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WO2026000074A1 - Utilisation d'inhibiteurs de cd38 pour réduire l'inflammation th2 - Google Patents

Utilisation d'inhibiteurs de cd38 pour réduire l'inflammation th2

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Publication number
WO2026000074A1
WO2026000074A1 PCT/CA2025/050888 CA2025050888W WO2026000074A1 WO 2026000074 A1 WO2026000074 A1 WO 2026000074A1 CA 2025050888 W CA2025050888 W CA 2025050888W WO 2026000074 A1 WO2026000074 A1 WO 2026000074A1
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carboxamide
cyclohexyl
inhibitor
midazol
composition
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Guy Fernand André TREMBLAY
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Welnx Co Inc
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Welnx Co Inc
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Definitions

  • the present disclosure relates to the field of T-helper cell type 2 (TH2 ) inflammation, and more particularly to the reduction of TH2 inflammation and to the treatment or prevention of TH2 inflammation-associated condition using inhibitors of the expression and/or activity of a CD38 protein.
  • TH2 T-helper cell type 2
  • T-helper cell type 2 (TH2) inflammation is a type of immune response characterized by the activation of TH2 cells and innate lymphoid cells (ILC2). This inflammatory process involves production of IgE antibodies, mediators that contribute to allergic reactions and chronicity, goblet cell hyperplasia, the activation of effector cells such as mast cells, eosinophils, and basophils.
  • TH2I is typically associated with interleukin-4 (IL-4), IL-5, and IL-13.
  • effector cells contributes to the TH2I response by releasing mediators like histamine, leukotrienes, prostaglandins, and chemokines that recruit immune cells to sites of inflammation leading to clinical signs and symptoms such as itching, swelling, redness, coughing, wheezing, sneezing, runny nose, fatigue, pain, and loss of function.
  • mediators like histamine, leukotrienes, prostaglandins, and chemokines that recruit immune cells to sites of inflammation leading to clinical signs and symptoms such as itching, swelling, redness, coughing, wheezing, sneezing, runny nose, fatigue, pain, and loss of function.
  • Persistent TH2I is linked with chronic TH2 conditions where the TH2 pathway is dysregulated or overactive. In allergic yet otherwise healthy subjects, persistent TH2I can transition into a chronic TH2 condition if the stimulus persists. Acute manifestations are present in both pre-chronic allergic subjects and chronic subjects with TH2 inflammation-associated conditions, such as asthma attacks upon exposure to environmental triggers, an acute lung infection in a subject with asthma, or symptomatic allergic rhinitis in response to an allergen.
  • TH2 immunity represents the typical adaptive immunity initiated by innate immunity in response to allergen exposure in atopic individuals resulting in a dysregulated immune response that leads to chronic inflammation in individuals with typical TH2 inflammation-associated conditions following overexpression of TH2 inflammatory pathways.
  • parasitic infections such as helminths worms
  • a TH2 response with an increase in eosinophils and IgE antibodies, however neither associated with allergy, hypersensitivity nor atopy.
  • Conditions such as ulcerative colitis or hypereosinophilic syndrome may not be associated with allergens. If some conditions have a predominant TH1 response, they may exhibit TH2 responses depending on chronicity, severity or other factors. As such, the clinical picture of TH2I is complex and spans many different conditions.
  • TH2 l-related conditions and diseases present features such as unresolved inflammation, hyperresponsiveness to triggers and allergens, TH2 cytokines, local tissue infiltration with immune cells and eosinophils, tissue dysfunction, remodeling, and fibrosis.
  • TH2 cells release TH2 cytokines stimulating the production and activation of eosinophils, leading to tissue damage, remodeling, dysfunction, and chronicity.
  • Variations in presentation of TH2 I include, but are not limited to, the nature of the condition, age of onset in childhood or adulthood, nature and extent of triggers and allergens, degree of eosinophilic infiltration and tissue-specific manifestations associated with different TH2 conditions.
  • TH2 I is notoriously implicated in allergic rhinitis, chronic rhinitis or rhinosinusitis (CRS), allergic asthma, atopic dermatitis (AD), eosinophilic esophagitis (EoE) and parasitic infections.
  • CRS chronic rhinitis or rhinosinusitis
  • AD atopic dermatitis
  • EoE eosinophilic esophagitis
  • parasitic infections Host defense against helminths promotes removal of parasites from the body through mucus production and tissue remodeling.
  • excessive TH2 responses can lead to chronic inflammation and tissue damage.
  • CRS is a clinical syndrome defined by persistent symptomatic inflammation of the mucosa of the nasal cavities and paranasal sinuses with a prevalence estimated to be 5-12% of the population in the Western world.
  • CRS etiology is correlated with multiple environmental, host and microbial factors implicated. Putative pathological factors include local or systemic immune system dysfunction, allergens, changes in the microbiota, toxins and genetic predisposition.
  • CRS is broadly classified into two phenotypes based on nasal endoscopy: CRS without nasal polyps (CRSsNP) and CRS with nasal polyps (CRSwNP). The distinction is useful in the clinical setting to help guide therapy since most nasal polyps are eosinophilic and steroid responsive.
  • the TH2 I signature in CRSwNP involves elevation in IL-4, IL-5, and IL-13, TH2 chemokines and eosinophils when compared to healthy controls.
  • Asthma is a prominent multifactorial inflammatory condition of the lower airways characterized by variable and returning symptoms, reversible airflow obstruction, and bronchial hyperresponsiveness.
  • TH2 I occurs in >80% of children and in the majority of adults with asthma with sensitization to allergens such as dust mites, fungi, pets and pollen.
  • AD Atopic dermatitis
  • eczema is a common chronic inflammatory skin disorder that affects both children and adults, with a prevalence of 15 to 18% in children and 7% to 10% in adults.
  • the symptoms of AD include dry, itchy, and red skin, which can lead to skin pain, sleep disturbance, and poor quality of life.
  • AD is a chronic, relapsing, and inflammatory skin disease that affects mostly children but also adults.
  • AD has a genetic background and is characterized by a disturbed skin barrier and excessive TH2I.
  • AD is considered as a biphasic T cell-mediated disease where not only the chronic phase but also the acute phase entails TH2 signaling.
  • Eosinophilic esophagitis is a chronic TH2 inflammation-associated condition of the esophagus.
  • the global pooled incidence and prevalence of EoE were >5 cases per 100,000 inhabitants-years and >40 cases per 100,000 inhabitants-years, respectively.
  • EoE is defined by symptoms of esophageal dysfunction such as vomiting, dysphagia, or feeding difficulties in a subject with esophageal biopsies demonstrating at least 15 eosinophils/high powered field in the absence of other associated conditions.
  • the gold standard for EoE diagnosis remains biopsies showing increased intraepithelial esophageal eosinophil counts.
  • Allergies are TH2 inflammation-associated conditions with responses to allergens that are generally harmless in most people.
  • allergic rhinitis affects between 10% and 30 % of the population, and sensitization with IgE antibodies to foreign proteins in the environment is present in up to 40% of the population. 7.8% of people 18 and over in the US have hay fever. It is estimated that 3.5-4% of the general US population exhibits IgE-mediated food allergy or sensitivity. Allergens can trigger symptoms such as sneezing, itching, swelling, wheezing, and hives in allergy-prone individuals.
  • allergens include pollen, house dust mites, pet dander, mold spores, certain foods such as peanuts, tree nuts, seafoods, and eggs, insect venoms, medications like penicillin or aspirin, and latex. Allergies can range from mild to severe, with the most serious type called anaphylaxis, typically associated with food allergies, which can be life-threatening.
  • TH2 cells play a central pathogenic role in promoting tissue inflammation.
