylguanidino-C _2-5 alkyl, amidinoC _2-5 alkyl, C _1-4 alkylamidinoC _2-5 alkyl, diC _{1 -4} alkylamidinoC _2-5 alkyl, C _1-3 alkoxy, phenyl, substituted phenyl (wherein the substituent is amino, amidino, guanidino, hydrazino, amidrazonyl, C _1-4 alkylamino, independently selected from C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, sulfuryl or one or more of the hydroxyl ), benzyl, substituted benzyl (wherein the substituent on the benzyl is amino, amidino, guanidino, hydrazino, amidrazonyl, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro Independently selected from one or more of C _1-4 alkyl, C _1-3 alkyl, nitro, carboxy, cyano, sulfuryl, or hydroxyl), naphthyl, substituted naphthyl, wherein the substituent is amino, amidino, Guanidino, hydrazino, amidrazonyl, C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro , Carboxy, cyano, sulfuryl or hydroxyl independently selected from one or more), bisphenyl methyl, substituted bis-phenyl methyl (wherein the substituents are amino, amidino, guanidino, hydrazino, amidrazonyl , C _1-4 alkylamino, C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, sulfuryl or hydrogen Independently selected from one or more of the hydroxyls), pyridyl, substituted pyridyl, wherein the substituents are amino, amidino, guanidino, hydrazino, amidrazonyl, C _1-4 alkylamino, C _1-4 di Alkyl Independently selected from one or more of amino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl), pyridyl C _{1 -4} alkyl, substituted pyridylC _1-4 alkyl (wherein the pyridine substituent is amino, amidino, guanidino, hydrazino, amidrazonyl, C _1-4 alkylamino, C _1-4 dialkylamino, Halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl independently selected from one or more), pyrimidyl C _1-4 Alkyl, substituted pyrimidylC _1-4 alkyl (wherein the pyrimidine substituent is amino, amidino, guanidino, hydrazino, amidrazonyl, C _1-4 alkylamino, C _1-4 dialkylamino, halogen , Perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, independently selected from one or more of nitro, carboxy, cyano, sulfuryl or hydroxyl), triazin-2-yl- C _1-4 alkyl, substituted triazin-2-yl-C _1-4 alkyl (wherein the triazine substituent is amino, amidino, guanidino, hydrazino, amidrazonyl, C _1-4 alkylamino, independently selected from C _1-4 dialkylamino, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, sulfuryl or one or more of the hydroxyl ), imidazo C _1-4 alkyl, substituted imidazole C _1-4 alkyl (wherein the imidazole substituent is amino, amidino, guanidino, hydrazino, amidrazonyl, C _1-4 alkylamino, C _1-4 D are independently selected from alkyl, halogen, perfluoro C _1-4 alkyl, C _1-4 alkyl, C _1-3 alkoxy, nitro, carboxy, cyano, sulfuryl or one or more hydroxyl) , Imidazolinylalkyl, N-amidinopiperazinyl-NC _0-4 alkyl, hydroxyC _2-5 alkyl, C _1-5 alkylaminoC _2-5 alkyl, hydroxyC _2-5 alkyl, C _1-5 tablets Independently from the group consisting of _{killaminoC 2-5} alkyl, C _1-5 dialkylaminoC _2-5 alkyl, N-amidinopiperidinylC _1-4 alkyl and 4-aminocyclohexylC _0-2 alkyl Is selected.

In one embodiment, R ₁ , R ₂ , R ₆ , and R ₇ , R ₈ and R _{9 of E} are the same or different and represent the remainder of the compound, and R ₃ of A, R _{4 of} B, or R ₅ of D is selected from amino acid side chain residues or derivatives thereof. As used herein, the term "remaining part of the compound" refers to any moiety covalently attached to the α-helix mimetic structure at the R ₁ , R ₂ , R ₅ , R ₆ , R ₇ , R ₈ and/or R ₉ positions. , Agent, compound, support, molecule, linker, amino acid, peptide or protein. The term also includes amino acid side chain residues and derivatives thereof as defined in US 7,563,825.

A is -(C=O)-CHR ₃ -, B is -NR ₄ , D is -(C=O)-, E is -(ZR ₆ )-, and G is -(C=O) In an embodiment where -(XR ₉ )-, the α-helix mimetic compound for use in the present invention has the formula III:

<Formula III>

In the above formula, R ₁ , R ₂ , R ₄ , R ₆ , R ₉ , W and X are as defined above, and Z is nitrogen or CH (when Z is CH, X is nitrogen). In a preferred embodiment, R ₁ , R ₂ , R ₆ and R ₉ represent the remainder of the compound and R ₄ is selected from amino acid side chain residues. A is -O-CHR ₃ -, B is -NR ₄ -, D is -(C=O)-, E is -(ZR ₆ )-, G is -(XR ₇ ) _n- In a specific embodiment, the α-helix mimetic compound for use in the present invention has the formula IV:

<Formula IV>

In the above formula, R ₁ , R ₂ , R ₄ , R ₆ , R ₇ , W, X and n are as defined above, and Z is nitrogen or CH (when Z is nitrogen, n is 0, and Z is CH In the case X is nitrogen and n is not zero). In a preferred embodiment, R ₁ , R ₂ , R ₆ and R ₇ represent the remainder of the compound and R ₄ is selected from amino acid side chain residues. In this case, R ₆ or R ₇ may each be selected from amino acid side chain residues when Z and X are CH.

WO 2010/128685. All compound genera, species and conformational forms of WO 2010/128685, including the exemplary compounds in the table of WO 2010/128685, the claimed compounds and each of the disclosed compounds, are exemplary compounds for use in the methods claimed herein by the applicant. All are incorporated herein by reference.

(1) a compound having the following formula (I) or a pharmaceutically acceptable salt thereof:

<Formula I>

는 단일 결합 또는 이중 결합이고;In the above formula,

Is a single bond or a double bond;

A is -CHR ⁷ -,

here

R ⁷ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl Alkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl;

E is a bond, -CHR ⁵ -, -O- or -NR ⁸ -,

here

R ⁵ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl or optionally substituted heteroarylalkyl;

R ⁸ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;

B is a void or an optionally substituted monocyclic ring formed with G and Y;

D void, or an optionally substituted spiro ring formed with Y,

Neither B nor D is present;

When B is present, G and Y are independently a carbon atom or a nitrogen atom,

When D is present, Y is a carbon atom, G is -NR ⁶ -, -O-, -CHR ⁶ -or -C(R ⁶ ) ₂ -,

When both B and D are voids, G and Y are the same or different and are each -NR ⁶ -, -O-, -CHR ⁶ -or -C(R ⁶ ) ₂ -,

here

Each R ⁶ is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, Optionally substituted arylalkyl or optionally substituted heteroarylalkyl,

When E is a bond, D is a void, B is an optionally substituted monocyclic ring, and G and Y are independently a carbon atom or a nitrogen atom;

R ¹ is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl;

R ² is -W ²¹ -W ²² -Rb-R ²⁰ ,

here

W ²¹ is -(CO)- or -(SO ₂ )-,

W ²² is a bond, -O-, -NH- or an optionally substituted lower alkylene,

Rb is a bond or optionally substituted alkylene,

R ²⁰ is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl;

R ³ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;

D is a void, E is a bond, B is benzene, R ² is -W ²¹ -W ²² -Rb-R ²⁰ (where W ²¹ is -(CO)-, W ²² is -NH-, Rb is a bond), R ²⁰ must not be an optionally substituted phenyl.

(2) a compound according to (1) mentioned above, wherein in formula (I),

D is the void,

B is an optionally substituted 3, 4, 5, 6 or 7 membered saturated or unsaturated monocyclic ring formed with G and Y.

(3) a compound according to (1) mentioned above, wherein in formula (I),

D is the void,

B is an optionally substituted 4, 5, 6 or 7 membered saturated or unsaturated heterocyclic ring formed with G and Y, the hetero atom is selected from S, N and O, and the number of heteroatoms is 1 to 3 It is an integer.

(4) a compound according to (1) mentioned above, wherein in formula (I),

D is a void;

B is an optionally substituted 5 or 6 membered saturated or unsaturated heterocyclic ring formed with G and Y, the hetero atom is selected from S, N and O, and the number of hetero atoms is an integer of 1 to 3.

(5) a compound according to (1) mentioned above, wherein in formula (I),

B is a void;

D is an optionally substituted spiro ring;

G is ^{-NR 6 '-, -CHR 6 -} , -C (R 6) 2 - or an -O-,

here

Each R ⁶ is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, Optionally substituted arylalkyl or optionally substituted heteroarylalkyl,

R ^6′ is optionally substituted cyclic or bicyclic lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl.

(6) a compound according to (1) mentioned above, wherein in formula (I),

B is a void;

D is an optionally substituted C _3-8 cycloalkane;

G is ^{-NR 6 '-, -CHR 6 -} , -C (R 6) 2 - or an -O-,

here

Each R ⁶ is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, Optionally substituted arylalkyl or optionally substituted heteroarylalkyl,

R ^6′ is optionally substituted cyclic or bicyclic lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl.

(7) a compound according to (1) mentioned above, wherein in formula (I),

B and D are both voids,

At least one of G and Y is ^{-NR 6 '-, -CHR 6 -} , -C (R 6) 2 - or an -O-,

here

Each R ⁶ is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, Optionally substituted arylalkyl or optionally substituted heteroarylalkyl,

R ^6′ is optionally substituted cyclic or bicyclic lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl.

(8) a compound according to (1) mentioned above, wherein in formula (I),

B and D are both voids;

G is ^{-NR 6 '-, -CHR 6'} -, -C (R 6 ') 2 - or an -O-,

here

Each R ^6′ is independently optionally substituted cyclic or bicyclic lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl.

(9) a compound according to (1) mentioned above, wherein in formula (I),

B and D are both voids;

G is -NR ^{6 '-} is or -O-,

here

R ^6′ is optionally substituted lower alkyl, optionally substituted alkenyl or optionally substituted aryl;

Y is -CHR ⁶ -or -C(R ⁶ ) ₂ -,

here

Each R ⁶ is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, Optionally substituted arylalkyl or optionally substituted heteroarylalkyl.

(10) a compound according to (1) mentioned above, wherein in formula (I),

B and D are both voids;

G is -NR ^{6 '-} is or -O-,

here

R ^{6 'is} optionally substituted lower alkyl, optionally substituted alkenyl, and;

Y is -CHR ⁶ -or -C(R ⁶ ) ₂ -,

here

R ⁶ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl.

(11) a compound according to (1) mentioned above, wherein in formula (I),

E is -CHR ⁵ -, -O- or -NR ⁸ -,

here

R ⁵ is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl or optionally substituted lower alkynyl,

R ⁸ is hydrogen, lower alkyl, lower alkenyl or lower alkynyl.

(12) a compound according to (1) mentioned above, wherein in formula (I),

E is -CHR ⁵ -, -O- or -NR ⁸ -,

here

R ⁵ is hydrogen or optionally substituted lower alkyl,

R ⁸ is hydrogen, lower alkyl, lower alkenyl or lower alkynyl.

(13) a compound according to (1) mentioned above, wherein in formula (I),

E is -CHR ⁵ -, -O- or -NR ⁸ -,

here

R ⁵ is hydrogen or lower alkyl,

R ⁸ is hydrogen, lower alkyl, lower alkenyl or lower alkynyl.

(14) a compound according to (1) mentioned above, wherein in formula (I),

E is -CHR ⁵ -, -O- or -NR ⁸ -,

here

R ⁵ is hydrogen, lower alkyl, lower alkenyl or lower alkynyl,

R ⁸ is hydrogen or alkyl.

(15) a compound according to (1) mentioned above, wherein in formula (I),

E is -CHR ⁵ -, -O- or -NR ⁸ -,

here

R ⁵ is hydrogen or lower alkyl,

R ⁸ is hydrogen or lower alkyl.

