Use of CD38 inhibitors for reducing th2 inflammation

Abstract

Methods for reducing TH2 inflammation and 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 are provided. There are also provided uses of a CD38 inhibitor for reducing TH2 inflammation and for treating or preventing a TH2 inflammation-associated condition in a subject; and for the manufacture of a medicament for reducing TH2 inflammation and for treating or preventing a TH2 inflammation-associated condition in a subject. CD38 inhibitors for use in reducing TH2 inflammation and for treating or preventing a TH2 inflammation-associated condition in a subject are further provided. In addition, pharmaceutical compositions for reducing TH2 inflammation and for treating or preventing a TH2 inflammation-associated condition in a subject are provided, the pharmaceutical compositions comprising a CD38 inhibitor and a pharmaceutically acceptable carrier.

Description

USE OF CD38 INHIBITORS FOR REDUCING TH2 INFLAMMATIONCROSS REFERENCE TO RELATED APPLICATIONSThe present application claims the benefit of U.S. provisional application No. 63 / 663,780, filed June 25, 2024, which is incorporated herein by reference.FIELD OF THE INVENTION

[0001] 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.BACKGROUND OF THE INVENTION

[0002] T-helper cell type 2 (TH2) inflammation (TH2I) 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. Activation of 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.

[0003] 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.

[0004] 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. In contrast, parasitic infections, such as helminths worms, trigger 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.Conditions and Diseases Associated with TH2 Inflammation

[0005] With distinct tissue and disease-specific clinical manifestations, 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. Host defense against helminths promotes removal of parasites from the body through mucus production and tissue remodeling. However, excessive TH2 responses can lead to chronic inflammation and tissue damage.

[0006] 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. A clinical manifestation of CRSwNP, often with comorbid asthma, is aspirin-exacerbated respiratory disease (AERD).

[0007] Asthma is a prominent multifactorial inflammatory condition of the lower airways characterized by variable and returning symptoms, reversible airflow obstruction, and bronchial hyperresponsiveness. There is a strong epidemiologic relationship between allergies and asthma. Asthma affects over 330 million people worldwide (>4% of the population globally). It is more prevalent in developed countries, and the United States. Over decades, there has been a rise in its prevalence. Asthma is often accompanied by co-morbidities including multi-organ allergies, such as allergic chronic sinusitis, conjunctivitis, atopic dermatits, food allergies, as well as non-allergic disorders, including obesity, gastro-esophageal reflux and psychiatric conditions. Allergic asthma tends to begin in childhood and is associated with TH2 responses. Non-TH2 forms are often associated with obesity, aging, and smoking whereas the TH2 form is often accompanied by CRSwNP, sensitivity to aspirin and high eosinophil counts in the airways. 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.

[0008] Atopic dermatitis (AD), also known as 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 geneticbackground 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.

[0009] Eosinophilic esophagitis (EoE) 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.

[0010] Allergies are TH2 inflammation-associated conditions with responses to allergens that are generally harmless in most people. Worldwide, 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. Common 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. In atopic and allergic diseases, TH2 cells play a central pathogenic role in promoting tissue inflammation. Specifically, 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.

[0011] Other ‘allergic’ conditions such as allergic bronchopulmonary aspergillosis (ABPA) or allergic conjunctivitis typically present TH2I. Formerly known as Churg-Strauss syndrome, eosinophilic granulomatosis with polyangiitis (eGPA) is a rare condition with systemic autoimmune necrotizing vasculitis characterized by granulomatous and eosinophilic infiltration with primarily a TH2 response. Hypereosinophilic syndromes (HES) refer to a group of rare and complex disorders characterized by persistent and substantial elevations in eosinophils. 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.

[0012] The presence of 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.

[0013] Inflammatory Bowel Disease (IBD) are chronic disorders affecting the digestive tract that include ulcerative colitis (UC) and Crohn's disease. There is mounting evidence pointing to a pivotal role for TH2I during chronic inflammatory pathways at the intestinal mucosa. The predominant cytokines in UC are from the TH2 profileproducing 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.

[0014] Systemic Lupus Erythematous (SLE) presents autoantibodies to the IgG subclass, and over 50% of SLE patients also present autoantibodies to the IgE subclass, the acquired immunity effector of TH2 I, which are strongly associated with disease severity. In a randomized clinical trial, 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.

[0015] Thus, 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.Conventional Treatment Options for TH2-lnflammation Associated Conditions

[0016] 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.