  • IL-4 and IL-13 two key cytokines involved in the TH2 immune pathway, IL-4 and IL-13, have been recognized as important mechanisms in allergic conditions such as AD, asthma and CRS.
  • the spectrum of allergy manifestations is wide-ranging and includes rhinitis, conjunctivitis, respiratory, urticaria, angioedema, anaphylaxis, and progression to chronic TH2 l-associated conditions.
  • eosinophilic granulomatosis with polyangiitis eGPA
  • eGPA eosinophilic granulomatosis with polyangiitis
  • HES Hypereosinophilic syndromes
  • the syndromes can be primary or secondary and are classified based on the underlying cause, including chronic eosinophilic leukemia, idiopathic HES, parasitic infestations, allergic reactions, and specific HES secondary to an underlying condition such as helminth infections or eGPA.
  • TH2I is also apparent in a subset of Chronic Obstructive Pulmonary Disease (COPD) patients with elevated eosinophil counts and altered gene and protein expression of several TH2 markers, as the clinical presentation of asthma and COPD are similar in older individuals.
  • COPD Chronic Obstructive Pulmonary Disease
  • IBD Inflammatory Bowel Disease
  • UC ulcerative colitis
  • Crohn's disease ulcerative colitis
  • cytokines in UC are from the TH2 profile producing cytokines such as IL-4, IL-5 and IL-13.
  • Mucosal TH2 I may be initiated by the release of alarmin-type molecules from injured epithelial cells.
  • TH2-induced fibrogenesis may underlie the mucosal and transmural fibrotic process found in Crohn’s disease and UC.
  • TH2 cells contribute to intestinal mucosa inflammation by secreting IL-4 in UC.
  • Despite a TH2 response in UC neutralization of IL-13 via monoclonal antibodies was ineffective as a therapeutic strategy in patients with UC.
  • Chronic IBD increases the risk of developing colon polyps and colon cancer.
  • SLE Systemic Lupus Erythematous
  • IgG subclass the IgG subclass
  • IgE subclass the acquired immunity effector of TH2 I, which are strongly associated with disease severity.
  • treatment of SLE patients with the monoclonal antibody omalizumab targeting IgE was associated with improvement in disease activity.
  • Emerging evidence is showing that eosinophils can act both as pro-inflammatory and pro-resolution in rheumatoid arthritis (RA), another autoimmune disease and as such the TH2 response is involved in regulation of the disease.
  • RA rheumatoid arthritis
  • TH2 I various clinical scenarios, diseases and conditions present TH2 I.
  • the diseases and disorders outlined share similar features of TH2 cell activation and cytokine production, leading to inflammation in the affected organs and tissues.
  • Inhaled corticosteroids remain the pillar in the treatment of asthma. For mild persistent asthma, low dose inhaled corticosteroids are indicated. Steroids have been shown to reduce asthma symptoms, increase lung function, improve quality of life, and reduce the risk of exacerbations, asthma-related hospitalizations, and death. In recent years, costly new biologic agents resulted in improved lung function, reduced the frequency of severe exacerbations, limited use of oral steroids, and improved quality of life in refractory subjects with a ‘TH2 -high’ inflammatory phenotype. Anti-lgE (Omalizumab) therapy has shown benefit for those with severe allergic asthma.
  • Anti-IL-5 (Mepolizumab, Reslizumab), anti-IL-5 receptor (Benralizumab), and anti-IL-4 receptor (Dupilumab) therapy can be used for treatment of uncontrolled, severe eosinophilic asthma.
  • Beta-2 adrenergic agonists selectively activate receptors in smooth muscle cells of the bronchioles, for treating asthma with bronchodilation and improved breathing.
  • CRS can be treated with over the counter or prescription corticosteroid nasal sprays to help relieve symptoms once or twice daily into each nostril.
  • CRSwNP symptoms negatively impact subjects' productivity along with physical and mental quality of life, perhaps more so than with asthma which may be better controlled with steroids.
  • Subjects with CRSwNP report significant nasal congestion, anosmia, and rhinorrhea among their most troublesome symptoms.
  • CRSwNP with large polyps surgery may be performed, however polyps typically recur. Continuous use of the medications will be necessary.
  • costly biologies have been approved such as Dupilumab and Omalizumab.
  • Short-term courses of antibiotics with oral corticosteroids are prescribed in subjects with acute infections, and there may be a need for stronger evidence on the role of antibiotics in CRS management.
  • the treatment for AD includes topical corticosteroids for mild-to-moderate cases, but there is an unmet need for topical agents due to safety concerns about topical corticosteroids use for AD.
  • topical crisaborole cream targeting PDE-4 and subcutaneously injected dupilumab, an anti-IL-4 have come on the market for mild-to-moderate and moderate-to-severe AD in both children and adults.
  • EoE is treated with a combination of therapies, including proton pump inhibitors, topical corticosteroids such as fluticasone and budesonide, and dietary modifications.
  • Treatments target both the global inflammatory response and eosinophils, as recommended in a systematic review and consensus guidelines for diagnosis and treatment. In some cases, endoscopic dilation may also be necessary.
  • the treatment aims to reduce the number of eosinophils in the esophagus.
  • Allergy is commonly treated with pharmacotherapy, commonly antihistamines and nasal corticosteroids for rhinitis, rhinoconjunctivitis and wheezing. Allergy immunotherapy changes the response to allergen exposure by inducing immunological tolerance.
  • the original administration form of allergy immunotherapy was by subcutaneous injection, nowadays tablet-based sublingual allergy immunotherapy is more common.
  • traditional antihistamines can be administered by mouth and for severe acute cases, short-term corticosteroids may be used.
  • Anaphylaxis can be treated with epinephrine, intravenous antihistamines and cortisone to control inflammation, and beta-agonists.
  • the treatment of COPD can involve bronchodilators alone or in combination with corticosteroids and phosphodiesterase-4 inhibitors.
  • Disease-modifying antirheumatic drugs like sulphasalazine, methotrexate, and azathioprine are effective in both acute and chronic RA cases.
  • Systemic glucocorticoids and other immunosuppressive drugs are used to suppress the immune response and lower antibody titers in SLE.
  • Drugs targeting IL-12/IL-23 currently approved or in clinical development for the treatment of IBD include ustekinumab, briakinumab, risankizumab, guselkumab, brazikumab and mirikizumab.
  • the treatment for eGPA typically involves the use of glucocorticoids such as prednisolone. Corticosteroids remain the first line therapy for most forms of HES.
  • CD38 was first characterized as a surface antigen on immune cells and is broadly distributed throughout cells and tissues in the body. In human immune cells, CD38 is expressed in activated B cells, plasma cells, activated T cells, macrophages, dendritic cells, ILC, eosinophils, NK cells, neutrophils, and monocytes. CD38 is highly expressed in hematopoietic immature B- and T-cells in the bone barrow and lymph nodes and CD38 expression is lost when immune cells mature, up until immune cell activation upregulates it back.
  • CD38 is most highly expressed in prostatic epithelial cells, pancreatic islet astrocytes, muscle cells, retinal tubes, kidney, gut, and brain in both mice and humans. CD38 is also present on erythrocytes and platelets. CD38 has not been found in any fetal organ or tissue. CD38 is constitutively expressed in airway smooth muscle cells and smooth muscle cells in general. CD38 is also expressed in airway epithelial cells (AECs).
  • AECs airway epithelial cells
  • a method for reducing TH2 inflammation in a subject comprising administering to the subject a therapeutically effective amount of CD38 inhibitor to said subject.
  • a method for treating or preventing a TH2 inflammation-associated condition in a subject comprising administering to the subject a therapeutically effective amount of CD38 inhibitor to said subject.
  • CD38 inhibitor for treating or preventing a TH2 inflammation-associated condition in a subject.