(16) a compound according to (1) mentioned above, wherein in formula (I),

E is -O- or -NR ⁸ -;

here

R ⁸ is hydrogen or lower alkyl.

(17) a compound according to (1) mentioned above, wherein in formula (I),

D is a void, B is an optionally substituted monocyclic ring, and E is a bond.

(18) a compound according to (1) mentioned above, wherein in formula (I),

R ³ is hydrogen or a C _1-4 alkyl group.

(19) a compound according to (1) mentioned above, wherein in formula (I),

R ³ is hydrogen.

(20) a compound according to (1) mentioned above, wherein in formula (I),

D is a void;

B is an optionally substituted cyclopropane formed with G and Y, optionally substituted cyclobutane, optionally substituted cyclopentane, optionally substituted cyclohexane, optionally substituted cycloheptane, optionally substituted pyrrolidine, optionally substituted pyra. Sol, optionally substituted cyclopropene, optionally substituted cyclobutene, optionally substituted cyclopentene, optionally substituted cyclohexene, optionally substituted cycloheptene, optionally substituted cyclopentadiene, optionally substituted dihydro-pyrrole, optionally substituted Substituted pyrrole, optionally substituted dihydro-pyrazole, optionally substituted imidazole, optionally substituted thiophene, optionally substituted thiazole, optionally substituted isothiazole, optionally substituted thiadiazole, optionally substituted furan, optionally Substituted oxazole, optionally substituted isoxazole, optionally substituted oxadiazole, optionally substituted benzene, optionally substituted pyridine, optionally substituted pyridazine, optionally substituted pyrimidine, optionally substituted pyrazine and optionally substituted triazine Is selected from

(21) a compound according to any one of (1) to (4) and (11) to (20) mentioned above, in formula (I),

B is present, -R ⁹ , -OR ⁹ , -COR ⁹ , -COOR ⁹ , -CONR ⁹ R ⁴ , -NR ⁹ R ⁴ , -SR ⁹ , -SO ₂ R ⁹ , -SO ₂ NR ⁹ R ⁴ , -SO ₃ R ⁹ , -NHC(NHR ⁹ )NR ⁴ and optionally substituted by one or more chemical moieties selected from the group consisting of halogen,

here

R ⁹ and R ⁴ are independently selected from a hydrogen atom, optionally substituted cyclic or bicyclic alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl.

(22) a compound according to (1) mentioned above, wherein in formula (I),

B is a void;

D is an optionally substituted cycloalkane.

(23) a compound according to (22) mentioned above, wherein in formula (I),

B is a void;

D is an optionally substituted C _3-8 cycloalkane.

(24) a compound according to (22) mentioned above, wherein in formula (I),

B is a void;

D is an optionally substituted C _3-6 cycloalkane.

(25) a compound according to (1) mentioned above, wherein in formula (I),

R ¹ is -Ra-R ¹⁰ ,

here

Ra is an optionally substituted lower alkylene,

R ¹⁰ is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl.

(26) a compound according to (23) mentioned above, wherein in formula (I),

R ¹ is -Ra-R ¹⁰ ,

here

Ra is an optionally substituted lower alkylene,

R ¹⁰ is hydrogen, optionally substituted aryl or optionally substituted heteroaryl.

(27) a compound according to (25) mentioned above, wherein in formula (I),

R ¹⁰ is hydrogen, optionally substituted methyl, optionally substituted ethyl, optionally substituted propyl, optionally substituted isopropyl, optionally substituted isobutyl, optionally substituted cyclohexyl, optionally substituted benzhydryl, optionally substituted biphenyl , Optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrimidyl, optionally substituted pyridazinyl, optionally substituted pyrazinyl, optionally substituted triazinyl, optionally substituted pyrrolyl, optionally substituted thienyl, optionally Substituted furanyl, optionally substituted thiazolyl, optionally substituted oxazolyl, optionally substituted imidazolyl, optionally substituted naphthyl, optionally substituted tetrahydronaphthyl, optionally substituted quinolinyl, optionally substituted isoqui Nolinyl, optionally substituted quinazolinyl, optionally substituted quinoxalinyl, optionally substituted cinnolinyl, optionally substituted naphthyridinyl, optionally substituted benzotriazinyl, optionally substituted pyridopyrimidinyl, optionally substituted Pyridopyrazinyl, optionally substituted pyridopyridazinyl, optionally substituted pyridotriazinyl, optionally substituted indenyl, optionally substituted benzofuranyl, optionally substituted benzothienyl, optionally substituted indolyl, optionally substituted Indazolyl, optionally substituted benzoxazolyl, optionally substituted benzimidazolyl, optionally substituted benzothiazolyl, optionally substituted benzothiadiazolyl, optionally substituted furopyridinyl, optionally substituted thienopyridinyl, optionally substituted Substituted pyrrolopyridinyl, optionally substituted oxazolopyridinyl, optionally substituted thiazolopyridinyl, or optionally substituted imidazopyridinyl.

The above-mentioned compounds, but in formula I,

R ¹⁰ is hydrogen, optionally substituted biphenyl, optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrimidyl, optionally substituted pyridazinyl, optionally substituted pyrazinyl, optionally substituted triazinyl, optionally substituted Pyrrolyl, optionally substituted thienyl, optionally substituted furanyl, optionally substituted thiazolyl, optionally substituted oxazolyl, optionally substituted imidazolyl, optionally substituted naphthyl, optionally substituted tetrahydronaphthyl, optionally substituted Substituted quinolinyl, optionally substituted isoquinolinyl, optionally substituted quinazolinyl, optionally substituted quinoxalinyl, optionally substituted cinnolinyl, optionally substituted naphthyridinyl, optionally substituted benzotriazinyl, optionally substituted Substituted pyridopyrimidinyl, optionally substituted pyridopyrazinyl, optionally substituted pyridopyridazinyl, optionally substituted pyridotriazinyl, optionally substituted indenyl, optionally substituted benzofuranyl, optionally substituted benzothienyl , Optionally substituted indolyl, optionally substituted indazolyl, optionally substituted benzoxazolyl, optionally substituted benzimidazolyl, optionally substituted benzothiazolyl, optionally substituted benzothiadiazolyl, optionally substituted furopyridinyl, Optionally substituted thienopyridinyl, optionally substituted pyrrolopyridinyl, optionally substituted oxazolopyridinyl, optionally substituted thiazolopyridinyl or optionally substituted imidazopyridinyl.

(29) a compound according to (1) mentioned above, wherein in formula (I),

R ² is -W ²¹ -W ²² -Rb-R ²⁰ ;

here

W ²¹ is -(CO)- or -(SO ₂ )-,

W ²² is a bond, -O-, -NH- or an optionally substituted lower alkylene,

Rb is a bond or optionally substituted lower alkylene,

R ²⁰ is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl.

(30) a compound according to (29) mentioned above, wherein in formula I,

R ² is -W ²¹ -W ²² -Rb-R ²⁰ ;

here

W ²¹ is -(CO)- or -(SO ₂ )-,

W ²² is -O- or -NH-,

Rb is a bond or optionally substituted lower alkylene,

R ²⁰ is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl.

(31) a compound according to (29) and (30) mentioned above, wherein in formula I,

R ²⁰ is optionally substituted methyl, optionally substituted ethyl, optionally substituted propyl, optionally substituted butyl, optionally substituted isopropyl, optionally substituted isobutyl, optionally substituted cyclohexyl, optionally substituted benzhydryl, optionally substituted Substituted biphenyl, optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrimidyl, optionally substituted pyridazinyl, optionally substituted pyrazinyl, optionally substituted triazinyl, optionally substituted pyrrolyl, optionally substituted thier Nyl, optionally substituted furanyl, optionally substituted thiazolyl, optionally substituted oxazolyl, optionally substituted imidazolyl, optionally substituted naphthyl, optionally substituted tetrahydronaphthyl, optionally substituted quinolinyl, optionally substituted Isoquinolinyl, optionally substituted quinazolinyl, optionally substituted quinoxalinyl, optionally substituted cinnolinyl, optionally substituted naphthyridinyl, optionally substituted benzotriazinyl, optionally substituted pyridopyrimidinyl, Optionally substituted pyridopyrazinyl, optionally substituted pyridopyridazinyl, optionally substituted pyridotriazinyl, optionally substituted indenyl, optionally substituted benzofuranyl, optionally substituted benzothienyl, optionally substituted indolyl, Optionally substituted indazolyl, optionally substituted benzoxazolyl, optionally substituted benzimidazolyl, optionally substituted benzothiazolyl, optionally substituted benzothiadiazolyl, optionally substituted furopyridinyl, optionally substituted thienopyridinyl , Optionally substituted pyrrolopyridinyl, optionally substituted oxazolopyridinyl, optionally substituted thiazolopyridinyl, optionally substituted benzodioxolyl or optionally substituted imidazopyridinyl.

(32) a compound according to (1) mentioned above, wherein in formula (I),

R ⁷ of A is -Rc-R ⁷⁰ ,

here

Rc is a bond or optionally substituted lower alkylene,

R ⁷⁰ is hydrogen, optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl.

(33) a compound according to (32) mentioned above, wherein in formula (I),

R ⁷ of A is -Rc-R ⁷⁰ ,

here

Rc is a bond or optionally substituted lower alkylene,

R ⁷⁰ is hydrogen, optionally substituted aryl or optionally substituted heteroaryl.

(34) a compound according to (32) mentioned above, wherein in formula (I),

R ⁷⁰ is hydrogen, optionally substituted methyl, optionally substituted ethyl, optionally substituted propyl, optionally substituted butyl, optionally substituted isopropyl, optionally substituted isobutyl, optionally substituted biphenyl, optionally substituted phenyl, optionally substituted Substituted pyridyl, optionally substituted pyrimidyl, optionally substituted pyridazinyl, optionally substituted pyrazinyl, optionally substituted triazinyl, optionally substituted pyrrolyl, optionally substituted thienyl, optionally substituted furanyl, optionally substituted Thiazolyl, optionally substituted oxazolyl, optionally substituted imidazolyl, optionally substituted naphthyl, optionally substituted tetrahydronaphthyl, optionally substituted quinolinyl, optionally substituted isoquinolinyl, optionally substituted quinazoli Nyl, optionally substituted quinoxalinyl, optionally substituted sinolinyl, optionally substituted naphthyridinyl, optionally substituted benzotriazinyl, optionally substituted pyridopyrimidinyl, optionally substituted pyridopyramidinyl, optionally substituted Pyridopyridazinyl, optionally substituted pyridotriazinyl, optionally substituted indenyl, optionally substituted benzofuranyl, optionally substituted benzothienyl, optionally substituted indolyl, optionally substituted indazolyl, optionally substituted benzooxa Zolyl, optionally substituted benzimidazolyl, optionally substituted benzothiazolyl, optionally substituted benzothiadiazolyl, optionally substituted furopyridinyl, optionally substituted thienopyridinyl, optionally substituted pyrrolopyridinyl, optionally substituted Substituted oxazolopyridinyl, optionally substituted thiazolopyridinyl or optionally substituted imidazopyridinyl.

(35) a compound according to (33) mentioned above, wherein in formula (I),

R ⁷⁰ is hydrogen, optionally substituted biphenyl, optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrimidyl, optionally substituted pyridazinyl, optionally substituted pyrazinyl, optionally substituted triazinyl, optionally substituted Pyrrolyl, optionally substituted thienyl, optionally substituted furanyl, optionally substituted thiazolyl, optionally substituted oxazolyl, optionally substituted imidazolyl, optionally substituted naphthyl, optionally substituted tetrahydronaphthyl, optionally substituted Substituted quinolinyl, optionally substituted isoquinolinyl, optionally substituted quinazolinyl, optionally substituted quinoxalinyl, optionally substituted sinolinyl, optionally substituted naphthyridinyl, optionally substituted benzotriazinyl, optionally substituted Substituted pyridopyrimidinyl, optionally substituted pyridopyrazinyl, optionally substituted pyridopyridazinyl, optionally substituted pyridotriazinyl, optionally substituted indenyl, optionally substituted benzofuranyl, optionally substituted benzothienyl , Optionally substituted indolyl, optionally substituted indazolyl, optionally substituted benzoxazolyl, optionally substituted benzimidazolyl, optionally substituted benzothiazolyl, optionally substituted benzothiadiazolyl, optionally substituted furopyridinyl, Optionally substituted thienopyridinyl, optionally substituted pyrrolopyridinyl, optionally substituted oxazolopyridinyl, optionally substituted thiazolopyridinyl or optionally substituted imidazopyridinyl.