[0017] 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. In CRSwNP with large polyps surgery may be performed, however polyps typically recur. Continuous use of the medications will be necessary. As with asthma, 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.

[0018] The treatment for AD includes topical corticosteroids for mild-to-moderate cases, but there is an unmet needfor topical agents due to safety concerns about topical corticosteroids use for AD. In recent years, the 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.

[0019] 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.

[0020] 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. For mild, acute cases of urticaria limited to the skin, 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.

[0021] The treatment of COPD can involve bronchodilators alone or in combination with corticosteroids and phosphodiesterase-4 inhibitors. Disease-modifying antirheumatic drugs (DMARDs) 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.

[0022] Considering the variable treatment effectiveness with chronic conditions associated with TH2 responses, the high costs of biopharmaceuticals, and a relative etiological uncertainty, there remains a need for the development of novel approaches to the treatment and prevention of conditions associated with TH2 I.Cluster of Differentiation 38 (CD38)

[0023] 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. In non-immune cell types, 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 smoothmuscle cells in general. CD38 is also expressed in airway epithelial cells (AECs).SUMMARY OF THE INVENTION

[0024] In accordance with the present invention, there is provided:1. A method for reducing TH2 inflammation in a subject, the method comprising administering to the subject a therapeutically effective amount of CD38 inhibitor to said subject.2. A method for treating or preventing a TH2 inflammation-associated condition in a subject, the method comprising administering to the subject a therapeutically effective amount of CD38 inhibitor to said subject.3. Use of a CD38 inhibitor for reducing TH2 inflammation in a subject.4. Use of a CD38 inhibitor for treating or preventing a TH2 inflammation-associated condition in a subject.5. Use of a CD38 inhibitor for the manufacture of a medicament for reducing TH2 inflammation in a subject.6. Use of a CD38 inhibitor for the manufacture of a medicament for treating or preventing a TH2 inflammation-associated condition in a subject.7. A CD38 inhibitor for use in reducing TH2 inflammation in a subject.8. A CD38 inhibitor for use in treating or preventing a TH2 inflammation-associated condition in a subject.9. A pharmaceutical composition for reducing TH2 inflammation in a subject, the pharmaceutical composition comprising a CD38 inhibitor and a pharmaceutically acceptable carrier.10. A pharmaceutical composition for treating or preventing a TH2 inflammation-associated condition in a subject, the pharmaceutical composition comprising a CD38 inhibitor and a pharmaceutically acceptable carrier.11 . The method / use / inhibitor for use / composition for use of any one of embodiments 1 to 10, wherein the subject is a human subject.12. The method / use / inhibitor for use / composition for use of any one of embodiments 1 to 11 , wherein said 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.13. The method / use / inhibitor for use / composition for use of embodiment 12, wherein the one or more TH2 inflammatory mediator is an interleukin, a cytokine, a leukotriene, a transcription factor, a prostaglandin, a chemokine, a hormone, and / or histamine.14. The method / use / inhibitor for use / composition for use of embodiment 12, wherein the one or more 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.The method / use / inhibitor for use / composition for use of any one of embodiments 1 to 14, wherein said 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. The method / use / inhibitor for use / composition for use of any one of embodiments 1 to 15, wherein the TH2 inflammation-associated condition is chronic or acute (present acute manifestations), preferably chronic. The method / use / inhibitor for use / composition for use of any one of embodiments 1 to 15, wherein the CD38 inhibitor is used to prevent the TH2 inflammation from becoming a chronic TH2 inflammation- associated condition. The method / use / inhibitor for use / composition for use of any one of embodiments 1 to 17, wherein the 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 (ABPA) and allergic conjunctivitis; eosinophilia; eosinophilic esophagitis; eosinophilic granulomatosis with polyangiitis (eGPA); hypereosinophilic syndrome (HES) including chronic eosinophilic leukemia, idiopathic HES, parasitic infestations, allergic reactions, or a HES secondary to an underlying condition such as helminth infections or eGPA; Chronic Obstructive Pulmonary Disease (COPD), preferably in subjects with elevated eosinophil counts and altered gene and protein expression of several TH2 markers; aspirin-exacerbated respiratory disease; Crohn’s disease; ulcerative colitis (UC); rheumatoid arthritis; lupus erythematosus; or urticaria. The method / use / inhibitor for use / composition for use of any one of embodiments 1 to 18, wherein the TH2 inflammation-associated condition is chronic rhinosinusitis (CRS), asthma, atopic dermatitis or eosinophilic esophagitis. 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. The method / use / inhibitor for use / composition for use of any one of embodiments 1 to 18, wherein the TH2 inflammation-associated condition is chronic rhinosinusitis (CRS), including CRSsNP and CRSwNP, preferably CRSwNP.22. The method / use / inhibitor for use / composition for use of embodiment 21 , wherein the CD38 inhibitor is used to prevent the occurrence or reoccurrence of nasal polyps with CRSwNP.23. The method / use / inhibitor for use / composition for use of any one of embodiments 1 to 18, wherein the TH2 inflammation-associated condition is COPD.24. The method / use / inhibitor for use / composition for use of any one of embodiments 1 to 18, wherein the TH2 inflammation-associated condition is rheumatoid arthritis.25. The method / use / inhibitor for use / composition for use of any one of embodiments 1 to 18, wherein the TH2 inflammation-associated condition is Systemic Lupus Erythematosus (SLE).26. The method / use / inhibitor for use / composition for use of any one of embodiments 1 to 18, wherein the TH2 inflammation-associated condition is ulcerative colitis.27. The method / use / inhibitor for use / composition for use of any one of embodiments 1 to 17, wherein the CD38 inhibitor is used 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, to prevent a TH2 inflammation-associated condition, such as asthma, CRS, or another TH2 inflammation- associated condition.28. The method / use / inhibitor for use / composition for use of any one of embodiments 1 to 17, wherein the TH2 inflammation-associated condition is TH2 inflammation-associated fibrogenesis or TH2 inflammation-associated fibrosis.29. The method / use / inhibitor for use / composition for use of any one of embodiments 1 to 17, wherein the TH2 inflammation-associated condition is TH2 inflammation-associated tissue remodeling.30. The method / use / inhibitor for use / composition for use of embodiment 29, wherein the TH2 inflammation- associated tissue remodeling is reduced by reducing fibrosis, preferably the deposition of collagen; and / or by reducing tissue hyperresponsiveness.31 . The method / use / inhibitor for use / composition for use of any one of embodiments 1 to 17, wherein said wherein the TH2 inflammation-associated condition is TH2 inflammation-associated epithelial dysfunction.32. The method / use / inhibitor for use / composition for use of embodiment 31, wherein said 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.33. The method / use / inhibitor for use / composition for use of any one of embodiments 1 to 32, wherein the CD38 inhibitor is a small molecule, preferably with a molecular weight up to 5000 Da, preferably up to 2000 Da, and most preferably up to about 1000 Da.34. The method / use / inhibitor for use / composition for use of any one of embodiments 1 to 33, wherein the CD38 inhibitor comprises a thiazole, imidazole, pyrazole, or pyridazole group, preferably a thiazole or imidazole group, and more preferably a thiazole group.35. The method / use / inhibitor for use / composition for use of any one of embodiments 1 to 34, wherein the CD38 inhibitor comprises a 4-(2-methoxyethoxy)cyclohexyl)amino) group, preferably a trans-4-(2- methoxyethoxy)cyclohexyl)amino) group.36. The method / use / inhibitor for use / composition for use of any one of embodiments 1 to 35, wherein the CD38 inhibitor comprises a trans-4-(2-methoxyethoxy)cyclohexyl)amino) group and an imidazole group or a thiazole group, preferably a thiazole group. 