  • CD38 inhibitor for the manufacture of a medicament for treating or preventing a TH2 inflammation-associated condition in a subject.
  • a CD38 inhibitor for use in reducing TH2 inflammation in a subject 7.
  • a CD38 inhibitor for use in treating or preventing a TH2 inflammation-associated condition in a subject.
  • a pharmaceutical composition for reducing TH2 inflammation in a subject comprising a CD38 inhibitor and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for treating or preventing a TH2 inflammation-associated condition in a subject comprising a CD38 inhibitor and a pharmaceutically acceptable carrier.
  • reducing TH2 inflammation include decreasing secretion of, decreasing the levels of, and/or modulating one or more TH2 inflammatory mediator, preferably a mediator for which signaling is calcium-dependent.
  • TH2 inflammatory mediator is an interleukin, a cytokine, a leukotriene, a transcription factor, a prostaglandin, a chemokine, a hormone, and/or histamine.
  • TH2 inflammatory mediator is IL-13, TGF-beta 1 , TGF-beta 3, IL-31 , IL-33, IL-12p40, IL-12p70, IL-23, L-27, IP- 10, fractalkine, Rantes, MIP-3 alpha, IL-2, Interferon gamma and/or Interferon beta.
  • reducing TH2 inflammation include decreasing secretion of, decreasing the levels of, and/or modulating at least one TH2 inflammatory mediator, preferably IL-2, IL-4, IL-5, IL-9, IL-10, IL-13, TGF-beta, TSLP, IL- 25, IL-27, IL-31 , IL-33, TNF-alpha, IgE, histamine, STAT6, GATA3, IP-10, Rantes, fractalkine, eotaxin, CCL17, CCL22, CXCL12, CXCL8, CCL1 , MCP, Interferon gamma and/or TGF-beta, and more preferably IL-2, IL-13, IL-27, IL-31 , IL-33, TGF-beta, IP-10, fractalkine, Interferon gamma, and/or Rantes.
  • TH2 inflammatory mediator preferably IL-2, IL-4, IL-5, IL-9, IL
  • TH2 inflammation-associated condition is one or more of: chronic rhinitis or rhinosinusitis (CRS), including CRS without nasal polyps (CRSsNP) and CRS with nasal polyps (CRSwNP); asthma; nasal polyps; atopic dermatitis (AD), also known as eczema; eosinophilic esophagitis (EoE); a parasitic infection, including helminths or malaria; an allergy including allergic rhinitis, allergic conjunctivitis, food allergy, drug allergy, pollen allergy, house dust mites allergy, pet dander allergy, mold spores allergy, certain foods such as peanuts, tree nuts, shellfish, and eggs, insect venom allergy, or medication allergy; hyperresponsiveness to triggers and allergens; allergic bronchopulmonary aspergillosis; another allergic condition such as allergic bronchopulmonary aspergillosis; another allergic condition such as allergic bronchopulmonary aspergillosis; another allergic condition such as
  • CRS chronic rhinosinusitis
  • the method/use/inhibitor for use/composition for use of any one of embodiments 1 to 18, wherein the TH2 inflammation-associated condition is an allergy.
  • TH2 inflammation-associated condition is TH2 inflammation-associated fibrogenesis or TH2 inflammation-associated fibrosis.
  • reducing TH2 inflammation-associated epithelial dysfunction includes decreasing hypersecretion, preferably by goblet cells; decreasing epithelial cell hyperplasia, preferably goblet cell hyperplasia; and/or decreasing epithelial thickness.
  • the CD38 inhibitor comprises a thiazole, imidazole, pyrazole, or pyridazole group, preferably a thiazole or imidazole group, and more preferably a thiazole group.
  • CD38 inhibitor comprises a 4-(2-methoxyethoxy)cyclohexyl)amino) group, preferably a trans-4-(2- methoxyethoxy)cyclohexyl)amino) group.
  • CD38 inhibitor is: a 6- thiazoloquinolin-2-one of formula (I), including those of formula (II); an indole-7-carboxamide of formula (III); a cyclohexyl-5-(thiazol-5-yl)-1 h-indole-7-carboxamide of formula (IV); a heterobicyclic amide of formula (V); a quinoline or azaquinoline of formula (VI); a pyridazine or pyrimidine of formula (VII); a pyrazine or pyrimidine carboxamide of formula (VIII); a tricyclic fused imidazole of formula (IXa) or (IXb), a N-(4-aminocyclohexyl)pyrimidine-4-carboxamide of formula (X), a 1,3-thiazoles and 1 ,2,4-thiadiazole of formula (XI), a 3-carbonyl imidazo[1 ,5-a]pyridine of
  • CD38 inhibitor is a 6-thiazoloquinolin-2-one of formula (I), preferably of formula (II), more preferably 4-((- 4-(2-methoxyethoxy)cyclohexyl)amino)-1-methyl-6-(thiazol-5-yl)quinolin-2(1 H)one, or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.
  • CD38 inhibitor for intranasal administration, preferably as a nasal powder, a nasal liquid spray, nasal drops, a nasal gel, a nasal insert, a nasal film, or a nasal foam.
  • glucocorticoid is alclometasone; aldosterone; algestone acetophenide; amcinonide; beclometasone; beclomethasone; beclomethasone dipropionate; betamethasone (including tamethasone dipropionate and betamethasone valerate); budesonide; chloroprednisone; ciclesonide; clobetasol; clobetasone; clocortolone; cloprednol; corticosterone; cortisol; cortisone; cortivazol; deflazacort; desonide; desoximetasone; dexamethasone (including dexamethasone acetate); diflorasone; difluocortolone; difluprednate; diprolene; flonase; fluclorolone;
  • glucocorticoid is triamcinolone; dexamethasone; momethasone; fluticasone; hydrocortisone; prednisolone; betamethasone; beclomethasone; ciclesonide; amcinonide; flunisolide; or budesonide.
  • beta-2 agonist or muscarinic antagonist is abediterol; albuterol; arformoterol; bambuterol; batefenterol; bitolterol; carmoterol; clenbuterol; fenoterol; formoterol; hexoprenaline; indacaterol; isoprenaline; isoproterenol; isoxsuprine; levalbuterol; levosalbutamol; mabuterol; metaproterenol; olodaterol; orciprenaline; pirbuterol; procaterol; reproterol; ritodrine; salbutamol; salmeterol; terbutaline; tulobuterol; umeclidinium; tiotropium; aclidinium; glycopyrronium; vilanterol; or zilpaterol.
  • the antibiotic is amoxicillin; ampicillin; azithromycin; aztreonam; aztreonam; cefdinir; cefixime; cefotaxime; cefpodoxime; ceftriaxone; ceftriaxone; cefuroxime; chloramphenicol; ciprofloxacin; clarithromycin; clavulanate; clindamycin; delafloxacin; doxycycline; ertapenem; erythromycin; gemifloxacin; gentamicin; lefamulin; levofloxacin; lincosamide; linezolid; moxifloxacin; mupirocin; omadacycline; penicillin; piperacillin; polymyxin B; rifamycin; streptomycin; thiamphenicol; tylosin; cephalexin; meropenem;
  • antihistamine is azelastine; benadryl; brompheniramine; cetirizine; chlor-trimeton; chlorpheniramine; cimetidine; clemastine; cyproheptadine; desipramine; desloratadine; dimenhydrinate; diphenhydramine; doxepin; dramamine; dymista; fexofenadine; hydroxyizine; imipramine; levocetirizine; loratadine; meclizine; mucinex; norpramin; nortriptyline; olaptadine; Pamelor; patanase; pheniramine; promethazine; prudoxin; pyrilamine; quetiapine; ranitidine; risperdal; triprolidine; hydroxyzine pamoate; carbinoxamine; rupatad
  • fungicide is azoxystrobin; benomyl; captan; carbendazim; chlorothalonil; copper oxychloride; cyproconazole; fludioxonil; mancozeb; metalaxyl; propiconazole; sulfur; tebuconazole; thiophanate-methyl; trifloxystrobin; or zineb.