(36) a compound according to (1) mentioned above, wherein in formula (I),

D is a void;

B is an optionally substituted 4-, 5-, 6- or 7-membered saturated or unsaturated heterocyclic ring formed with G and Y, the hetero atom is selected from S, N and O, and the number of hetero atoms is It is an integer of 1 to 3.

R ¹ is -Ra-R ¹⁰ ,

here

Ra is an optionally substituted lower alkylene,

R ¹⁰ is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

R ² is -W ²¹ -W ²² -Rb-R ²⁰ ,

here

W ²¹ is -(CO)- or -(SO ₂ )-,

W ²² is a bond, -O-, -NH- or an optionally substituted lower alkylene,

Rb is a bond or optionally substituted lower alkylene,

R ²⁰ is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

R ⁷ of A is -Rc-R ⁷⁰ ,

here

Rc is a bond or optionally substituted lower alkylene,

R ⁷⁰ is hydrogen, optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl.

(37) a compound according to (1) mentioned above, wherein in formula (I),

B is a void;

D is an optionally substituted C _3-8 cycloalkane;

G is -NR ⁶ or a ^{-O-, - '-, -CHR 6} ' -, -C (R 6 ') 2

here

Each R ^{6 'are} independently hydrogen, optionally substituted when clicking or acyclic lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl or optionally substituted heteroaryl alkyl;

R ¹ is -Ra-R ¹⁰ ,

here

Ra is an optionally substituted lower alkylene,

R ¹⁰ is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

R ² is -W ²¹ -W ²² -Rb-R ²⁰ ,

here

W ²¹ is -(CO)- or -(SO ₂ )-,

W ²² is a bond, -O-, -NH- or an optionally substituted lower alkylene,

Rb is a bond or optionally substituted lower alkylene,

R ²⁰ is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

R ⁷ of A is -Rc-R ⁷⁰ ,

here

Rc is a bond or optionally substituted lower alkylene,

R ⁷⁰ is hydrogen, optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl.

(38) a compound according to (1) mentioned above, wherein in formula (I),

B and D are both voids;

G is -NR ⁶ or a ^{-O-, - '-, -CHR 6} ' -, -C (R 6 ') 2

here

Each R ^{6 'are} independently hydrogen, optionally substituted when clicking or acyclic lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl or optionally substituted heteroaryl alkyl;

R ¹ is -Ra-R ¹⁰ ,

here

Ra is an optionally substituted lower alkylene,

R ¹⁰ is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

R ² is -W ²¹ -W ²² -Rb-R ²⁰ ,

here

W ²¹ is -(CO)- or -(SO ₂ )-,

W ²² is a bond, -O-, -NH- or an optionally substituted lower alkylene,

Rb is a bond or optionally substituted lower alkylene,

R ²⁰ is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

R ⁷ of A is -Rc-R ⁷⁰ ,

here

Rc is a bond or optionally substituted lower alkylene,

R ⁷⁰ is hydrogen, optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl.

(39) a compound according to (1) mentioned above, wherein in formula (I),

E is -CHR ⁵ -, -O- or -NR ⁸ -,

here

R ⁵ is hydrogen or optionally substituted lower alkyl,

R ⁸ is hydrogen, lower alkyl, lower alkenyl or lower alkynyl;

R ¹ is -Ra-R ¹⁰ ,

here

Ra is an optionally substituted lower alkylene,

R ¹⁰ is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

R ² is -W ²¹ -W ²² -Rb-R ²⁰ ,

here

W ²¹ is -(CO)- or -(SO ₂ )-,

W ²² is a bond, -O-, -NH- or an optionally substituted lower alkylene,

Rb is a bond or optionally substituted lower alkylene,

R ²⁰ is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

R ⁷ of A is -Rc-R ⁷⁰ ,

here

Rc is a bond or optionally substituted lower alkylene,

R ⁷⁰ is hydrogen, optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl.

(40) a compound according to (1) mentioned above, wherein in formula (I),

D is a void, E is a bond;

R ¹ is -Ra-R ¹⁰ ,

here

Ra is an optionally substituted lower alkylene,

R ¹⁰ is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

R ² is -W ²¹ -W ²² -Rb-R ²⁰ ,

here

W ²¹ is -(CO)- or -(SO ₂ )-,

W ²² is a bond, -O-, -NH- or an optionally substituted lower alkylene,

Rb is a bond or optionally substituted lower alkylene,

R ²⁰ is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

R ⁷ of A is -Rc-R ⁷⁰ ,

here

Rc is a bond or optionally substituted lower alkylene,

R ⁷⁰ is hydrogen, optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl.

(41) a compound according to (1) mentioned above, wherein in formula (I),

B and D are both voids;

G is -NR ⁶ or a ^{-O-, - '-, -CHR 6} ' -, -C (R 6 ') 2

here

Each R ^{6 'are} independently hydrogen, optionally substituted when clicking or acyclic lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl or optionally substituted heteroaryl alkyl;

E is -CHR ⁵ -, -O- or -NR ⁸ -,

here

R ⁵ is hydrogen or optionally substituted lower alkyl,

R ⁸ is hydrogen, lower alkyl, lower alkenyl or lower alkynyl.

(42) a compound according to (1) mentioned above, wherein in formula (I),

B is a void;

D is an optionally substituted C _3-8 cycloalkane;

G is -NR ⁶ or a ^{-O-, - '-, -CHR 6} ' -, -C (R 6 ') 2

here

Each R ^{6 'are} independently hydrogen, optionally substituted when clicking or acyclic lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl or optionally substituted heteroaryl alkyl;

E is -CHR ⁵ -, -O- or -NR ⁸ -,

here

R ⁵ is hydrogen or optionally substituted lower alkyl,

R ⁸ is hydrogen, lower alkyl, lower alkenyl or lower alkynyl;

R ¹ is -Ra-R ¹⁰ ,

here

Ra is an optionally substituted lower alkylene,

R ¹⁰ is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

R ² is -W ²¹ -W ²² -Rb-R ²⁰ ;

here

W ²¹ is -(CO)- or -(SO ₂ )-,

W ²² is a bond, -O-, -NH- or an optionally substituted lower alkylene,

Rb is a bond or optionally substituted lower alkylene,

R ²⁰ is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

R ⁷ of A is -Rc-R ⁷⁰ ,

here

Rc is a bond or optionally substituted lower alkylene,

R ⁷⁰ is hydrogen, optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl.

(43) a compound according to (1) mentioned above, wherein in formula (I),

B and D are both voids;

G is -NR ⁶ or a ^{-O-, - '-, -CHR 6} ' -, -C (R 6 ') 2

here

Each R ^{6 'are} independently hydrogen, optionally substituted when clicking or acyclic lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl or optionally substituted heteroaryl alkyl;

E is -CHR ⁵ -, -O- or -NR ⁸ -,

here

R ⁵ is hydrogen or optionally substituted lower alkyl,

R ⁸ is hydrogen, lower alkyl, lower alkenyl or lower alkynyl;

R ¹ is -Ra-R ¹⁰ ,

here

Ra is an optionally substituted lower alkylene,

R ¹⁰ is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl.

R ² is -W ²¹ -W ²² -Rb-R ²⁰ ,

here

W ²¹ is -(CO)- or -(SO ₂ )-,

W ²² is a bond, -O-, -NH- or an optionally substituted lower alkylene,

Rb is a bond or optionally substituted lower alkylene,

R ²⁰ is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl.

R ⁷ of A is -Rc-R ⁷⁰ ,

here

Rc is a bond or optionally substituted lower alkylene,

R ⁷⁰ is hydrogen, optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl.

In a further embodiment of formula I, the compound comprises formula Ia

<Formula Ia>

In the above formula,

은 단일 결합 또는 이중 결합이고;

Is a single bond or a double bond;

A is -CHR ⁷ -,

here

R ⁷ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl Alkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl;

E is -CHR ⁵ -, -O- or -NR ⁸ -,

here

R ⁵ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl or optionally substituted heteroarylalkyl;

R ⁸ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;

B is an optionally substituted monocyclic ring formed with G and Y;

G and Y are independently a carbon atom or a nitrogen atom;

R ¹ is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl;

R ² is -W ²¹ -W ²² -Rb-R ²⁰ ,

here

W ²¹ is -(CO)- or -(SO ₂ )-,

W ²² is a bond, -O-, -NH- or an optionally substituted lower alkylene,

Rb is a bond or optionally substituted alkylene,

R ²⁰ is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl;

R ³ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl.

In yet another embodiment of formula I, said compound comprises formula Ib

<Formula Ib>

Wherein A is -CHR ⁷ -,

here

R ⁷ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl Alkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl;

E is -CHR ⁵ -, -O- or -NR ⁸ -,

here

R ⁵ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl or optionally substituted heteroarylalkyl;

R ⁸ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;

D is an optionally substituted spiro ring,

G is -NR ⁶ -, -O-, -CHR ⁶ -or -C(R ⁶ ) ₂ -,

here

Each R ⁶ is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally Substituted arylalkyl or optionally substituted heteroarylalkyl;

R ¹ is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl;

R ² is -W ²¹ -W ²² -Rb-R ²⁰ ,

here

W ²¹ is -(CO)- or -(SO ₂ )-,

W ²² is a bond, -O-, -NH- or an optionally substituted lower alkylene,

Rb is a bond or optionally substituted alkylene,

R ²⁰ is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl;

R ³ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl.

In yet another embodiment of formula I, the compound comprises formula Ic

<Formula Ic>

Wherein A is -CHR ⁷ -,

here

R ⁷ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl Alkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl;

E is -CHR ⁵ -, -O- or -NR ⁸ -,

here

R ⁵ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl or optionally substituted heteroarylalkyl,

R ⁸ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;

G is -NR ⁶ -, -O-, -CHR ⁶ -or -C(R ⁶ ) ₂ -,

here

Each R ⁶ is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally Substituted arylalkyl or optionally substituted heteroarylalkyl;

R ¹ is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl;

R ² is -W ²¹ -W ²² -Rb-R ²⁰ ,

here

W ²¹ is -(CO)- or -(SO ₂ )-,

W ²² is a bond, -O-, -NH- or an optionally substituted lower alkylene,

Rb is a bond or optionally substituted alkylene,

R ²⁰ is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl;

R ³ is hydrogen or optionally substituted alkyl.

In yet another embodiment of formula I, the compound comprises formula Id

<Formula Id>

은 단일 결합 또는 이중 결합이고;In the above formula,

Is a single bond or a double bond;

A is -CHR ⁷ -,

here

R ⁷ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl Alkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl;

B is an optionally substituted monocyclic ring;

G is a carbon atom or a nitrogen atom;

R ¹ is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl;

R ² is -W ²¹ -W ²² -Rb-R ²⁰ ,

here

W ²¹ is -(CO)- or -(SO ₂ )-,

W ²² is a bond, -O-, -NH- or an optionally substituted lower alkylene,

Rb is a bond or optionally substituted alkylene,

R ²⁰ is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl;

R ³ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl,

Provided that when B is benzene, R ² is -W ²¹ -W ²² -Rb-R ²⁰ ; Where W ²¹ is -(CO)-; W ²² is -NH-; If Rb is a bond, then R ²⁰ must not be an optionally substituted phenyl.

WO 2010/044485 . All compound genera, species and conformational forms thereof of WO 2010/044485, including the exemplary compounds in the table of WO 2010/044485, the claimed compounds and each of the disclosed compounds are in their entirety as exemplary compounds for use in the methods claimed herein by the applicant. Is incorporated herein by reference.