37. The method / use / inhibitor for use / composition for use of any one of embodiments 1 to 36, wherein theCD38 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 formula (XII),a pyrazole of formula (Xllla), (Xlllb), or (Xlllc),a heterobicyclic amide of formula (XIV),a heteroaryl amide of formula (XV) or (XV*), ora picolinamide and pyrimidine carboxamide of formula (XVI),wherein the substituents are as described above, or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof. The method / use / inhibitor for use / composition for use of any one of embodiments 1 to 37, wherein theCD38 inhibitor is:• 4-((-4-(2-Methoxyethoxy)cyclohexyl)amino)-1 -methy l-6-(th i azol-5-y l)q u i nol i n-2( 1 H)one, corresponding to compound 78c of Haffner 2015 and Bosslet 2019,• 1 -Methyl-4-((tetrahydro-2Hpyran-4-yl)amino)-6-(thiazol-5-yl)quinolin-2(1 H)-one, corresponding to compound 78b of Haffner 2015,• 4-(((1 r,4r)-4-(2-Methoxyethoxy)cyclohexyl)amino)-1 , 8-d i methy l-6-(thiazol-5-y l)quinol i n2( 1 H)-one, corresponding to compound 79c of Haffner 2015,• 4-(((1 r,4r)-4-Methoxycyclohexyl)amino)-1 , 8-d i methy l-6-(th i azol-5-yl)qui nolin-2( 1 H)-one, corresponding to compounds 79d of Haffner 2015,• 5-(1 H-imidazol-1-yl)-N-(4-(2-methoxyethoxy)cyclohexyl)-1H-indole-7-carboxamide (corresponding to Example 5 of WO 2016 / 087975),• 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,• 2-(1 H-lmidazol-1-yl)-N-(4-(2-methoxyethoxy)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, corresponding to compound RBN013209 of WO 2021 / 021986,• 5-(1H-midazol-1 -yI)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)-1H-pyrazolo[3,4-c]pyridine-7- carboxamide, corresponding to Example 115 of WO 2021 / 021986,• N-((1 r,4r)-4-(2-hydroxypropan-2-yl)cyclohexyl)-5-(1H-midazol-1 -yI)-1H-pyrazolo[4,3-d]pyrimidine-7- carboxamide, corresponding to Example 182 of WO 2021 / 021986.• 5-(1 H-imidazol-1-yl)-N-((1 r,4r)-4-((3,3,3-trifluoropropyl)amino)cyclohexyl)-1H-pyrazolo[3,4-c]pyridine-7- carboxamide, corresponding to Example 189 of WO 2021 / 021986,• 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, corresponding to Example 191 of WO 2021 / 021986,• N-((1 r,4r)-4-((2,2-difluoropropyl)amino)cyclohexyl)-5-(1H-midazol-1 -yI)-1 H-pyrazolo[3,4-c]pyridine-7- carboxamide, corresponding to Example 193 of WO 2021 / 021986,• N-((1 r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-5-(1H-midazol-1 -yI)-1H-pyrazolo [3,4-c] pyridine-7- carboxamide, corresponding to Example 195 of WO 2021 / 021986,• 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 WO 2022 / 165114,• 2-(1 H-imidazol-1 -y l)-N-(2-(2-methoxyethoxy) py ri mid i n-5-y l)-6-(trif I uoromethy I) pyrimidine-4-carboxamide, corresponding to Compound 1 of WO / 2022 / 228496,• 2-(1 H-i m id azol -1 -yl)-N-(4-(2-methoxyethoxy)cyclohexyl)-6-methylpyrimidine-4-carboxamide, corresponding to Example 35 of WO 2021 / 207186,• 6-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(1-methyl-1 H-pyrazol-4-yl)picolinamide, corresponding to Example 12 of 2021 / 207186,• 4-amino-6-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide, corresponding to Example 15 of 2021 / 207186,• 4, 6-di(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide, corresponding to Example 16 of 2021 / 207186,• 6-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(thiazol-5-yl)picolinamide, corresponding to Example 17 of 2021 / 207186,• 4-chloro-6-(1 H-imidazol-1-yl)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-picolinamide, corresponding to Example 18 of 2021 / 207186,• 2-(1 H-imidazol-1-yl)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1 -methyl-1 H-pyrazol-4-yl)pyrimidine-4- carboxamide, corresponding to Example 27 of 2021 / 207186,• N-((1 r,4r)-4-(difluoromethoxy)cyclohexyl)-2-(1 H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide, corresponding to Example 42 of 2021 / 207186,• 6-(fluoromethyl)-2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide, corresponding to Example 51 of 2021 / 207186,• 2-(1 H-imidazol-1-yl)-N-((1s,4s)-4-(2-methoxyethoxy)cyclohexyl)-6-methylpyrimidine-4-carboxamide, corresponding to Example 60 of 2021 / 207186,• (R)-N-(Tetrahydro-2H-pyran-3-yl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1,4]oxazepine-10-carboxamide, corresponding to Compound 1A of WO 2024 / 226685,• (R)-N-(1 , 1 -Dioxidotetrahyd rothiophen-3-y l)-5,6-d i hyd robenzo[f]i mid azo[1 , 5-d][ 1 ,4]oxazepine-10- carboxamide, corresponding to Compound 2A of WO 2024 / 226685,• N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10- carboxamide, corresponding to Compound 3A of WO 2024 / 226685,• N-(1-(Methylsulfonyl)piperidin-4-yl)-5,6-dihydrobenzo[f]imidazo[1,5-d][1 ,4]oxazepine-10-carboxamide, corresponding to Compound 4A of WO 2024 / 226685,• (R)-N-(1,1-Dioxidotetrahydrothiophen-3-yl)-4-oxo-4,5-dihydroimidazo[1 ,5-a]quinoxaline-8-carboxamide, corresponding to compound 12A of WO 2024 / 226685,• 2-(1H-midazol-1 -yI)-6-methyl-N-((1 r,4r)-4-((2, 2, 2- trifluoroethyl)amino)cyclohexyl)pyrimidine-4-carboxamide, corresponding to Example 1 of WO 2023 / 084206,• N-((1r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-2-(1 H- imidazol-1-yl)-6-methyl-pyrimidine-4-carboxamide, corresponding to Example 2 of W0 2023 / 084206,• 6-cyclopropyl-N-((1 r,4r)-4-((2,2- difluoroethyl)amino)cyclohexyl)-2-(1 H-imidazol-1 -yl)pyrimidine-4- carboxamide, corresponding to Example 3 of WO 2023 / 084206,• N-((1 r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-2-(1 H- imidazol-1-yl)-6-methyl-pyrimidine-4-carboxamide, corresponding to Example 10 of WO 2023 / 084206,• 2-(1H-midazol-1 -yI)-6-methy l-N-(( 1 r, 4r)-4-(( 1 , 1 , 1 -trifluoro-2- methylpropan-2- yl)amino)cyclohexyl)pyrimidine-4-carboxamide, corresponding to Example 21 of WO 2023 / 084206,• 4-(1-methyl-1H-imidazol-5-yl)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)thiazole-2-carboxamide, corresponding to Example 1 of WO 2024 / 236315,• 3-(1-methyl-1 H-imidazol-5-yl)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)-1,2,4-thiadiazole-5- carboxamide, corresponding to Example 2 of WO 2024 / 236315,• 2-(1-methyl-1 H-imidazol-5-yl)-N-((1r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)thiazole-4-carboxamide, corresponding to Example 4 of WO 2024 / 236315,• N-((1 r,4r)-4-(3,3-difluoropyrrolidin-1 -yl)cyclohexyl)-4-(1 -methyl- 1 H-imidazol-5-yl)thiazole-2-carboxamide, corresponding to Example 9 of WO 2024 / 236315,• 1-(1 H-imidazol-1-yl)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)imidazo[1,5-a]pyridine-3- carboxamide, corresponding to Example 1 of WO 2024 / 236316,• N-((1 r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-1-(1 H-imidazol-1-yl)imidazo[1 ,5-a]pyridine-3- carboxamide, corresponding to Example 2 of WO 2024 / 236316,• 4-{[(1 r,4r)-4-(2-Methoxyethoxy)cyclohexyl]amino}-1-methyl-6-[1-(oxan-2-yl)-1 H-pyrazol-4-yl]quinolin-2(1 H)- one, corresponding to Compound 11 of Doyle 2023,• 4-{[(1 r,4r)-4-(2-Methoxyethoxy)cyclohexyl]amino}-1-methyl-6-(1 H-pyrazol-4yl)quinolin-2(1 H)-one, Compound corresponding to Compound 12 of Doyle 2023,• 8-{[(1 r,4r)-4-Hydroxy-4-methylcyclohexyl]amino}2-(1H-midazol-1 -yI)-5-methylpyrido[3,2-d]pyrimidin-6(5H)- one, corresponding to Compound 13 of Doyle 2023,• 2-(1 H-lmidazol-1 -yl)-5-methyl-8-[(oxan-4-yl)amino]pyrido[3,2-d]pyrimidin-6(5H)-one, corresponding to Compound 14 of Doyle 2023,• 2-(1H-midazol-1 -yI)-N-((1r,4r)-4-((2, 2, 2-trifluoroethyl)amino)cyclohexyl)pyrido[2,3-d]pyrimidine-4- carboxamide, corresponding to Example 4 of WO 2023 / 227867,• N-((1 r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-2-(1H-midazol-1 -yI)pyrrolo[2,1-f][1, 2, 4]triazine-4- carboxamide, corresponding to Example 12 of WO 2023 / 227867,• N-((1s,4r)-4-((S)-3-fluoropyrrolidin-1-yl)cyclohexyl)-2-(1H-midazol-1 -yI)pyrrolo[2,1-f][1 ,2,4]triazine-4- carboxamide, corresponding to Example 13 of W0 2023 / 227867,• N-((1r,4r)-4-((R)-3-fluoropyrrolidin-1-yl)cyclohexyl)-2-(1 H-imidazol-1-yl)pyrrolo[2,1-f][1,2,4]triazine-4- carboxamide, corresponding to Example 14 of WO 2023 / 227867,• 8-(1 H-i m id azol-1 -yl)-N-((1 r, 4r)-4-((2, 2, 2-trifl uoroethy l)am i no)cyclohexy l)i m idazo[ 1 ,2-a]pyrazine-6- carboxamide, corresponding to Example 19 of WO 2023 / 227867,• 8-(1H-midazol-1 -yI)-N-((1r,4r)-4-((2, 2, 2-trifluoroethyl)amino)cyclohexyl)-[1 ,2,4]triazolo[1 ,5-a]pyrazine-6- carboxamide, corresponding to Example 20 of WO 2023 / 227867,• 4-(1 H-imidazol-1-yl)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)pyrazolo[1 ,5-a]pyrazine-6- carboxamide, corresponding to Example 21 of WO 2023 / 227867,• 2-(1 H-imidazol-1-yl)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)pyrrolo[2,1 -f][1 ,2,4]triazine-4- carboxamide, corresponding to Example 29 of WO 2023 / 227867,• N-((1 r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-8-(1 H-imidazol-1-yl)imidazo[1,2-a]pyrazine-6- carboxamide, corresponding to Example 41 of WO 2023 / 227867,• N-((1 r,4r)-4-(3,3-difluoroazetidin-1-yl)cyclohexyl)-8-(1 H-imidazol-1-yl)-[1,2,4]triazolo[1 ,5-a]pyrazine-6- carboxamide, corresponding to Example 45 of WO 2023 / 227867,• N-((1 r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-8-(1 H-imidazol-1-yl)-[1 ,2,4]triazolo[i,5-a]pyrazine-6- carboxamide, corresponding