  • the immunotherapeutic agent is adalimumab; benralizumab; certolizumab; dupilumab; etanercept; golimumab; infliximab; mepolizumab; omalizumab; reslizumab; tezepelumab; tralokinumab; nivolumab; pembrolizumab; atezolizumab; avelumab; durvalumab; ipilimumab; interleukin-2; interferon-alpha; rituximab; bevacizumab; alemtuzumab; basiliximab; ;Risankizumab; guselkumab; brazikumab; mirikizumab; ustekinumab; briakinumab; GSK2618
  • FIG. 1 Murine IL-13 in Nasal Lavage Fluid of CRS Mouse Model of CRS Mouse Model
  • Figure 9 Goblet Cell Count and Size in and in Nasal Septum Detail of CRS Mouse Model (A) Healthy Animal, (B) CRS- Untreated, (C) CRS - WX-001 , and (D) CRS - Positive Control
  • CT Computerized Tomography
  • a method for reducing TH2 inflammation or for treating or preventing a TH2 inflammation-associated condition in a subject comprising administering to the subject a therapeutically effective amount of CD38 inhibitor to said subject.
  • the present disclosure also provides the use of a CD38 inhibitor for reducing TH2 inflammation or for treating or preventing a TH2 inflammation-associated condition in a subject.
  • the present disclosure also provides the use of a CD38 inhibitor for the manufacture of a medicament for reducing TH2 inflammation or for treating or preventing a TH2 inflammation-associated condition in a subject.
  • the present disclosure also provides a CD38 inhibitor for use in reducing TH2 inflammation or for treating or preventing a TH2 inflammation-associated condition in a subject.
  • compositions for reducing TH2 inflammation or for treating or preventing a TH2 inflammation-associated condition in a subject comprising a CD38 inhibitor and a pharmaceutically acceptable carrier.
  • the method, uses, compound for use, and compositions for use of the invention are novel, safe, therapeutically effective, and cost-effective approaches to the treatment and prevention of TH2 inflammation- associated conditions.
  • the subject is a human subject.
  • the words “treat”, “treating”, and “treatment” refer to the care provided to improve the condition of a subject afflicted with a TH2 inflammation-associated condition.
  • the words “prevent” and “preventing” refer to stopping or avoiding the effects of a TH2 inflammation-associated condition in a subject.
  • reducing TH2 inflammation includes any of reduction of TH2 inflammation, alleviation of TH2 inflammation, and amelioration of TH2 inflammation or TH2 -mediated immune responses.
  • reducing TH2 inflammation include decreasing secretion of and/or decreasing the levels of and/or modulating one or more TH2 inflammatory mediator, preferably a mediator for which signaling is calcium- dependent.
  • the one or more TH2 inflammatory mediator is an interleukin, a cytokine, a leukotriene, a prostaglandin, a transcription factor, a chemokine, a hormone, and/or histamine.
  • the TH2 inflammatory mediator is IL-13, TGF-beta 1, TGF-beta 3, IL-31 , IL-33, IL-12p40, IL-12p70, IL-23, L-27, IP-10, fractalkine, Rantes, MIP-3 alpha, IL-2, Interferon gamma and/or Interferon beta.
  • reducing TH2 inflammation includes decreasing secretion of, decreasing the levels of, and/or modulating at least one TH2 inflammatory mediator, preferably IL-2, IL-4, IL-5, IL-9, IL-10, IL-13, TGF-beta, TSLP, IL-25, IL-27, IL-31, IL-33, TNF-alpha, IgE, histamine, STAT6, GATA3, NFAT, IP-10, Rantes, fractalkine, eotaxin, CCL17, CCL22, CXCL12, CXCL8, CCL1, MCP, Interferon gamma and/or TGF-beta, and more preferably IL- 2, IL-13, IL-27, IL-31 , IL-33, TGF-beta, IP-10, fractalkine, Interferon gamma, and/or Rantes.
  • TH2 inflammatory mediator preferably IL-2, IL-4, IL-5, IL-9,
  • a therapeutically effective amount with respect to a compound of the invention means that amount of therapeutic agent alone, or in combination with other therapies, that provides a therapeutic benefit in the treatment or prevention of a disease.
  • the term can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease, or enhances the therapeutic efficacy or synergies with another therapeutic agent.
  • a “patient” or “subject” includes an animal, such as a human, cow, horse, sheep, lamb, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig.
  • the animal can be a mammal such as a non-primate and a primate (e.g., monkey and human).
  • a patient is a human, such as a human infant, child, adolescent or adult.
  • CD38 inhibitors are found herein to be a new class of anti-inflammatory compounds that reduce inflammation, TH2 inflammation-associated fibrogenesis, TH2 inflammation-associated tissue remodeling, epithelial dysfunction, and chemotaxis. Oxidative stress and metabolic dysfunction in tissues affected with TH2 I is another area where CD83 inhibitors can contribute to the relief of TH2 I. Aiming to improve epithelial barrier dysfunction, chronic TH2 inflammation-associated tissue remodeling can also be addressed with CD38 inhibitors. Significant improvements in different aspects of TH2 I make CD38 inhibitors tools of choice in the arsenal on TH2 inflammation- associated conditions.
  • Example 1 reduction of TH2 I was demonstrated with IL-13, a pleiotropic TH2 cytokine affecting airway contractility, critical for mucus production, remodeling and important in the pathogenesis of TH2 inflammation- associated disorders.
  • Reduction of fibrosis from TGF-beta, and a reduction in deposition of collagen with 4-((-4-(2- methoxyethoxy)cyclohexyl)amino)-1-methyl-6-(thiazol-5-yl)quinolin-2(1 H)one, a representative CD38 inhibitor are also favorable outcomes in the relief of TH2 I.
  • the reduction in epithelial thickness relieving epithelial barrier dysfunction by the CD38 inhibitor.
  • IL-33 with a key role in host barrier defense is produced by epithelial cells in response to damage or injury, activates ILC2 and is a potent inducer of TH2 cytokines.
  • IL-33 Reduction of IL-33 further demonstrates the impact of CD38 inhibition in mitigating TH2 I.
  • Chemokines involved in chemotaxis also are reduced by CD38 inhibitors and thus show the chemotaxis portion of the anti-inflammatory effects of the present invention.
  • conditions with a TH2 response whether in the context severity or chronicity, such as autoimmune diseases, COPD, rare inflammatory diseases, parasitic infections, and IBD, will also benefit from CD38 inhibitors.
  • CD38 inhibitors can be administered in a subject as prevention, for example in combination therapies with corticosteroids or antihistamines.
  • CD38 inhibitors can be used for conditions such as allergy, for example in a nasal spray.
  • chronic TH2 conditions like CRS, where a nasal spray is also commonly used a CD38 inhibitor is envisioned administered alongside a corticosteroid.
  • a case report for the use of CD38 inhibitors by a human subject in Example 2 posits that CD38 inhibitors can prevent the reoccurrence of nasal polyps following polypectomy in addition to consistently reducing TH2 I in a human subject with CRSwNP, providing real-world ethnopharmacological evidence that CRSwNP can be treated successfully with CD38 inhibitors.
  • the apparent persistence of treatment outcomes may provide insights into the mechanisms of CD38 in chronic TH2 inflammation.
  • CD38 is an etiological agent of TH2 inflammation-associated conditions.
  • CD38 inhibitors demonstrate beneficial effects at least on inflammation, epithelial dysfunction and tissue remodeling in subjects with TH2 inflammation-associated conditions.