(1) A compound having the following formula (I) or a pharmaceutically acceptable salt thereof:

Wherein A is -(CHR ⁷ )-;

here

R ⁷ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl Alkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl;

B and E are the same or different and are independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl, or

Or forming an optionally substituted spiro ring indicated by a broken line,

G is -NH-, -NR ⁶ -, -O-, -CH ₂ -, -CHR ⁶ -or -C(R ⁶ ) ₂ -;

here

Each R ⁶ is the same or different and is independently selected from optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl;

R ¹ is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl;

R ² is -W ²¹ -W ²² -Rb-R ²⁰ ;

here

W ²¹ is -(CO)- or -(SO ₂ )-;

W ²² is a bond, -O-, -NH- or an optionally substituted lower alkylene;

Rb is a bond or optionally substituted lower alkylene;

R ²⁰ is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl;

R ³ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, provided that

1) If Rb is an optionally substituted lower alkylene, W ²² must be -O- or -NH-,

2) If E and B are hydrogen, then R ³ must be hydrogen,

3) When G is -NH-, -CH ₂ -, -CHR ⁶ -or -NR ⁶ -, B and E must not be hydrogen,

4) If G is -O-, B and E are hydrogen, and R ³ is hydrogen, then R ¹ must not be 8-quinolylmethyl.

(2) a compound according to (1) mentioned above, wherein in formula (I),

B and E are the same or different and are independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl, or optionally substituted 3-, 4-, 5-, 6- or 7 When a -membered unsaturated monocyclic ring is formed, and the spiro ring formed is a heterocyclic ring, the hetero atom is selected from S, N and O, and the number of hetero atoms is 1.

(3) a compound according to (1) mentioned above, wherein in formula (I),

B and E are the same or different and are independently selected from hydrogen and optionally substituted alkyl, or form an optionally substituted 3-, 4-, 5-, 6- or 7-membered unsaturated monocyclic ring, and formed When the spiro ring is a heterocyclic ring, the hetero atom is selected from S, N and O, and the number of hetero atoms is 1.

(4) a compound according to (1) mentioned above, wherein in formula (I),

G is -NR ⁶ -, -O-, -CH ₂ -or -C(R ⁶ ) ₂ -;

here

Each R ⁶ is the same or different and is independently selected from optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl.

(5) a compound according to (1) mentioned above, wherein in formula (I),

G is -O-.

(6) a compound according to (1) mentioned above, wherein in formula (I),

G is -O-,

B and E are hydrogen.

(7) a compound according to (1) mentioned above, wherein in formula (I),

R ³ is hydrogen.

(8) a compound according to (1) mentioned above, wherein in formula (I),

A is -(CHR ⁷ )-;

here

R ⁷ is optionally substituted alkyl, optionally substituted aryl or optionally substituted arylalkyl.

(9) a compound according to (1) mentioned above, wherein in formula (I),

R ¹ is optionally substituted alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl or optionally substituted cycloalkylalkyl.

(10) a compound according to (1) mentioned above, wherein in formula (I),

R ² is -W ²¹ -W ²² -Rb-R ²⁰ ;

here

W ²¹ is -(CO)- or -(SO ₂ )-;

W ²² is a bond, -O-, -NH- or an optionally substituted lower alkylene;

Rb is a bond or optionally substituted lower alkylene;

R ²⁰ is optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl.

(11) a compound according to (1) mentioned above, wherein in formula (I),

A is -(CHR ⁷ )-;

here

R ⁷ is optionally substituted alkyl or optionally substituted arylalkyl;

R ¹ is optionally substituted alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl or optionally substituted cycloalkylalkyl;

R ² is -W ²¹ -W ²² -Rb-R ²⁰ ;

here

W ²¹ is -(CO)- or -(SO ₂ )-;

W ²² is a bond, -O-, -NH- or an optionally substituted lower alkylene;

Rb is a bond or optionally substituted lower alkylene;

R ²⁰ is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl.

(12) a compound according to (1) mentioned above, wherein in formula (I),

R ¹ is -Ra-R ¹⁰ ;

here

Ra is an optionally substituted lower alkylene,

R ¹⁰ is optionally substituted aryl or optionally substituted heteroaryl.

(13) a compound according to (12) mentioned above, wherein in formula (I),

R ¹⁰ is optionally substituted biphenyl, optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrimidyl, optionally substituted pyridazinyl, optionally substituted pyrazinyl, optionally substituted triazinyl, optionally substituted pyrrolyl , Optionally substituted thienyl, optionally substituted furyl, optionally substituted thiazolyl, optionally substituted oxazolyl, optionally substituted imidazolyl, optionally substituted naphthyl, optionally substituted tetrahydronaphthyl, optionally substituted quinoli Nyl, optionally substituted isoquinolinyl, optionally substituted quinazolinyl, optionally substituted quinoxalinyl, optionally substituted sinolinyl, optionally substituted naphthyridinyl, optionally substituted benzotriazinyl, optionally substituted pyrido Pyrimidinyl, optionally substituted pyridopyrazinyl, optionally substituted pyridopyridazinyl, optionally substituted pyridotriazinyl, optionally substituted indenyl, optionally substituted benzofuryl, optionally substituted benzothienyl, optionally substituted Indolyl, optionally substituted indazolyl, optionally substituted benzoxazolyl, optionally substituted benzimidazolyl, optionally substituted benzothiazolyl, optionally substituted benzothiadiazolyl, optionally substituted furopyridinyl, optionally substituted thier Nopyridinyl, optionally substituted pyrrolopyridinyl, optionally substituted oxazolopyridinyl, optionally substituted thiazolopyridinyl or optionally substituted imidazopyridinyl.

(14) a compound according to (1) mentioned above, wherein in formula (I),

R ² is -W ²¹ -W ²² -Rb-R ²⁰ ;

here

W ²¹ is -(CO)- or -(SO ₂ )-;

W ²² is a bond, -O-, -NH- or an optionally substituted lower alkylene;

Rb is a bond or optionally substituted lower alkylene;

R ²⁰ is optionally substituted aryl or optionally substituted heteroaryl.

(15) a compound according to (14) mentioned above, wherein in formula (I),

R ²⁰ is optionally substituted biphenyl, optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrimidyl, optionally substituted pyridazinyl, optionally substituted pyrazinyl, optionally substituted triazinyl, optionally substituted pyrrolyl , Optionally substituted thienyl, optionally substituted furyl, optionally substituted thiazolyl, optionally substituted oxazolyl, optionally substituted imidazolyl, optionally substituted naphthyl, optionally substituted tetrahydronaphthyl, optionally substituted quinoli Nyl, optionally substituted isoquinolinyl, optionally substituted quinazolinyl, optionally substituted quinoxalinyl, optionally substituted sinolinyl, optionally substituted naphthyridinyl, optionally substituted benzotriazinyl, optionally substituted pyrido Pyrimidinyl, optionally substituted pyridopyrazinyl, optionally substituted pyridopyridazinyl, optionally substituted pyridotriazinyl, optionally substituted indenyl, optionally substituted benzofuryl, optionally substituted benzothienyl, optionally substituted Indolyl, optionally substituted indazolyl, optionally substituted benzoxazolyl, optionally substituted benzimidazolyl, optionally substituted benzothiazolyl, optionally substituted benzothiadiazolyl, optionally substituted furopyridinyl, optionally substituted thier Nopyridinyl, optionally substituted pyrrolopyridinyl, optionally substituted oxazolopyridinyl, optionally substituted thiazolopyridinyl or optionally substituted imidazopyridinyl.

(16) a compound according to (1) mentioned above, wherein in formula (I),

R ³ is selected from hydrogen and C _1-4 lower alkyl groups.

(17) a compound according to (1) mentioned above, wherein in formula (I),

R ⁷ of A is -Rc-R ⁷⁰ ,

here

Rc is a bond or optionally substituted lower alkylene,

R ⁷⁰ is optionally substituted aryl or optionally substituted heteroaryl.

(18) a compound according to (17) mentioned above, wherein in formula I,

R ⁷⁰ is optionally substituted biphenyl, optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrimidyl, optionally substituted pyridazinyl, optionally substituted pyrazinyl, optionally substituted triazinyl, optionally substituted pyrrolyl , Optionally substituted thienyl, optionally substituted furyl, optionally substituted thiazolyl, optionally substituted oxazolyl, optionally substituted imidazolyl, optionally substituted naphthyl, optionally substituted tetrahydronaphthyl, optionally substituted quinoli Nyl, optionally substituted isoquinolinyl, optionally substituted quinazolinyl, optionally substituted quinoxalinyl, optionally substituted sinolinyl, optionally substituted naphthyridinyl, optionally substituted benzotriazinyl, optionally substituted pyrido Pyrimidinyl, optionally substituted pyridopyrazinyl, optionally substituted pyridopyridazinyl, optionally substituted pyridotriazinyl, optionally substituted indenyl, optionally substituted benzofuryl, optionally substituted benzothienyl, optionally substituted Indolyl, optionally substituted indazolyl, optionally substituted benzoxazolyl, optionally substituted benzimidazolyl, optionally substituted benzothiazolyl, optionally substituted benzothiadiazolyl, optionally substituted furopyridinyl, optionally substituted thier Nopyridinyl, optionally substituted pyrrolopyridinyl, optionally substituted oxazolopyridinyl, optionally substituted thiazolopyridinyl or optionally substituted imidazopyridinyl.

(19) a compound according to (2) mentioned above, wherein in formula (I),

R ¹ is -Ra-R ¹⁰ ;

here

Ra is an optionally substituted lower alkylene,

R ¹⁰ is optionally substituted aryl or optionally substituted heteroaryl,

R ³ is selected from hydrogen and C _1-4 lower alkyl groups.

(20) a compound according to (2) mentioned above, wherein in formula I,

R ² is -W ²¹ -W ²² -Rb-R ²⁰ ;

here

W ²¹ is -(CO)- or -(SO ₂ )-;

W ²² is a bond, -O-, -NH- or an optionally substituted lower alkylene;

Rb is a bond or optionally substituted lower alkylene;

R ²⁰ is optionally substituted aryl or optionally substituted heteroaryl;

R ³ is selected from hydrogen and C _1-4 lower alkyl groups.

(21) a compound according to (2) mentioned above, wherein in formula (I),

R ⁷ of A is -Rc-R ⁷⁰ ,

here

Rc is a bond or optionally substituted lower alkylene,

R ⁷⁰ is optionally substituted aryl or optionally substituted heteroaryl;

R ³ is selected from hydrogen and C _1-4 lower alkyl groups.

(22) a compound according to (2) mentioned above, wherein in formula (I),

G is -NR ⁶ -, -O-, -CH ₂ -or -C(R ⁶ ) ₂ -;

here

Each R ⁶ is the same or different and is independently selected from optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl;

R ³ is selected from hydrogen and C _1-4 lower alkyl groups.

(23) a compound according to (2) mentioned above, wherein in formula I,

G is -NR ⁶ -, -O-, -CH ₂ -or -C(R ⁶ ) ₂ -;

here

Each R ⁶ is the same or different and is independently selected from optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl;

R ³ is hydrogen.

(24) a compound according to (3) mentioned above, wherein in formula (I),

R ¹ is -Ra-R ¹⁰ ;

here

Ra is an optionally substituted lower alkylene,

R ¹⁰ is an optionally substituted allyl,

R ³ is selected from hydrogen and C _1-4 lower alkyl groups.

(25) a compound according to (3) mentioned above, wherein in formula (I),

R ² is -W ²¹ -W ²² -Rb-R ²⁰ ;

here

W ²¹ is -(CO)- or -(SO ₂ )-;

W ²² is a bond, -O-, -NH- or an optionally substituted lower alkylene;

Rb is a bond or optionally substituted lower alkylene;

R ²⁰ is optionally substituted aryl or optionally substituted heteroaryl,

R ³ is selected from hydrogen and C _1-4 lower alkyl groups.