to Example 48 of WO 2023 / 227867,• 4-((cyclopropyl)oxy)-6-(1H-midazol-1 -yI)-N-(2-(trifluoromethyl)pyridin-4-yl)picolinamide, corresponding to Compound 32 of WO 2022 / 077034,• 6-(1H-midazol-1 -yI)-4-methoxy-N-(2-(trifluoromethyl)pyridin-4-yl)picolinamide, corresponding to Compound 35 of WO 2022 / 077034,• 2-(1H-midazol-1 -yI)-6-methoxyethoxy-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide, corresponding to Compound 39 of WO 2022 / 077034, or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.39. The method / use / inhibitor for use / composition for use of any one of embodiments 1 to 38, wherein 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, or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.40. The method / use / inhibitor for use / composition for use of any one of embodiments 37 to 39, wherein the prodrug is an ester, an amide, a guanidine, a carbamate, a carbonate, or a phosphate.41 . The method / use / inhibitor for use / composition for use of any one of embodiments 1 to 40, wherein the CD38 inhibitor is for oral administration to the subject.42. The method / use / inhibitor for use / composition for use of any one of embodiments 1 to 40, wherein the CD38 inhibitor is for topical administration to the skin of the subject.43. The method / use / inhibitor for use / composition for use of any one of embodiments 1 to 40, wherein the CD38 inhibitor is for cutaneous administration to the skin of the subject.44. The method / use / inhibitor for use / composition for use of any one of embodiments 1 to 40, wherein the CD38 inhibitor is for transdermal administration to the skin of the subject.45. The method / use / inhibitor for use / composition for use of any one of embodiments 1 to 40, wherein the CD38 inhibitor is for local administration to the airway of the subject.46. The method / use / inhibitor for use / composition for use of any one of embodiments 1 to 40, wherein the CD38 inhibitor is for inhalational or intranasal administration.47. The method / use / inhibitor for use / composition for use of embodiment 46, wherein the CD38 inhibitor is for inhalational administration, and is preferably formulated as a suspension, a dry powder, or an aerosol.48. The method / use / inhibitor for use / composition for use of embodiment 46, wherein the CD38 inhibitor is 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.49. The method / use / inhibitor for use / composition for use of any one of embodiments 1 to 48, wherein the CD38 inhibitor is formulated as a spray.50. The method / use / inhibitor for use / composition for use of embodiment 48, wherein the CD38 inhibitor is contained in an inhaler or a nasal spray comprising a canister containing the CD38 inhibitor, an atomizer for dispersing the CD38 inhibitor into an aerosol, and an outlet to disperse the aerosol into the nose or mouth of a patient.51 . The method / use / inhibitor for use / composition for use of any one of embodiments 1 to 50, wherein the CD38 inhibitor is used in combination with one or more other pharmaceutically active ingredient(s).52. The method / use / inhibitor for use / composition for use of embodiment 51, wherein the one or more other pharmaceutically active ingredient(s) is a prophylactic agent and / or a therapeutic agent.53. The method / use / inhibitor for use / composition for use of embodiment 51 or 52, wherein the CD38 inhibitor and said one or more other pharmaceutically active ingredient(s) are administered in a single dosage form or in separate dosage forms.54. The method / use / inhibitor for use / composition for use of any one of embodiments 51 to 53, wherein the CD38 inhibitor is administered to the subject before, concomitantly, before, or after said one or more other pharmaceutically active ingredient(s) is administered.55. The method / use / inhibitor for use / composition for use of any one of embodiments 51 to 54, wherein the one or more other pharmaceutically active ingredient(s) is for preventing or treating the TH2 inflammation-associated condition.56. The method / use / inhibitor for use / composition for use of any one of embodiments 51 to 55, wherein the CD38 inhibitor is used / administered in combination with said one or more other pharmaceutically active ingredient(s), which is already used by the subject to prevent or treat the TH2 inflammation-associated condition.57. The method / use / inhibitor for use / composition for use of any one of embodiments 51 to 56, wherein the one or more other pharmaceutically active ingredient(s) is a one