  • TH2 inflammation refers to a type of immune response characterized by the activation and differentiation of T Helper Cells Type 2 (TH2 ) that secrete interleukin (IL)-4, IL-5, and IL-13.
  • TH2 T Helper Cells Type 2
  • the TH2 response is typically associated with the activation of effector cells, eosinophilia, production of IgE antibodies, and/or overproduction of mediators causing clinical signs and symptoms.
  • Persistent TH2 I can lead to tissue dysfunction, remodeling, hyperreactivity, and fibrosis.
  • the dysregulated TH2 pathway can develop into chronic TH2 inflammation- associated conditions that require specific therapeutic interventions targeting the TH2 response.
  • TH2 inflammation-associated condition refers to a condition, disease or disorder associated with, or known to usually be associated with, or mediated by TH2 inflammation. These conditions may comprise allergy-associated conditions, chronic TH2 conditions, acute TH2 manifestations, allergy, parasitic and other infections, rare diseases, autoimmune disorders and conditions that are known to display TH2 inflammation in certain clinical context such as the severity of the condition or when associated with eosinophilia.
  • the TH2 inflammation-associated condition can be chronic or acute (present acute manifestations).
  • the TH2 inflammation-associated condition is associated with acute signs and symptoms.
  • the TH2 inflammation-associated condition is chronic.
  • the CD38 inhibitor is used to prevent TH2 inflammation from becoming a chronic TH2 inflammation-associated condition.
  • the TH2 inflammation-associated condition is one or more of the following: chronic rhinitis or rhinosinusitis (CRS), including CRS without nasal polyps (CRSsNP) and CRS with nasal polyps (CRSwNP); asthma; nasal polyps; atopic dermatitis (AD), also known as eczema; eosinophilic esophagitis (EoE); a parasitic infection, including helminths or malaria; an allergy including allergic rhinitis, allergic conjunctivitis, food allergy, drug allergy, pollen allergy, house dust mites allergy, pet dander allergy, mold spores allergy, certain foods such as peanuts, tree nuts, shellfish, and eggs, insect venom allergy, or medication allergy; hyperresponsiveness to triggers and allergens; allergic bronchopulmonary aspergillosis; another allergic condition such as allergic bronchopulmonary aspergillosis (ABPA) and allergic conjunctivitis;
  • CRS chronic r
  • the TH2 inflammation-associated condition is allergy, chronic rhinosinusitis (CRS), asthma, atopic dermatitis or eosinophilic esophagitis.
  • the TH2 inflammation-associated condition is allergy.
  • the TH2 inflammation-associated condition is chronic rhinosinusitis (CRS), including CRSsNP and CRSwNP, preferably CRSwNP.
  • the TH2 inflammation-associated condition is COPD.
  • the TH2 inflammation-associated condition is rheumatoid arthritis.
  • the TH2 inflammation-associated condition is Systemic Lupus Erythematosus (SLE).
  • the TH2 inflammation- associated condition is ulcerative colitis (UC).
  • the prevention of TH2 inflammation-associated conditions with CD38 inhibitors include use of a CD38 inhibitor in a subject having symptoms in response to allergens, environmental pollutants and/or other triggers, said symptoms including for example sneezing, coughing, and/or wheezing.
  • a CD38 inhibitor in a subject having symptoms in response to allergens, environmental pollutants and/or other triggers, said symptoms including for example sneezing, coughing, and/or wheezing.
  • Such allergic reactions when persistent, can lead to asthma, CRS, or other TH2 inflammation-associated conditions, for example in a subject with allergies, a subject with significant occupational exposures, or a subject with hypersensitivities.
  • any subject having one or more risk factors for a TH2 inflammation-associated condition can benefit from preventively treating via the administration of CD38 inhibitors.
  • reducing TH2 inflammation with a CD38 inhibitor is used for preventing TH2 inflammation from developing into a chronic TH2 inflammation-associated condition.
  • the TH2 inflammation-associated condition is TH2 inflammation-associated fibrogenesis or TH2 inflammation-associated fibrosis.
  • TH2 inflammation-associated fibrogenesis refers to the process of forming fibrous tissue, particularly the early or active phase of tissue remodeling.
  • TH2 inflammation- associated fibrosis refers to is the end result of fibrogenesis— a late, often chronic state characterized by the accumulation of extracellular matrix and scarring of tissue.
  • the TH2 inflammation-associated condition is TH2 inflammation-associated tissue remodeling.
  • TH2 inflammation-associated tissue remodeling refers to disease-specific and/or tissue-specific variations on tissue fibrosis, collagen deposition, subepithelial fibrosis, extracellular matrix remodeling, hyperplasia and hypertrophy of smooth muscle cells, fibroblast and myofibroblast proliferation, epithelial-to-mesenchymal transition, extracellular matrix (ECM) degradation, excessive ECM deposition, hyperresponsiveness, hypersensitivity, angiogenesis, excessive tissue repair and scarring, tissue stiffness, tissue degeneration, and organ dysfunction that is associated with, or that are known to usually be associated with or mediated by TH2 inflammation.
  • ECM extracellular matrix
  • reducing TH2 inflammation-associated tissue remodeling includes:
  • the TH2 inflammation-associated condition is TH2 inflammation-associated epithelial dysfunction.
  • TH2 inflammation-associated epithelial dysfunction refers to disease-specific and/or tissue- specific variations on epithelial thickening, barrier loss, disruption of cell junctions, edema, basal and goblet cell hyperplasia, basal and goblet cell hypersecretion, hypersecretion of mucus, impaired ciliary cell function, oxidative stress, hypersecretion of mucus, epithelial-to-mesenchymal transition, and epithelial dysfunction that is associated with, or that are known to usually be associated with or mediated by TH2 inflammation. Therefore, in embodiments, reducing TH2 inflammation-associated epithelial dysfunction includes:
  • CD38 cluster of differentiation 38 refers to the 45kDa type II transmembrane glycoprotein enzyme also known as NADase, ADP ribosyl cyclase, cyclic ADP-ribose hydrolase 1 , or ADP ribosyl cyclase/hydrolase, particularly from a mammalian species, more particularly a human CD38.
  • a “CD38 inhibitor” is an agent that inhibits the expression and/or activity of a CD38 protein. Preferably, it is an agent that reduces or blocks CD38-mediated NAD catabolism in a subject, typically resulting in an increase of NAD and a reduction in the associated CD38-mediated cADPR, ADPR, NAAD and NAADP catalytic reaction products. It is noted that some agents that are known from the literature to be CD38 inhibitors may be considered CD38 inhibitor prodrugs, for example if acting as adduct-forming uncompetitive inhibitors. The invention is meant to encompass all such compounds.
  • NAD as used herein refers to Nicotinamide Adenine Dinucleotide, whether in the form NAD+ or NADH, or whether in the form NADP, NADP+ or NADPH, insofar as they can be considered substrates of CD38 enzymatic activity.
  • CD38-mediated NAD catabolism refers to the enzymatic activities of CD38, namely the cyclase, glycohydrolase, hydrolase and base exchange reaction that are known to lead to, or participate in, an overall decrease of NAD or NADP in a subject, and are associated with the production in a subject of the enzymatic products, also termed second messengers, namely cADPR, ADPR, NAAD and NAADP, all of which constitute the enzymatic activities, substrates and products known to those skilled in the art to be related to mammalian CD38 biochemistry and NAD metabolism in general, and more specifically NAD catabolism.
  • the CD38 inhibitor is a small molecule.
  • small molecule refers to a low molecular weight organic compound e.g., a molecular weight up to 5000 Da, preferably up to 2000 Da, and most preferably up to about 1000 Da.
  • the CD38 inhibitor used in the present invention can be any CD38 inhibitor known to the skilled person.