(26) a compound according to (3) mentioned above, wherein in formula (I),

R ⁷ of A is -Rc-R ⁷⁰ ,

here

Rc is a bond or optionally substituted lower alkylene,

R ⁷⁰ is optionally substituted aryl or optionally substituted heteroaryl;

R ³ is selected from hydrogen and C _1-4 lower alkyl groups.

(27) a compound according to (3) mentioned above, wherein in formula (I),

G is -NR ⁶ -, -O-, -CH ₂ -or -C(R ⁶ ) ₂ -;

here

Each R ⁶ is the same or different and is independently selected from optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl;

R ³ is selected from hydrogen and C _1-4 lower alkyl groups.

(28) a compound according to (3) mentioned above, wherein in formula (I),

G is -NR ⁶ -, -O-, -CH ₂ -or -C(R ⁶ ) ₂ -;

here

Each R ⁶ is the same or different and is independently selected from optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl;

R ³ is hydrogen.

(29) a compound according to (5) mentioned above, wherein in formula (I),

R ¹ is -Ra-R ¹⁰ ;

here

Ra is an optionally substituted lower alkylene,

R ¹⁰ is an optionally substituted allyl,

R ³ is selected from hydrogen or C _1-4 lower alkyl groups.

(30) a compound according to (5) mentioned above, wherein in formula (I),

R ² is -W ²¹ -W ²² -Rb-R ²⁰ ;

here

W ²¹ is -(CO)- or -(SO ₂ )-;

W ²² is a bond, -O-, -NH- or an optionally substituted lower alkylene;

Rb is a bond or optionally substituted lower alkylene;

R ²⁰ is optionally substituted aryl or optionally substituted heteroaryl,

R ³ is selected from hydrogen and C _1-4 lower alkyl groups.

(31) a compound according to (5) mentioned above, wherein in formula (I),

R ⁷ of A is -Rc-R ⁷⁰ ,

here

Rc is a bond or optionally substituted lower alkylene,

R ⁷⁰ is optionally substituted aryl or optionally substituted heteroaryl;

R ³ is selected from hydrogen and C _1-4 lower alkyl groups.

(32) a compound according to (5) mentioned above, wherein in formula I,

R ³ is hydrogen.

(33) a compound according to (6) mentioned above, wherein in formula (I),

R ¹ is -Ra-R ¹⁰ ;

here

Ra is an optionally substituted lower alkylene,

R ¹⁰ is an optionally substituted allyl,

R ³ is selected from hydrogen and C _1-4 lower alkyl groups.

(34) a compound according to (6) mentioned above, wherein in formula (I),

R ² is -W ²¹ -W ²² -Rb-R ²⁰ ;

here

W ²¹ is -(CO)- or -(SO ₂ )-;

W ²² is a bond, -O-, -NH- or an optionally substituted lower alkylene;

Rb is a bond or optionally substituted lower alkylene;

R ²⁰ is optionally substituted aryl or optionally substituted heteroaryl,

R ³ is selected from hydrogen and C _1-4 lower alkyl groups.

(35) a compound according to (6) mentioned above, wherein in formula (I),

R ⁷ of A is -Rc-R ⁷⁰ ,

here

Rc is a bond or optionally substituted lower alkylene,

R ⁷⁰ is optionally substituted aryl or optionally substituted heteroaryl;

R ³ is selected from hydrogen and C _1-4 lower alkyl groups.

(36) a compound according to (6) mentioned above, wherein in formula (I),

R ³ is hydrogen.

(37) a compound according to any one of (2), (3) and (5) mentioned above, wherein in formula I,

R ¹ is -Ra-R ¹⁰ ;

here

Ra is an optionally substituted lower alkylene,

R ¹⁰ is optionally substituted aryl or optionally substituted heteroaryl,

R ² is -W ²¹ -W ²² -Rb-R ²⁰ ;

here

W ²¹ is -(CO)- or -(SO ₂ )-;

W ²² is a bond, -O-, -NH- or an optionally substituted lower alkylene;

Rb is a bond or optionally substituted lower alkylene;

R ²⁰ is optionally substituted aryl or optionally substituted heteroaryl;

R ³ is selected from hydrogen and C _1-4 lower alkyl groups;

R ⁷ of A is -Rc-R ⁷⁰ ,

here

Rc is a bond or optionally substituted lower alkylene,

R ⁷⁰ is optionally substituted aryl or optionally substituted heteroaryl.

(38) a compound according to any one of (2), (3) mentioned above, wherein in formula I,

G is -NR ⁶ -, -O-, -CH ₂ -or -C(R ⁶ ) ₂ -;

here

Each R ⁶ is the same or different and is independently selected from optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl;

R ¹ is -Ra-R ¹⁰ ;

here

Ra is an optionally substituted lower alkylene,

R ¹⁰ is optionally substituted aryl or optionally substituted heteroaryl,

R ² is -W ²¹ -W ²² -Rb-R ²⁰ ;

here

W ²¹ is -(CO)- or -(SO ₂ )-;

W ²² is a bond, -O-, -NH- or an optionally substituted lower alkylene;

Rb is a bond or optionally substituted lower alkylene;

R ²⁰ is optionally substituted aryl or optionally substituted heteroaryl;

R ³ is hydrogen;

R ⁷ of A is -Rc-R ⁷⁰ ,

here

Rc is a bond or optionally substituted lower alkylene,

R ⁷⁰ is optionally substituted aryl or optionally substituted heteroaryl.

(39) a compound according to any one of (19), (24) and (38) mentioned above, wherein in formula I,

R ¹⁰ is optionally substituted biphenyl, optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrimidyl, optionally substituted pyridazinyl, optionally substituted pyrazinyl, optionally substituted triazinyl, optionally substituted pyrrolyl , Optionally substituted thienyl, optionally substituted furyl, optionally substituted thiazolyl, optionally substituted oxazolyl, optionally substituted imidazolyl, optionally substituted naphthyl, optionally substituted tetrahydronaphthyl, optionally substituted quinoli Nyl, optionally substituted isoquinolinyl, optionally substituted quinazolinyl, optionally substituted quinoxalinyl, optionally substituted sinolinyl, optionally substituted naphthyridinyl, optionally substituted benzotriazinyl, optionally substituted pyrido Pyrimidinyl, optionally substituted pyridopyrazinyl, optionally substituted pyridopyridazinyl, optionally substituted pyridotriazinyl, optionally substituted indenyl, optionally substituted benzofuryl, optionally substituted benzothienyl, optionally substituted Indolyl, optionally substituted indazolyl, optionally substituted benzoxazolyl, optionally substituted benzimidazolyl, optionally substituted benzothiazolyl, optionally substituted benzothiadiazolyl, optionally substituted furopyridinyl, optionally substituted thier Nopyridinyl, optionally substituted pyrrolopyridinyl, optionally substituted oxazolopyridinyl, optionally substituted thiazolopyridinyl or optionally substituted imidazopyridinyl.

(40) a compound according to any one of (20), (25) and (38) mentioned above, wherein in formula I,

R ²⁰ is optionally substituted biphenyl, optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrimidyl, optionally substituted pyridazinyl, optionally substituted pyrazinyl, optionally substituted triazinyl, optionally substituted pyrrolyl , Optionally substituted thienyl, optionally substituted furyl, optionally substituted thiazolyl, optionally substituted oxazolyl, optionally substituted imidazolyl, optionally substituted naphthyl, optionally substituted tetrahydronaphthyl, optionally substituted quinoli Nyl, optionally substituted isoquinolinyl, optionally substituted quinazolinyl, optionally substituted quinoxalinyl, optionally substituted sinolinyl, optionally substituted naphthyridinyl, optionally substituted benzotriazinyl, optionally substituted pyrido Pyrimidinyl, optionally substituted pyridopyrazinyl, optionally substituted pyridopyridazinyl, optionally substituted pyridotriazinyl, optionally substituted indenyl, optionally substituted benzofuryl, optionally substituted benzothienyl, optionally substituted Indolyl, optionally substituted indazolyl, optionally substituted benzoxazolyl, optionally substituted benzimidazolyl, optionally substituted benzothiazolyl, optionally substituted benzothiadiazolyl, optionally substituted furopyridinyl, optionally substituted thier Nopyridinyl, optionally substituted pyrrolopyridinyl, optionally substituted oxazolopyridinyl, optionally substituted thiazolopyridinyl or optionally substituted imidazopyridinyl.

(41) a compound according to any one of (21), (26) and (38) mentioned above, wherein in formula I,

R ⁷⁰ is optionally substituted biphenyl, optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrimidyl, optionally substituted pyridazinyl, optionally substituted pyrazinyl, optionally substituted triazinyl, optionally substituted pyrrolyl , Optionally substituted thienyl, optionally substituted furyl, optionally substituted thiazolyl, optionally substituted oxazolyl, optionally substituted imidazolyl, optionally substituted naphthyl, optionally substituted tetrahydronaphthyl, optionally substituted quinoli Nyl, optionally substituted isoquinolinyl, optionally substituted quinazolinyl, optionally substituted quinoxalinyl, optionally substituted sinolinyl, optionally substituted naphthyridinyl, optionally substituted benzotriazinyl, optionally substituted pyrido Pyrimidinyl, optionally substituted pyridopyrazinyl, optionally substituted pyridopyridazinyl, optionally substituted pyridotriazinyl, optionally substituted indenyl, optionally substituted benzofuryl, optionally substituted benzothienyl, optionally substituted Indolyl, optionally substituted indazolyl, optionally substituted benzoxazolyl, optionally substituted benzimidazolyl, optionally substituted benzothiazolyl, optionally substituted benzothiadiazolyl, optionally substituted furopyridinyl, optionally substituted thier Nopyridinyl, optionally substituted pyrrolopyridinyl, optionally substituted oxazolopyridinyl, optionally substituted thiazolopyridinyl or optionally substituted imidazopyridinyl.

(42) a compound according to any one of (37) and (38) mentioned above, wherein in formula I,

R ¹⁰ is optionally substituted biphenyl, optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrimidyl, optionally substituted pyridazinyl, optionally substituted pyrazinyl, optionally substituted triazinyl, optionally substituted pyrrolyl , Optionally substituted thienyl, optionally substituted furyl, optionally substituted thiazolyl, optionally substituted oxazolyl, optionally substituted imidazolyl, optionally substituted naphthyl, optionally substituted tetrahydronaphthyl, optionally substituted quinoli Nyl, optionally substituted isoquinolinyl, optionally substituted quinazolinyl, optionally substituted quinoxalinyl, optionally substituted sinolinyl, optionally substituted naphthyridinyl, optionally substituted benzotriazinyl, optionally substituted pyrido Pyrimidinyl, optionally substituted pyridopyrazinyl, optionally substituted pyridopyridazinyl, optionally substituted pyridotriazinyl, optionally substituted indenyl, optionally substituted benzofuryl, optionally substituted benzothienyl, optionally substituted Indolyl, optionally substituted indazolyl, optionally substituted benzoxazolyl, optionally substituted benzimidazolyl, optionally substituted benzothiazolyl, optionally substituted benzothiadiazolyl, optionally substituted furopyridinyl, optionally substituted thier Nopyridinyl, optionally substituted pyrrolopyridinyl, optionally substituted oxazolopyridinyl, optionally substituted thiazolopyridinyl or optionally substituted imidazopyridinyl;