or more other CD38 inhibitor.58. The method / use / inhibitor for use / composition for use of any one of embodiments 51 to 56, wherein the one or more other pharmaceutically active ingredients(s) is a glucocorticoid, a beta-2 agonist, a muscarinic antagonist, an antimicrobial, an antibiotic, an antihistamine, a leukotriene modifier, a probiotic, a TRP channel modulator, an anthelmintic, a fungicide, an antifibrotic agent, a PARP modulator, an immunotherapeutic agent, and / or hyaluronic acid., preferably a glucocorticoid.59. The method / use / inhibitor for use / composition for use of embodiment 58, wherein the 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; fluclorolone acetonide; flucloronide; fludrocortisone; fludroxycortide; flugestone; flumetasone; flunisolide; fluocinolone; fluocinolone acetonide; fluocinonide; fluocortin; fluocortolone; fluoroformylone; fluoromethoIone (including fluoromethoIone acetate); fluperolone; fluprednidene; fluprednisolone; flurandrenolide; flurandrenolone; flurogestone; fluticasone; fluticasone furoate; fluticasone propionate; fluticonase; formocortal; halcinonide; halobetasol; halometasone; hydrocortisone (including hydrocortisone butyrate and hydrocortisone valerate); loteprednol; medrysone (hydroxymethylprogesterone); meprednisone; methylprednisolone (including methylprednisolone acetate); methylprednisone; mometasone; mometasone furoate; paramethasone; prebediolone; prebediolone acetate; prednicarbate; prednisolone (including prednisolone sodium phosphate and prednisone acetate); prednisone; prednylidene; pregnenolone; progesterone; rimexolone; tixocortol (including tixocortol pivalate); triamcinolone; triamcinolone acetonide; ulobetasol; vamorolone; or RU- 28362.60. The method / use / inhibitor for use / composition for use of embodiment 59, wherein the glucocorticoid is triamcinolone; dexamethasone; momethasone; fluticasone; hydrocortisone; prednisolone; betamethasone; beclomethasone; ciclesonide; amcinonide; flunisolide; or budesonide.The method / use / inhibitor for use / composition for use of embodiment 58, wherein the 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 method / use / inhibitor for use / composition for use of embodiment 58, wherein the beta-2 agonist or muscarinic antagonist is formoterol; salmeterol; vilanterol; albuterol; umeclidinium; or salbutamol. The method / use / inhibitor for use / composition for use of embodiment 58, wherein the the antimicrobial is cetylpyridinium chloride; chlorhexidine; clove; eucalyptol; hydrogen peroxide; mandelic acid; menthol; methyl salicylate; peppermint; povidone iodine; tea tree oil; thymol; triclosan; or xylitol. The method / use / inhibitor for use / composition for use of embodiment 58, wherein 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; imipenem; tigecycline; fosfomycin; nitrofurantoin; metronidazole; trimethoprim-sulfamethoxazole; or vancomycin. The method / use / inhibitor for use / composition for use of embodiment 58, wherein the 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; rupatadine; bilastine; ebastine; famotidine; nizatidine; or rynatan. The method / use / inhibitor for use / composition for use of embodiment 58, wherein the leukotriene modifier is montelukast; zileuton; pranlukast; or zafirlukast. The method / use / inhibitor for use / composition for use of embodiment 58, wherein the TRP channel modulator is camphor; capsaicin; clemizole; flufenamic acid; ginsenoside Rd; icilin; menthol; neomycin sulfate; parthenolide; peimine; peiminine; piperine; resiniferatoxin; riluzole; sumatriptan; or tranilast. The method / use / inhibitor for use / composition for use of embodiment 58, wherein the anthelmintic is include albendazole; diethylcarbamazine; ivermectin; mebendazole; miltefosine; moxidectin; praziquantel; pyrantel pamoate; or triclabendazole. The method / use / inhibitor for use / composition for use of embodiment 58, wherein the fungicide is azoxystrobin; benomyl; captan; carbendazim; chlorothalonil; copper oxychloride; cyproconazole;fludioxonil; mancozeb; metalaxyl; propiconazole; sulfur; tebuconazole; thiophanate-methyl; trifloxystrobin; or zineb.70. The method / use / inhibitor for use / composition for use of embodiment 58, wherein 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; GSK2618960; MEDI9929 / AMG 157; or TQC2731.71 . The method / use / inhibitor for use / composition for use of embodiment 58, wherein the PARP modulators is niraparib; olaparib; rucaparib; or talazoparib.BRIEF DESCRIPTION OF THE DRAWINGS