  • the CD38 inhibitor is one developed in recent years e.g. CD38 inhibitors described in publications since approximately 2015. The later generations of CD38 inhibitors tend to have improved potency and pharmacokinetic parameters, at least in animal studies. These include the CD38 inhibitors disclosed or referred to in:
  • the CD38 inhibitor is:
  • a “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
  • the present invention contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are non-superimposeable mirror images of one another.
  • CD38 inhibitors may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids.
  • the present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms.
  • Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization.
  • tautomer refers to a proton shift from one atom of a molecule to another atom of the same molecule.
  • Non-limiting examples of tautomers include enol/keto, lactam/lactim, amide/imidic and amine/imine forms.
  • a “pharmaceutically acceptable salt” is a pharmaceutically acceptable, organic or inorganic acid or base salt of a compound of the invention.
  • Representative pharmaceutically acceptable salts include, e.g., alkali metal salts, alkali earth salts, ammonium salts, water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, formate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexy
  • prodrug means any compound which releases the CD38 inhibitor in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs are prepared by modifying functional groups present in the CD38 inhibitor in such a way that the modifications may be cleaved in vivo to release the parent compound.
  • Prodrugs may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.
  • Prodrugs include CD38 inhibitors wherein a hydroxy, amino, carboxyl or sulfhydryl is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively.
  • Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl), carbonates, and phosphates of hydroxy functional groups in CD38 inhibitors, and the like. Preparation, selection, and use of prodrugs is discussed in T. Higuchi and V.
  • the CD38 inhibitor is:
  • the CD38 inhibitor comprises a thiazole, imidazole, pyrazole, or pyridazole group, preferably a thiazole or imidazole group, and more preferably a thiazole group.
  • the CD38 inhibitor comprises a 4-(2-methoxyethoxy)cyclohexyl)amino) group, preferably a trans-4-(2-methoxyethoxy)cyclohexyl)amino) group.
  • the CD38 inhibitor comprises a trans-4-(2-methoxyethoxy)cyclohexyl)amino) group and an imidazole group or a thiazole group, preferably a thiazole group.
  • the CD38 inhibitor is a 6-thiazoloquinolin-2-one of formula (I), preferably of formula (II), more preferably 4-((-4-(2-methoxyethoxy)cyclohexyl)amino)-1-methyl-6-(thiazol-5-yl)quinolin-2(1 H)one, corresponding to compound 78c of Haffner 2015 and Bosslet 2019.
  • the CD38 inhibitor is a 6-thiazoloquinolin-2-one as described in Haffner CD, Becherer JD, Boros EE, Cadilla R, Carpenter T, Cowan D, et al. Discovery, Synthesis, and Biological Evaluation of Thiazoloquin(az)olin(on)es as Potent CD38 Inhibitors. J Med Chem. 2015 Apr 23;58(8):3548— 71 ; and Boslett J, Reddy N, Alzarie YA, Zweier JL, Inhibition of CD38 with the Thiazoloquin(az)olin(on)e 78c Protects the Heart against Postischemic Injury, J Pharmacol Exp Ther. 2019 Apr;369(1):55-64. doi: 10.1124/jpet.118.254557, both incorporated herein by reference.
  • the CD38 inhibitor is of formula (I):
  • R 1 represents H, alkyl (preferably methyl), O-alkyl (preferably O-methyl), or haloalkyl (preferably CF 3 ),
  • R 2 represents H or alkyl (preferably methyl or ethyl),
  • R 3 represents:
  • alkyl preferably C1-4 alkyl
  • R 12 is H or alkyl (preferably methyl); cycloalkyl (preferably C 3-6 cycloalkyl), unsubstituted or substituted with one or more alkyl (preferably methyl), heterocycloalkyl (preferably y-lactam), -OR 14 , wherein R 14 is H or alkyl (preferably methyl), -OR 15 -OR 16 , wherein R 15 alkyl (preferably ethyl), and wherein R 16 is H or alkyl (preferably methyl), -CO-NHR 11 , wherein R 11 is H or alkyl (preferably methyl or ethyl), -COOH, or - SO 2 -alkyl (preferably SO 2 -methyl); heterocycloalkyl (preferably y-lactam, tetrafuranyl, pyranyl, or piperidinyl), unsubsituted
  • CD38 inhibitor is of formula (I) is of formula (II):
  • R 1 represents H, alkyl (preferably methyl), O-alkyl (preferably O-methyl), or haloalkyl (preferably CF 3 ),
  • R 2 represents H or alkyl (preferably methyl or ethyl), and
  • R 3 represents:
  • alkyl preferably C1-4 alkyl
  • R 12 is H or alkyl (preferably methyl); cycloalkyl (preferably C 3-6 cycloalkyl), unsubstituted or substituted with one or more alkyl (preferably methyl), heterocycloalkyl (preferably y-lactam), -OR 14 , wherein R 14 is H or alkyl (preferably methyl), -OR 15 -OR 16 , wherein R 15 alkyl (preferably ethyl), and wherein R 16 is H or alkyl (preferably methyl), -CO-NHR 11 , wherein R 11 is H or alkyl (preferably methyl or ethyl), -COOH, or - SO 2 -alkyl (preferably SO 2 -methyl); heterocycloalkyl (preferably y-lactam, tetrafuranyl, pyranyl, or piperidinyl), unsubsituted
  • the CD38 inhibitor is of formula (II), wherein:
  • R 1 represents H or alkyl (preferably methyl),
  • R 2 represents H or alkyl (preferably methyl or ethyl), and
  • R 3 represents cycloalkyl (preferably C 3-6 cycloalkyl), unsubstituted or substituted with one or more -OR 14 , wherein R 14 is H or alkyl (preferably methyl), -OR 15 -OR 16 , wherein R 15 alkyl (preferably ethyl), and wherein R 16 is H or alkyl (preferably methyl), -CO-NHR 11 , wherein R 11 is H or alkyl (preferably methyl or ethyl); or heterocycloalkyl (preferably pyranyl), preferably unsubstituted, or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.
  • the CD38 inhibitor is of formula (II), wherein:
  • R 1 represents H
  • R 2 represents alkyl (preferably methyl or ethyl)
  • R 3 represents cycloalkyl substituted with -OR 15 -OR 16 , wherein R 15 represents alkyl (preferably ethyl), and wherein R 16 represents H or alkyl (preferably methyl), or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.
  • the CD38 inhibitor is:
  • the CD38 inhibitor is 1 -Methyl-4-((tetrahydro-2Hpyran-4-yl)amino)-6-(thiazol-5- yl)quinolin-2(1 H)-one, 4-((-4-(2-Methoxyethoxy)cyclohexyl)amino)-1-methyl-6-(thiazol-5-yl)quinolin-2(1 H)one, 4- (((1 r,4r)-4-(2-Methoxyethoxy)cyclohexyl)amino)-1 ,8-dimethyl-6-(thiazol-5-yl)quinolin2(1 H)-one, 4-(((1r,4r)-4- Methoxycyclohexyl)amino)-1,8-dimethyl-6-(thiazol-5-yl)quinolin-2(1 H)-one, corresponding respectively to compounds 78b, 78c, 79c, 79d of H
  • the CD38 inhibitor is 4-((4-(2-Methoxyethoxy)cyclohexyl)amino)-1-methyl-6- (thiazol-5-yl)quinolin-2(1 H)one, corresponding to compound 78c of Haffner 2015 and Bosslet 2019, which is of formula: or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.
  • the CD38 inhibitor is an indole-7-carboxamide as described in WO 2016/087975, incorporated herein by reference.