R ²⁰ is optionally substituted biphenyl, optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrimidyl, optionally substituted pyridazinyl, optionally substituted pyrazinyl, optionally substituted triazinyl, optionally substituted pyrrolyl , Optionally substituted thienyl, optionally substituted furyl, optionally substituted thiazolyl, optionally substituted oxazolyl, optionally substituted imidazolyl, optionally substituted naphthyl, optionally substituted tetrahydronaphthyl, optionally substituted quinoli Nyl, optionally substituted isoquinolinyl, optionally substituted quinazolinyl, optionally substituted quinoxalinyl, optionally substituted sinolinyl, optionally substituted naphthyridinyl, optionally substituted benzotriazinyl, optionally substituted pyrido Pyrimidinyl, optionally substituted pyridopyrazinyl, optionally substituted pyridopyridazinyl, optionally substituted pyridotriazinyl, optionally substituted indenyl, optionally substituted benzofuryl, optionally substituted benzothienyl, optionally substituted Indolyl, optionally substituted indazolyl, optionally substituted benzoxazolyl, optionally substituted benzimidazolyl, optionally substituted benzothiazolyl, optionally substituted benzothiadiazolyl, optionally substituted furopyridinyl, optionally substituted thier Nopyridinyl, optionally substituted pyrrolopyridinyl, optionally substituted oxazolopyridinyl, optionally substituted thiazolopyridinyl or optionally substituted imidazopyridinyl;

R ⁷⁰ is optionally substituted biphenyl, optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrimidyl, optionally substituted pyridazinyl, optionally substituted pyrazinyl, optionally substituted triazinyl, optionally substituted pyrrolyl , Optionally substituted thienyl, optionally substituted furyl, optionally substituted thiazolyl, optionally substituted oxazolyl, optionally substituted imidazolyl, optionally substituted naphthyl, optionally substituted tetrahydronaphthyl, optionally substituted quinoli Nyl, optionally substituted isoquinolinyl, optionally substituted quinazolinyl, optionally substituted quinoxalinyl, optionally substituted sinolinyl, optionally substituted naphthyridinyl, optionally substituted benzotriazinyl, optionally substituted pyrido Pyrimidinyl, optionally substituted pyridopyrazinyl, optionally substituted pyridopyridazinyl, optionally substituted pyridotriazinyl, optionally substituted indenyl, optionally substituted benzofuryl, optionally substituted benzothienyl, optionally substituted Indolyl, optionally substituted indazolyl, optionally substituted benzoxazolyl, optionally substituted benzimidazolyl, optionally substituted benzothiazolyl, optionally substituted benzothiadiazolyl, optionally substituted furopyridinyl, optionally substituted thier Nopyridinyl, optionally substituted pyrrolopyridinyl, optionally substituted oxazolopyridinyl, optionally substituted thiazolopyridinyl or optionally substituted imidazopyridinyl.

Additional exemplary compounds

In certain exemplary aspects, the CBP/β-catenin antagonist (e.g., the CBP/β-catenin antagonist in Table 1) has the following ICG-001 and salts thereof (e.g., physiologically acceptable Salts) and derivatives.

<ICG-001>

In certain aspects, useful CBP/β-catenin antagonists (e.g., CBP/β-catenin antagonists in Table 1) are fatty acid groups esterified with a hydroxy benzyl group, for example by analogy in the following exemplary preferred compounds. (E.g., lauryl ester).

In certain aspects, fatty acid esters are those derived from one of the fatty acids in Table 2.

In a preferred aspect, the ester compounds of Table 1 include lauryl esters (e.g., the lauric ester of ICG-001 (Laura-8)).

<Laura-8>

In certain aspects,

As such, the alkyl derivatives of the useful CBP/β-catenin antagonists in Table 1 are used:

Wherein R ₁ is selected from C1-C6 alkyl, wherein the moiety adjacent on the ring (here, an exemplary bicyclic moiety) may be any of the substitutions at this position exemplified by the compound of Table 1. . In a preferred aspect, R ₁ is -CH ₃ . In certain aspects, R ₁ has the following conformation.

In certain aspects, the alkyl derivatives of the useful CBP/β-catenin antagonists of Table 1 include fatty acid groups (e.g., lauryl esters) esterified with, for example, a hydroxy benzyl group, such as the following exemplary compounds.

Wherein R ₁ is selected from C1-C6 alkyl. In a preferred aspect, R ₁ is -CH ₃ . In certain aspects, R ₁ has the following conformation.

In certain aspects, fatty acid esters are those derived from one of the fatty acids in Table 2. In a preferred aspect, lauryl esters are used.

<Table 2>

Prodrug

The invention also relates to prodrugs using libraries containing one or more compounds of formula (I). Prodrugs are typically designed to release the active drug in the body during or after absorption by enzymatic and/or chemical hydrolysis. The prodrug approach is an effective means to improve topical, oral, etc. bioavailability or intravenous administration of poorly water-soluble drugs by chemically derivatizing them into more water-soluble compounds. The most commonly used prodrug approach to increase the water solubility of drugs containing hydroxyl groups is to produce esters containing ionizable groups such as phosphate groups, carboxylate groups, alkylamino groups (literature [Fleisher et al., Advanced Drug Delivery Reviews, 115-130, 1996]; [Davis et al., Cancer Res., 7247-7253, 2002]; [Golik et al., Bioorg. Med. Chem. Lett., 1837-1842, 1996]).

In certain embodiments of the compounds of the present invention, the prodrugs of the present invention may serve as a substrate for a phosphatase, carboxylase or another enzyme.

Screening assays for compounds having utility in the present invention

According to a further aspect of the present invention, high-throughput assays may allow for the usual easy screening of compound libraries for compounds having utility in the present invention.

β-catenin:CBP interaction inhibitor . As a first problem, various methods for identifying the interacting small molecule inhibitors of β-catenin:CBP are well described in the art, e.g. discussed in detail in the patents and patent applications listed in Table 1 herein, and thus It will not be repeated herein.

Primary screen for compounds affecting asymmetric versus symmetric division in stem cells. In vitro. Based on the effect that epidermal stem cells are heterogeneous in their capacity to be activated based on the state of the molecular circadian clock of epidermal stem cells, an assay for screening an activator for asymmetric division of the stem cell pool is the present invention. It is used to identify compounds having the utility of. More specifically, Janisch P. et al. Nature 2011] demonstrated that a population of CD34 expressing lobe stem cells expressing high levels of the gene Per1/2 are more likely to respond to stimuli and activities that remove them from dormancy. The transcription factor BMAL1, a member of the ARNt family of transcription factors along with the molecular partner clock, drives key expression of circadian genes, including Per1 and Per2. Mice deficient in BMAL1 exhibit a premature aging phenotype including premature aging of the skin.

Thus, a high-throughput screen for selecting compounds that induce asymmetric division of epidermal stem cells is provided by human keratinocytes transfected with the Per/luciferase reporter gene. Keratinocytes stably transfected with the human Per/luc promoter are grown in vitro, then plated in 96 or 384 well plates, and screened by compound collection for compounds that increase luciferase expression. After treatment with the compound for 24 hours, cells will be lysed, treated with a luciferase substrate, and then read for luciferase activity on a high throughput plate reader (e.g., HP Topcount). . Good compounds can be screened a second time (see, for example, below).

Second screen for compounds affecting asymmetric versus symmetric division in stem cells. In vitro (human skin assay). Culture conditions and assays based on the literature [Varani J et al Experimental and Molecular Pathology, 2004].

According to a further aspect, human skin (eg, surgical waste from a plastic surgery procedure) is obtained and the subcutaneous fat layer is manually trimmed (eg, using a scalpel). Then, the skin is cut into small pieces of about 2 mm square and placed in a 6 well plate. 1 ml of keratinocyte culture medium (Gibco 10724-011) containing 1% P/S is added to each well. Place the epidermis contained in the medium face up. The next day (incubation in the medium overnight), the skin pieces are transferred to new wells each containing the compound to be tested. Skin samples of approximately 24 hours and 48 hours in culture are taken out for RNA isolation and qRT-PCR analysis of the gene of interest (eg Per1, 2). Several skin pieces are transferred every other day to a well of a fresh medium and treated continuously with the compound. Approximately 7 days after ex vivo culture, BrdU (final concentration of 20 uM per well) is added to assess proliferation. On approximately 9 days of ex vivo skin culture, skin fragments are harvested for histology, immunohistochemistry (eg staining of Per1, 2) and BrdU staining to assess proliferation. A good compound can be applied to a third screen (see, for example, below).

Third screen for compounds affecting asymmetric versus symmetric division in stem cells. In vivo . Asymmetric cell division is an important regulator of stem cell niches. During this procedure, a set of evolutionarily conserved proteins (eg, from C. elegans and Drosophila to humans) are asymmetrically distributed to daughter cells during mitosis. These include Par complex proteins, such as Par3 in mammals (Bazooka of Drosophila), Par 6 and atypical protein kinase C (aPKC), as well as transcriptional regulators (e.g., numb, Notch A voice modulator of signaling). This procedure is also important for the regulation of asymmetric division in epidermal stem cell niches (Williams S et al Nature 2011). According to certain aspects, thus, an in vivo assay can investigate the asymmetric distribution of the protein during mitosis in epidermal stem cell locus.

For example, Bultje et al. described an assay to measure asymmetric distribution in the ventricular zone (vz) to assess asymmetric division during neurogenesis (Bultje R Neuron 63, 189-202 , 2009]). Essentially, it is the treatment of the animal (adult or intrauterine) with the compound (orally, subcutaneous, intravenous or topical) for one set of periods with the compound, followed by sacrifice of the animal and distribution of Par3 in mitotic cells (Eg, via immunohistochemistry) versus DNA distribution (eg, using DAPI staining). Par3 distributes evenly between two daughter cells during symmetric division and unevenly (essentially, all in one daughter cell) during asymmetric differentiation. Applicants used this assay to show that after topical or oral administration to pregnant mice, the CBP/catenin antagonist ICG-001 did not affect the number of asymmetric divisions compared to vehicle control. However, p300/catenin antagonist IQ-1, which increases CBP/catenin signaling while impairing p300/catenin signaling, decreases the number of asymmetric cleavage and increases the number of symmetric cleavage. Importantly, as discussed in more detail herein, treatment with an excess of ICG-001 corrects for defects in the asymmetric cleavage caused by IQ-1, which results in increased symmetry (i.e., CBP/catenin dependence). ) Confirm that the re-equilibration of cleavage can be corrected with a CBP/catenin antagonist such as ICG-001.

Example

Example 1

(CBP/β-catenin antagonists have been shown to stimulate hair growth and increase wound healing in a leukemia mouse model.)

summary:

According to certain aspects described herein, the CBP/β-catenin antagonists surprisingly had substantial utility in stimulating hair growth and/or preventing hair loss. Applicants tested the ability of CBP/β-catenin antagonists to sensitize drug resistant leukemia cells to standard chemotherapy treatments. From the above experiment, the unexpected result was demonstrated that the CBP/β-catenin antagonist stimulates hair growth in a leukemia mouse model. Further surprising results were seen in the skin wounds of the mice in this experiment.

Materials and methods :

NOD/SCIDIL2R gamma-/- mice were shaved, irradiated with lethal dose, and then 50,000 cells per animal were injected intravenously. Leukemia animals were treated with a combination of vincristine/dexamethasone/L-asparaginase (VDL) and ICG-001 (50mg/kg/d) administered intraperitoneally, which was followed by a subcutaneous osmotic pump to ensure stable plasma levels. And the control group was treated with VDL alone for 20 days. The animals were periodically checked for survival, hair growth and wound healing.

Result :

Surprising results can be presented in FIG. 1. Within 2 weeks, treatment with intraperitoneal administration of ICG-001 (50mg/kg/d) rather than VDL alone treatment resulted in substantial hair growth covering the entire previously shaved area. Additionally, wounds induced while inserting the pump showed rapid healing in mice treated with ICG-001 compared to VDL treatment alone.

Conclusion :

A surprising result of stimulation of hair growth and increased healing rate was found in this experiment, which Applicants increased healing in normal and hairless mouse models (Example 2), and hair growth in hairless mouse models. The ability of stimulating (Example 3) CBP/catenin (eg, CBP/β-catenin) antagonists was tested.

Example 2

(CBP/catenin (e.g., CBP/β-catenin) antagonists have been shown to stimulate wound healing in both normal and hairless mouse models.)

The ability of CBP/catenin (eg, CBP/β-catenin) antagonists to accelerate damaged skin recovery in normal mouse models (having sufficient hair growth and normal hair) and hairless mouse models was tested. Briefly, on day 0, animals were subjected to skin injuries at two points on the back (the posterior end of each animal). Each skin injury site was treated with 500 μM petrolatum (mineral oil) (vehicle) or laura-8 of petrolatum once daily for 8 days.

As shown in Figure 2, in both animal models, Laura-8 (a derivative of ICG-001) significantly accelerated the skin healing process for 8 days.

Example 3

(CBP/catenin (eg, CBP/β-catenin) antagonists have been shown to stimulate hair growth in a hairless mouse model.)

The ability of CBP/β-catenin antagonists to stimulate hair growth in a hairless mouse model was tested. Briefly, animals were treated with mineral oil jelly or Laura-8 for 16 days. Additionally, skin samples from each animal were taken and examined for hair-vesicle formation.

As shown in FIG. 3, animals treated with Laura-8 in the hairless mouse model resulted in significant hair growth more than animals treated with mineral oil jelly. Figure 4 shows the skin pathology of skin samples taken from animals treated as described. The figure shows that there is substantial new hair-vesicle formation in mice treated with Laura-8 rather than in mice treated with mineral oil jelly.

Example 4

(CBP/catenin (eg, CBP/β-catenin) antagonists dramatically increased the expression of adenosine receptors.)

Overview :

The activity of minoxidil, the active ingredient of Rogaine, was mediated through adenosine receptors in dermal papillary cells. Some adenosine receptors were expressed in dermal papillary cells (A1, A2A and A2B) (Li M., J. Invest. Dermatol. 117, 1594-1600, 2001).

Applicants tested the ability of CBP/catenin antagonists to up-regulate the expression of adenosine receptors.

Result :

Applicants believe that treatment of cells in a culture medium with a CBP/catenin antagonist (e.g., ICG-001; 10 uM) dramatically (about 10) the expression of adenosine receptors, e.g. in colon epithelial adenosine receptor A2B (ADORA2B). Fold) to prove that the gene expression array experiment was performed.

According to certain embodiments, therefore, for example, to increase the expression of the adenosine receptor, for example, topical treatment of the scalp with a CBP/catenin (e.g. CBP/β-catenin) antagonist and/or minoxidil When modulating the sulfonylurea receptor 2B, which is believed to be a molecular target, administration of a CBP/catenin (e.g., CBP/β-catenin) antagonist along with another hair stimulant (e.g., minoxidil) may result in hair growth and / Or provided a strong additive or synergistic effect on regeneration.

Example 5

(Assay of ICG-001 and methylated ICG-001 compared to RA)

According to a specific aspect, Me-ICG-001 has substantial utility of the present invention.

Way . In vitro human skin assay culture conditions were based on the paper of Varani J et al Experimental and Molecular Pathology, 2004.

Briefly, human skin (surgical waste from a plastic surgery procedure) was obtained, and the subcutaneous fat layer was manually trimmed using a scalpel. Then, the skin was cut into small pieces of about 2 mm square and placed in a 6 well plate. 1 ml of keratinocyte culture medium (Gibco 10724-011) containing 1% P/S (penstrep antibiotic) was added to each well. The epidermis contained in the medium was placed facing up. The next day (cultivation in the above medium overnight), skin pieces were transferred to new wells containing 5uM ICG-001, 5uM methylated ICG-001 or 1ug/ml retinoic acid (RA). After 24 hours, the skin samples of the culture medium were subjected to RNA isolation and qRT- Taken out for PCR analysis.

Result . 18 shows the treatment of surgically discarded human skin as described herein. All compounds showed an increase in the expression of both elastin and aquaporin 1 with Me-ICG-001, which showed a greater increase than ICG-001 or RA at 5 uM.

Example 6

(Exemplary adjuvant therapy)

According to certain aspects, the CBP/catenin (e.g., CBP/β-catenin) antagonists described herein in the setting of adjuvant therapy (including but not limited to the use of one or more of the following exemplary compositions and/or methods). Had practical utility in the use of.

The use of one or more other hair growth stimulants is at least one selected from the group consisting of minoxidil, finasteride, dutasteride, bimatoprost and anti-androgen receptor blockers, such as fluridil.

Use of at least one anti-inflammatory agent is a short-acting β ₂ - agonists, persistence, β ₂ - agonists, anticholinergics, corticosteroids, systemic corticosteroids, mast cell stabilizers, leukotriene modifiers, methyl xanthine, β ₂ - agonist, albuterol, Levbuterol, pirbuterol, arformoterol, formoterol, salmeterol, anticholinergic agents such as ipatropium and tiotropium; Corticosteroids such as beclomethasone, budesonide, flunisolide, fluticasone, mometasone, triamcinolone, methylprednisolone, prednisolone, prednisone; Leukotriene modifiers such as montelukast, zapyrleukast and zileuton; Mast cell stabilizers such as cromoline and nedocromil; Methylzan, such as theophylline; Combination drugs such as ipatropium and albuterol, fluticasone and salmeterol, glucocorticoid steroids, budesonide and formoterol; Antihistamines such as hydroxyzine, diphenhydramine, loratadine, cetirizine and hydrocortisone; Immune system modulating drugs such as tacrolimus and pimecrolimus; Cyclosporine; Azathioprine; Mycophenolate mofetil; And it is selected from the group consisting of a combination thereof.

Absorbent dressing . Medipore (3M); Ceylon Dual-Dress 04P ^® Multi-Function Wound Dressing & Ceylon Dual-Dress 20F ^® Multi-Function Wound Dress (Bio Med Sciences); Aquacel Hydrofiber CombiDERM (ConvaTec); Absorptive Border (DermaRite); MULTIPAD, SOFSORB (DeRoyal); IODOFLEX (HEALTHPOINT); TIELLE (Johnson &Johnson); Curity ABD, TELFAMAX, TENDERSORB ABD (Kendall); Mepore (Molnlycke Health Care); EXU-DRY, Primapore (Smith & Nephew).

Alginate . AlgiCell (Dumex Medical); AlgiDERM (Bard); AlgiSite M (Smith & Nephew, Inc. Wound Management Division); Askina Sorg (Swiss-American); CarraSorb H, CarraGinate (Carrington) using Acemannan gel; CURASORB, CURASORB Zinc (Kendall/Tyco); Dermacea (Sherwood-Davis & ?┖?(Davis &Geck)); DermaGinate, DermaGinate AG (Dermarat); FyBron (B. Braun); Gentell (Gentell); Hyperion Advanced Alginate Dressing (Hyperion Medical, Inc.); KALTOSTAT (various appearance) (Convatech); KALGINATE, Algidex (various appearance) (DeRoyal); Maxorb (Medline); Melgisorb (Molnlikke Health Care); PolyMem (Ferris Mfg.); Restore CalciCare (Hollister); SILVERCELL (Johnson &Johnson); Sorbalgon (Hartmann-Conco Inc.); SORBSAN (Mylan Bertek); SeaSorb (Coloplast Corp.); Tegagen HG, Tegagen HI (3M Health Care).

Antibacterial agent . 3M Tegaderm Ag Mesh (3M); Amerigel (various appearance) (Amerx Health Care Corp); Anasept (Anacapa); Silverlon (Argentum Medical LLC); Di-Dak-Sol (Century Pharmaceuticals); Contreet (various appearances) (Coloplast Corporation); Aquacell Ag (Convatech); SilverDerm7 (The Marrit); Algidex (Deroyal); ColActive Ag (Hartman-Conco Inc.); Hydrofera Blue (Hydrofera Inc.); Actisorb (Johnson &Johnson); Kerlix AMD, Curity AMD, Excilon AMD, TELFA AMD (Kendall/Tico); Arglase (various appearances), Maxov Extra Ag, Optifoam AG, SilvaSorb (various appearances), XCell AM (Medlin); SelectSilver (Milliken Company); Acticoat 3, Acticoat 7, Acticoat Moisture Control, Iodoplex, IODOSORB (Smith &Nephew); Silver Seal (X-Static / Noble Biomaterials).

Cleanser . 3M Cavilon (3M); Wound Wash Saline (Blairex Labs); Clinical Care, Techni-Care (Care-Tech); Puri-Clens, Sea-Clens (Coloplast); Optipore Sponge, Saf-Clens, Shur-Clens (Convatech); Clean'N Moist, Repair Wound Cleanser (Darja Laboratories Inc.); DermaKlenz (The Maritt); Dermagran (Derma Sciences); ALLCLENZ (Health Point); Restore (hollister); Hyperion Wound Cleanser (Hyperion Medical, Inc.); DEBRISAN (Johnson &Johnson); Constant-Clens (Kendall); Skin Tegrity (Medlin); MPM, MPM Antimicrobial (MPM); Elta Dermal (Swiss-American Products).

Closure device . WoundTek's STAR Device (Woodtech, Inc); DP Woundcare Dressing (DP Woundcare); Dermabond (JnJ / Ethicon, www.dermabond.com): DermaClose RC (Woundcare Technologies).

Collagen . Medifil, Skin Temp (BioCore); BGC Matrix (Brennen); WOUN'DRESS (Coloplast Sween); Collagen/AG (Dermarat); Colactive Ag (Hartman-Konko, Inc); Fibracol plus Collagen Prisma, Promogran Prisma (Johnson &Johnson); Mephor Pro (Molnlikke); Stimulen (Southwest); Primatrix (TEI Biosciences); HyCURE, hyCURE Smart Gel (The Hymed Group); CellerateRx (Wound Care Innovations).

Compression dressing & wrap (leg) . 3M Coban 2 layer (3M); ArtAssist (ACI Medical); Gelocast Unna Boot, Artiflex, Comprilan, Tricofix (BSN); CIRCULON, DuoDERM SCB, Setopress, SurePress, UNNA-FLEX (Convatech); Primer, Unna-Pak (Glenwood, Inc.); 4-Layer Compression (Hartman-Conco); DYNA-FLEX (Johnson &Johnson); TENDERWRAP (Kendall); Profore, Profor LF, Profor Light (Smith & Nephew).

Complex dressing. Tegaderm Trasparent Dressing (3M) using Absorbent Pad; Ceylon Dual-Dress 04P ^® Multi-Function Wound Dress & Ceylon Dual-Dress 20F ^® Multi-Function Wound Dress (Bio Med Sciences); Coverlet (BSN); COVADERM (Deroyal); Telpa, VENTEX (Kendall); StrataSorb (Medlin); Oldress (Molnlikke Healthcare); MPM (MPM); Viasorb (Sherwood-Davis &?┖?); AIRSTRIP, Corberett, CovRSite Plus, Cutifilm, OpSite Plus, OpSite Post-Op (Smith &Nephew); Centurion SorbaView (Tri-State Hospital Supply).

Contact layer . Tegapore (3M); Silon-TSR ^® Temporary Skin Replacement (Bio Med Sciences); DERMANET (DeRoyal); Telpa clear (Kendall); Mepitel (Molnlikke Healthcare) Profore Wound Contact Layer (Smith &Nephew); N-TERFACE (Winfield Laboratories).

Enzyme Debrider . Accumzyme, Panafil, Collagenase (Health Point); Ethezyme™ 830 Papain Urea Debriding Ointment (Ethex); Etezyme™ Papain Urea Debriding Ointment (Etex); Kovia Ointment, Ziox Ointment (Stratus Pharmaceutical); Gladas (Smith & Nephew).

Filling (wound) . AcryDerm Strands (AcryMed); DermAssist (AssisTec); Cutinova Cavity (Beiersdorf-Jobst); Humatrix Microclysmic Gel (Care-Tech); Mesalt (Molnlikke Healthcare); MULTIDEX (Deroyal); PolyWic (Peris MFG.); BIAFINE (Medix).