  • the indole-7-carboxamide is of formula (III):
  • Q is 0, NH, N(H)C(O), or C(O)N(H);
  • R 1 is Ci.5alkylS(O) 2 CH 3 , or C 1-6 alkyl, wherein said alkyl can comprise straight-chain portions, branched chain portions, cycloalkyl portions, and wherein said C 1-6 alkyl is optionally substituted by one OH or OCH 3 and wherein said C 1-6 alkyl is optionally further substituted by 1 to 3 fluorine atoms; and
  • R 2 is H, C 1-3 alkyl, or halogen, or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.
  • R 2 is H or Cl. Most preferably, R 2 is H.
  • the indole-7-carboxamide of formula III have the trans orientation on the cyclohexyl ring depicted below :
  • the CD38 inhibitor is:
  • the CD38 inhibitor is 5-(1H-midazol-1 -yI)-N-(4-(2- methoxyethoxy)cyclohexyl)-1 H-indole-7-carboxamide (corresponding to Example 5 of WO 2016/087975), which is of formula: or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.
  • the CD38 inhibitor is a cyclohexyl-5-(thiazol-5-yl)-1h-indole-7-carboxamide as described in Lagu B, Wu X, Kulkarni S, Paul R, Becherer JD, Ravani S, et al.
  • the CD38 inhibitor is of formula (IV): wherein:
  • A1 and A2 are independently CH or N, provided that A1 and A2 are not both N;
  • X 1 is CR 1A and X 2 is NR 5A , when bond a is a double bond and bond b is a single bond; or X 1 is NR 1B and X 2 is CR 5B , when bond a is a single bond and bond b is a double bond;
  • R 1A is H, C 1-4 alkyl, NO 2 , CN, CONR a R b , CH 2 NR a R b , (CHR c ) m OH, C 1-4 haloalkyl, CHO, COO-R a , or halo;
  • R a , R b , and R c are each independently H or C 1-4 alkyl
  • R 1B is H or C 1-4 alkyl optionally substituted with 3-5 membered monocyclic heterocyclyl or hydroxy;
  • R 5A is H or C 1-4 alkyl
  • R 5B is H, halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, NHR b or CONHR c ;
  • R 2 is 5-membered heteroaryl
  • R 3 is C 1-4 alkyl, C 3-6 cycloalkyl, bridged C 7-12 cycloalkyl, 5-6 membered monocyclic heterocyclyl optionally substituted with one or two oxo groups, or phenyl, wherein said alkyl, cycloalkyl, bridged cycloalkyl, heterocyclyl or phenyl is optionally substituted with one or two R x groups, wherein R x is halo, 3 to 6- membered heterocyclyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, SO 2 Me or OR d ;
  • R d is H or C 1-4 alkyl optionally substituted with C 1-4 alkoxy;
  • R 4 is H, halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, NHR e or CONHR f ;
  • R e and R f are each independently H or C 1-4 alkyl
  • R 6 is H or C 1-4 alkyl; n is O or 1 ; and m is 1, 2 or 3, provided that, when R 1A is H or C 1-4 alkyl; and R 2 is , then n is 1; and provided that when A1 is N, X 1 is N and R 1B is C 1-4 alkyl, then n is 1 ; and, in an alternative, when A1 is N; X 1 is N; R 1B is C 1-4 alkyl; and R 3 is an optionally substituted phenyl, then n is 1 , or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.
  • A1 and A2 are CH.
  • R 2 is
  • n 0.
  • R 3 is , wherein Y is O, NH, SO 2 , CH 2 or CHR X , and p is 0 or 1.
  • R 3 is
  • Rx is C 1-4 hydroxy alkyl or OR d , preferably wherein Rd is H or C 1-4 alkyl substituted with C 1-4 alkoxy.
  • Rx is OH, OCH 2 CH 2 OMe or OCH 2 CH 2 CH 2 OMe.
  • the CD38 inhibitor is:
  • the CD38 inhibitor is N-(4-(2-methoxyethoxy)cyclohexyl)-6-(thiazol-5-yl)-1 H- pyrrolo[2,3-b]pyridine-4-carboxamide, corresponding to compound MK-0159 of Lagu 2022 and WO 2021/087087, which is of formula: or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.
  • Heterobicyclic amide of formula (V) including RBN013209 and Examples 7, 1 15, 182, 189, 191 , 193, and 195 of WO 2021/021986
  • the CD38 inhibitor is a heterobicyclic amide as described in WO 2021/021986, incorporated herein by reference.
  • the CD38 inhibitor is of formula (V): wherein:
  • V is N or CR V , wherein R v is H, halo, or C 1-4 alkyl;
  • W is N or CR W , wherein R w is H, halo, or C 1-4 alkyl; Ring A is a 5-membered heteroaryl group having 1 , 2 or 3 ring-forming heteroatoms selected from N, 0, and S, wherein the 5-membered heteroaryl group of Ring A is optionally substituted by 1 , 2, or 3 substituents independently selected from halo and C 1-4 alkyl; each R N is independently selected from H, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, wherein said C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3 ' 7 cycloalkyl, 5-10 membered heteroaryl,
  • L is a C 1-4 alkylene linker; n is O or 1 ;
  • Q is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 haloalkyl, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, or 4-14 membered heterocycloalkyl, wherein said C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 haloalkyl, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, or 4-14 membered heterocycloalkyl of Q are each optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from Cy 1 , Cy 1 - C 1-4 alkyl, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 2 , OR a1 , SR a1 , C(O)R
  • V is CH
  • W is CH; the moiety represented by n is O;
  • V is N.
  • W is N or CH, preferably N.
  • Ring A is a 5-membered heteroaryl group having 2 ring-forming N heteroatoms, , preferably
  • each R N is H.
  • each R A , and R B is H.
  • n 0.
  • Q is a C 3-14 cycloalkyl (preferably cyclohexyl) substituted with OR a1 , NR c1 R d1 , or - C(CH 3 ) 2 -OH.
  • each R a1 is C 1-6 alkyl (preferably ethyl) substituted with OR a3 .
  • each R c1 is H.
  • each R d1 is C 1-6 alkyl (preferably ethyl or propyl) substituted with halogen.
  • each R a3 is independently C 1-6 alkyl, preferably methyl.
  • the CD38 inhibitor is:
  • the CD38 inhibitor is 2-(1 H-lmidazol-1 -yl)-N-(4-(2- methoxyethoxy)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide (Example 7), corresponding to compound RBN013209 of WO 2021/021986, which is of formula: or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.
  • the CD38 inhibitor can also be 5-(1 H-imidazol-1 -yl)-N-((1 r,4r)-4-((2,2,2- trifluoroethyl)amino)cyclohexyl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide (Example 115), 5-(1 H-imidazol-1 -yl)-N- ((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)-1H-pyrazolo[4,3-d]pyrimidine-7-carboxamide (Example 191), N- ((1 r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-5-(1H-midazol-1 -yI)-1H-pyrazolo [3,4-c] pyridine-7-carboxamide (
  • the CD38 inhibitor is a quinoline or azaquinoline as described in WO 2022/165114, incorporated by reference herein.
  • the CD38 inhibitor is of formula (VI):
  • X 3 is CR 3 or N
  • X 4 is CR 4 or N
  • A is a 5-membered heteroaryl group having 1 , 2 or 3 ring-forming heteroatoms selected from N, 0, and S, wherein the 5-membered heteroaryl group of A is optionally substituted by 1 , 2, or 3 substituents independently selected from halo and C 1-4 alkyl;
  • L is a C 1-4 alkylene linker; n is O or 1 ;
  • Q is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 haloalkyl, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, or 4-14 membered heterocycloalkyl, wherein said C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 haloalkyl, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, or 4-14 membered heterocycloalkyl of Q are each optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from Cy 1 , Cy 1 -C 1-4 alkyl, halo, C 1-6 alkyl, C 2.6 alkenyl, C 2.6 alkynyl, C 1-6 haloalkyl, CN, N0 2 , 0R a , SR a , C(O)R
  • R 1 is C 1-6 alkyl
  • X 3 is N.