Foam dressing. 3M Foam Dressing (non-adhesive), 3M Foam Advanced Dressing (3M); Vigi-FOAM (Bard), FLEXZAN (Bertek (Dow Hickam)); Ceylon Dual-Dress 20F ^® Multi-Function Wound Dress (Bio Med Sciences); Lyfoam, Lyoform A, Lyoform C, Lyoform Extra, Lyoform T (Convatech); POLYDERM (DeRoyal); Polymem (Peris MFG.); Hydrofera Blue (Hydrofera LLC); BIOPATCH (Johnson &Johnson); CURAFOAM (Kendall); Mepilex, Mepilex Border, Mitraflex, Mitraflex Plus (Molnlikke Health Care); Allevyn Adhesive, Allevyn Cavity, Allevyn Dressing, Allevyn Island, Allevyn Tracheostomy, Allevyn Sacral (Allevyn Sacral) (Smith & Nephew).

Hydrocolloid . Tegasorb, Tegasorb THIN (3M); Hydrocol (Vertech (Dow Hickcam)); BGC Matrix (Brennen); Comfeel (multiple appearance) (coloplast); Duoderm CGF, Duoderm (multiple appearances), SignaDRESS Sterile (Convatech); DermaFilm HD, DermaFilm Thin (The Marit); Restore (multiple appearance) (hollister); NU-DERM (Johnson &Johnson); Ultec (Kendall); ExuDERM (multiple appearance) (Medlin); RepliCare (multiple appearances), Cutinova Hydro, Cutinova Thin (Smith & Nephew).

Hydrofiber . Aqua Cell (Convatech).

Hydrogel . Tegagel (3M); Amerigel Topical Ointment (Amerigel Health Care); Bard Absorption Dressing, Biolex, Iamin (Bard Medical); Karasorb, Carrasyn, DIAB GEL (Carrington Laboratories); Un'dress, Purilon (Coloplast); Duoderm, SAF-Gel (Convatech); Repair Hydrogel (Daza Laboratories Inc.); DermaSyn (The Maritt); Derma Gran (Derma Sciences, Inc.); CURASOL (Health Point); Restore (Hollister Inc.); NU-GEL (Johnson &Johnson); CURAFIL (Kendall); SkinTegrity (Medlin); Hypergel, Normlgel (Molnlikke Healthcare), MPM (MPM Medical, Inc.); Diamine (ProCyte); PanoPlex (Sage Laboratories); IntraSite, SoloSite (Smith &Nephew); Elta Dermal (Swiss-American Products, Inc.).

Hydrogel immersed gauze . Dumb Assist (Assist Tech Medical, Inc.); Biorex (Bard); Carragauze (Carrington); ClearSite (Conmed Corp.); DermaGauze (The Maritt); Derma Gran (Derma Sciences); Gentel (Gentel); Kurasol (Health Point); Restore (hollister); Hyperion Hydrophilic Wound Dressings (Hyperion Medical, Inc.); INTEGRA-GEL (Integrity Medical Devices, Inc.); Kurafil (Kendall); Skintegrity (Medlin Industries); Normlgel Impregnated Gauze (Molnlikke Healthcare); MPM Conductive Gel Pad, MPM Gel Pad (MPM); Panogauze (sage); SoloSite Gel Conformable (Smith &Nephew); Elta Dermal (Swiss-American Products, Inc.).

Hydrogel sheet . Tegagel (3M); Vigilon (Bard); Clearsite (Conmed Corporation); Aquasorb (Deroyal); FLEXDERM (Vertech (Dow Hickkam)); Nu-Gel (Johnson &Johnson); CURAGEL (Kendall); Derma-Gel (Medlin Industries); FlexiGel (Smith & Nephew).

Measuring device . (Molnlikke Healthcare); Tru-Area Determination (NTL).

Various devices . EPIFLO-transdermal continuous delivery of oxygen (Ogenix, www.ogenix.net); Circulator Boot (Circulator Boot Corporation, www.circulatorboot.com).

Negative pressure wound therapy . Engenex (Boehringer Wound Systems, LLC, www.boehringerwound.com); Prospera PRO-I (Medica-Rents, Inc., www.medicarents.com); VAC (various models) (KCI, www.kci1.com); Versatile 1, V1STA (Smith &Nephew); Invia (Medela).

Odor absorbent . CarboFlex, Rioform C (Convatech); Odor Absorbing Dressing (Dumex).

Scar therapy and makeup . Oleeva (various), Ceylon (Bio Med Sciences); Mepiform (Molnlikke); Cica-Care (Smith &Nephew); Various (Local Pharmacy).

Skin care

For patients with wounds or at risk of skin destruction, several exemplary categories include antifungal agents, anti-inflammatory agents, barriers, moisturizers and sealants.

Skin replacement . Dermagraft, Transcyte (Advanced Biohealing); Hyalofil-F, Hyalofil-R (Convatech); Integra (various appearances) (Integra LifeSciences); Alloderm (Lifecell); Biobrane (Milan Vertech); Apligraf (Organogenesis); Free Matrix (Tay Biosciences).

Tissue Engineering/Growth Factor . Appligraf (Organogenesis, http://www.apligraf.com); Dermagraft, Transsheet (Advanced Biohealing, http://www.advancedbiohealing.com); GraftJACKET ^® Regenerative Tissue Matrix Ulcer Repair (Wright Medical Technologies, Inc.), http://www.wmt.com/graftjacket /); Graft Jacket ^® XPRESS Flowable Soft-Tissue Scaffold (Light Medical Technologies, Inc., http://www.wmt.com); Oasis (Healthpoint, http://www.healthpoint.com); Orcel (Ortec International, Inc., http://ortecinternational.com); Regranex (Johnson & Johnson, www.regranex.com).

Transparent film . Tegaderm HP, Tegaderm (3M); Ceylon-TSR ^® Temporary Skin Replacement (Bio Med Sciences); CarraFilm (Carrington); DermaView (The Maritt); TRANSEAL (Deroyal); BIOCLUSIVE MVP, Bioclusive (Johnson &Johnson); Blisterfilm, POLYSKIN II, Polyskin MR (Kendall); SureSite (Medline); Mefilm (Molnlikke Healthcare); Prosheet (prosheet); OpSite FLEXIGRID, Obsite, UniFlex (Smith & Nephew).

Included as reference

All such U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications mentioned herein and/or listed in the application data sheet are incorporated herein by reference in their entirety.

It is to be understood that the drawings and detailed description herein are to be regarded in an illustrative manner rather than a restrictive manner, and are not intended to limit the invention to the specific forms and embodiments disclosed. Conversely, the present invention includes any further modifications, changes, rearrangements, substitutions, substitutions, design choices and embodiments apparent to those skilled in the art, without departing from the spirit and scope of the present invention, as defined by the following claims. do. Accordingly, the following claims are intended to be construed as including all of the above additional modifications, changes, rearrangements, substitutions, substitutions, design choices and embodiments.

The embodiments described above depict different components contained within or linked to different other components. It should be understood that this illustrated architecture is merely exemplary and in fact many other architectures may be implemented that achieve the same functionality. From a conceptual point of view, any arrangement of components to achieve the same function is effectively "related" so that the desired function is achieved. Thus, any two components combined herein to achieve a particular function, regardless of architecture or intermediate components, may be viewed as “related” to each other such that the desired function is achieved. Similarly, any two components so related may also be viewed as “operably connected” or “operably coupled” to each other to achieve a desired function.

Although specific embodiments of the present invention have been shown and described, based on the teachings herein, changes and modifications may be made without departing from the present invention and its broader aspects, and thus the appended claims are subject to the true spirit of the present invention. And it will be apparent to those skilled in the art that all such changes and modifications as being within the scope should be included within the scope of the claims. Moreover, it should be understood that the invention is defined only by the appended claims. In general, terms used herein and in particular in the appended claims (eg, the text of the appended claims) are generally intended as “open” terms (eg, the term “includes That "having" should be interpreted as "including but not limited to", the term "having" should be interpreted as "having at least", the term "comprising" should be interpreted as "including but not limited to", etc.) It will be understood by those skilled in the art. Where reference to a particular number of introduced claims is intended, it will also be understood by those skilled in the art that such intent will be expressly stated in the claims, and in the absence of such reference, such intent does not exist. For example, for ease of understanding, the following appended claims may include the use of the introductory phrases “at least one” and “one or more” to introduce claim recitations. However, the use of such phrases is not limited to the indefinite article "a" or "an" even when the same claim includes the inclusive phrases "one or more" or "at least one" and indefinite articles such as "a" or "an". The introduction of a claim reference by by is not to be construed as implying to limit any particular claim including such introduced claim reference to the present invention including only one such reference ( For example, “a” and/or “an” should be interpreted to mean “at least one” or “one or more” as usual); The same holds true for the use of the definite article used to introduce a claim reference. In addition, although references to a particular number of introduced claims are expressly stated, those skilled in the art will recognize that such references should be interpreted as meaning more than the number commonly recited (eg, "without other modifiers" A reference to “two references” as-is usually means at least two references, or two or more references).

Accordingly, the present invention is not limited except as by the appended claims.

Claims (9)

A compound having the following formula (I) or a pharmaceutically acceptable salt thereof
<Formula I>

(Wherein, R ¹ is selected from hydrogen or C ₁ -C ₆ alkyl, R ² is selected from -OH or -O(CO)(CH ₂ ) _n CH ₃ , and n is a value from 0 to 34 However, if R ¹ is hydrogen, R ² cannot be -OH) The compound of claim 1, wherein R ¹ is selected from C ₁ -C ₆ alkyl, R ² is selected from -OH or -O(CO)(CH ₂ ) _n CH ₃ and n is a value from 0 to 34. The compound of claim 2, wherein n is a value from 0 to 14. The compound according to claim 2, having the following formula (II).
<Formula II>

5. The compound of claim 4, wherein C ₁ -C ₆ alkyl is -CH ₃ and R ² is -OH. The compound of claim 4, wherein C ₁ -C ₆ alkyl is -CH ₃ and R ² is selected from -O(CO)(CH ₂ ) _n CH ₃ , and n is a value from 0 to 34. The compound according to claim 6, wherein n is a value from 0 to 14. The method of claim 7, wherein n is 10 and 4-(((6S,9S)-1-(benzylcarbamoyl)-9-methyl-8-(naphthalen-1-ylmethyl)-4,7-di The compound which is oxooctahydro-1H-pyrazino[1,2-a]pyrimidin-6-yl)methyl)phenyl dodecanoate. The method of claim 1,
4-(((6S,9S,9aS)-1-(benzylcarbamoyl)-9-methyl-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[ 1,2-a]pyrimidin-6-yl)methyl)phenyl acetate;
4-(((6S,9S,9aS)-1-(benzylcarbamoyl)-9-methyl-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[ 1,2-a]pyrimidin-6-yl)methyl)phenyl hexanoate;
4-(((6S,9S,9aS)-1-(benzylcarbamoyl)-9-methyl-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[ 1,2-a]pyrimidin-6-yl)methyl)phenyl dodecanoate;
4-(((6S,9S,9aS)-1-(benzylcarbamoyl)-9-methyl-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[ 1,2-a]pyrimidin-6-yl)methyl)phenyl palmitate;
4-(((6S,9aS)-1-(benzylcarbamoyl)-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a] Pyrimidin-6-yl)methyl)phenyl acetate;
4-(((6S,9aS)-1-(benzylcarbamoyl)-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a] Pyrimidin-6-yl)methyl)phenyl pentanoate;
4-(((6S,9aS)-1-(benzylcarbamoyl)-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a] Pyrimidin-6-yl)methyl)phenyl nonanoate;
4-(((6S,9aS)-1-(benzylcarbamoyl)-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a] Pyrimidin-6-yl)methyl)phenyl dodecanoate;
4-(((6S,9aS)-1-(benzylcarbamoyl)-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a] Pyrimidin-6-yl)methyl)phenyl tridecanoate; And
4-(((6S,9aS)-1-(benzylcarbamoyl)-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a] Pyrimidin-6-yl)methyl)phenyl palmitate
A compound selected from the group consisting of.

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