  • X 4 is N.
  • R 1 is C 1-6 alkyl, preferably methyl.
  • R 2 is H.
  • A is a 5-membered heteroaryl group having 2 ring-forming N heteroatoms, preferably
  • n is O.
  • Q is C 3-14 cycloalkyl (preferably cyclohexyl) substituted with OR a .
  • R a is C 1-6 alkyl substituted with OR a3 .
  • R a3 is C 1-6 alkyl, preferably methyl.
  • the CD38 inhibitor is:
  • Example 3 388) 4-(((1 r,4r)-4-(2-hydroxypropan-2-yl)cyclohexyl)amino)-6-(1 H-imidazol-1-yl)-1-methyl-1,5-naphthyridin-2(1 H)- one, Example 4;
  • the CD38 inhibitor is 2-(1H-midazol-1 -yI)-8-((4-(2- methoxyethoxy)cyclohexyl)amino)-5-methylpyrido[3,2-d]pyrimidin-6(5H)-one, corresponding to Example 7 of (65) WO 2022/165114, which is of formula: or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.
  • the CD38 inhibitor is a pyridazine or pyrimidine compound as described in WO 2022/228496, incorporated by reference herein.
  • the CD38 inhibitor is of formula (VII): wherein
  • Ai is halogen; or 5 or 6 membered unsaturated monocyclic heterocycle containing 1 to 3 heteroatoms selected from the group consisting of N, 0 and S, and optionally substituted with one or two C 1-6 alkyl optionally substituted with 1 , 2 or 3 halogen;
  • A2 is optionally having one or two carbon atoms replaced with nitrogen; wherein A2 is optionally substituted with 0 or 1 -OH; -CN; halogen; C 1-6 alkyl optionally substituted with 1 , 2 or 3 halogen; C 2-6 alkynyl; C 1-6 alkoxy; C 3-6 cycloalkoxy, in which the cycloalkyl optionally has one carbon atom replaced with 0 or S; -NR 1 R 2 , in which each of R1 and R2 independently is H, C 1-6 alkyl, -C(O)C 1-6 is a 5 or 6 membered saturated or unsaturated heterocycle containing 1 to
  • heteroatoms selected from the group consisting of N, 0 and S, and optionally substituted with 1-2 C 1-6 alkyl;
  • A3 is selected from the group consisting of C 1-6 alkyl; -(CHR 3 )n-C 3-8 cycloalkyl, in which the C 3-8 cycloalkyl optionally has one or two carbon atoms replaced with N, 0 or S, n is 0, 1 or 2, and R3 is H or C 1-6 alkyl; or in which the phenyl optionally has one or two carbon atoms replaced with
  • N, and k is O, 1 or 2; wherein A3 is optionally substituted with 0, 1 or 2 substituents independently selected from the group consisting of -OH; -CN; -OCH 2 CH 2 OCH 3 ; -CO-C 1-6 alkyl; halogen; C 1-6 alkyl optionally substituted with 1-3 halogen, methoxy or hydroxy; C 1-6 alkoxy optionally substituted with NH 2 , dimethylamino, hydroxy or carboxy; C 3-6 cycloalkoxy; or C 3-8 cycloalkyl, in which the C 3-8 cycloalkyl optionally has one or two carbon atoms replaced with N, 0 or S and is optionally substituted with 1-3 halogen, C 1-6 alkyl, C 1-6 alkyl or hydroxy; and
  • R is H or C 1-6 alkyl; or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.
  • A1 is a 5 membered unsaturated monocyclic heterocycle containing two N heteroatoms
  • A1 is unsubstituted.
  • A2 is having two carbon atoms replaced with nitrogen, preferably
  • A2 is substituted C 1-6 alkyl optionally substituted with 1 , 2 or 3 halogen (preferably -CF 3 ).
  • A3 is optionally substituted with -OCH 2 CH 2 OCH 3 .
  • R is H.
  • the CD38 inhibitor is:
  • the CD38 inhibitor is 2-(1 H-imidazol-1-yl)-N-(2-(2-methoxyethoxy)pyrimidin- 5-yl)-6-(trifluoromethyl) pyrimidine-4-carboxamide of WO/2022/228496, corresponding to Compound 1 of Li. et al. (J. Med. Chem. 2023, 66, 12762-12775), which is of formula: or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.
  • the CD38 inhibitor is a pyrazine or pyrimidine carboxamide as described in WO 2021/207186, which is incorporated herein by reference.
  • the CD38 inhibitor is of formula (VIII): wherein:
  • X 1 and X 2 are independently CH or N, provided that X 1 and X 2 are not both CH;
  • Cy is C 3-7 cycloal kyl optionally substituted with an oxo group or with one or two R x groups, wherein R x is halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, -NHSO 2 C1-C4 alkyl, or -SO 2 C 1-C4 alkyl;
  • R 2 is a 5-membered heteroaryl optionally substituted with one, two or three deuterium or C 1-4 alkyl groups;
  • R d is H, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, or C 1-4 alkyl optionally substituted with C 1-4 alkoxy;
  • R a and R b independently are -H or C 1-4 alkyl; and n is 0 or 1 , or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.
  • X 1 and X 2 are N.
  • Xi is CH and X2 is N.
  • R 1 is C 1-4 alkyl (preferably methyl), halo (preferably Cl), C 1-4 haloalkyl (preferably -CH 2 F), a 5-membered heteroaryl (preferably ), or -NR a R b , wherein R a and R b are -H.
  • R 2 is a 5-membered heteroaryl
  • Cy is cyclohexyl.
  • R d is C 1-4 alkyl (preferably ethyl) substituted with C 1-4 alkoxy (preferably methoxy); or C 1-4 haloalkyl (preferably -CHF2).
  • n is 1.
  • the CD38 inhibitor is:

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des méthodes de réduction de l'inflammation TH2 et de traitement ou de prévention d'une affection associée à une inflammation TH2 chez un sujet, comprenant l'administration au sujet d'une quantité thérapeutiquement efficace d'inhibiteur de CD38 audit sujet. L'invention concerne également des utilisations d'un inhibiteur de CD38 pour réduire l'inflammation TH2 et pour traiter ou prévenir une affection associée à une inflammation TH2 chez un sujet ; et pour la fabrication d'un médicament pour réduire l'inflammation TH2 et pour traiter ou prévenir une affection associée à une inflammation TH2 chez un sujet. L'invention concerne en outre des inhibiteurs de CD38 destinés à être utilisés dans la réduction de l'inflammation TH2 et pour le traitement ou la prévention d'une affection associée à une inflammation TH2 chez un sujet. De plus, l'invention concerne des compositions pharmaceutiques pour réduire l'inflammation TH2 et pour traiter ou prévenir une affection associée à une inflammation TH2 chez un sujet, les compositions pharmaceutiques comprenant un inhibiteur de CD38 et un support pharmaceutiquement acceptable.
PCT/CA2025/050888 2024-06-25 2025-06-25 Utilisation d'inhibiteurs de cd38 pour réduire l'inflammation th2 Pending WO2026000074A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202463663780P 2024-06-25 2024-06-25
US63/663,780 2024-06-25

Publications (1)

Publication Number Publication Date
WO2026000074A1 true WO2026000074A1 (fr) 2026-01-02

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Application Number Title Priority Date Filing Date
PCT/CA2025/050888 Pending WO2026000074A1 (fr) 2024-06-25 2025-06-25 Utilisation d'inhibiteurs de cd38 pour réduire l'inflammation th2

Country Status (1)

Country Link
WO (1) WO2026000074A1 (fr)

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