[0025] In the appended drawings:Figure 1 . Murine IL-13 in Nasal Lavage Fluid of CRS Mouse Model of CRS Mouse ModelFigure 2. (A) Murine TGF-beta 1 and (B) TGF-beta 3 in Nasal Lavage Fluid of CRS Mouse ModelFigure 3. (A) Murine IL-33 and (B) IL-31 in Nasal Lavage Fluid of CRS Mouse ModelFigure 4. (A) Murine RANTES (B) IP-10 (C) M I P-3 alpha and (D) Fractalkine in Nasal Lavage Fluid of CRSMouse ModelFigure 5. (A) Murine IL-12p40, (B) IL-12p70, (C) IL-23 and (D) IL-27 in Nasal Lavage Fluid of CRS MouseModelFigure 6. Murine IL-2 in Nasal Lavage Fluid of CRS Mouse ModelFigure 7. (A) Murine Interferon gamma and (B) Interferon beta in Nasal Lavage Fluid of CRS Mouse ModelFigure 8. Collagen Distribution and Epithelium Thickness in Nasal Septum Detail of CRS Mouse Model (A)Healthy Animal, (B) CRS - Untreated, (C) CRS - WX-001, and (D) CRS - Positive ControlFigure 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 ControlFigure 10. Computerized Tomography (CT) scan of a Human Subject with CRSwNP (A) upon Diagnosis, (B) 4 Months Prior and (C) 7 Months Following In-Clinic PolypectomyFigure 11. Nasoendoscopy of a Human Subject with CRSwNP 13 Months Following In-Clinic PolypectomyDETAILED DESCRIPTION OF THE INVENTION

[0026] Turning now to the invention in more details, there is provided a method for reducing TH2 inflammation orfor 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.

[0027] 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.

[0028] 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.

[0029] Furthermore, there is a pharmaceutical composition for reducing TH2 inflammation or for treating or preventing a TH2 inflammation-associated condition in a subject, the pharmaceutical composition comprising a CD38 inhibitor and a pharmaceutically acceptable carrier.

[0030] 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.

[0031] In preferred embodiments, the subject is a human subject.

[0032] As used herein, 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. As used herein, the words “prevent” and “preventing” refer to stopping or avoiding the effects of a TH2 inflammation-associated condition in a subject.

[0033] As used herein, the words “reducing TH2 inflammation” includes any of reduction of TH2 inflammation, alleviation of TH2 inflammation, and amelioration of TH2 inflammation or TH2 -mediated immune responses.

[0034] In embodiments, 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. In embodiments, 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. In some embodiments, 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.

[0035] In embodiments, 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.

[0036] The term “effective amount” refers to an amount of a compound of the invention or other active ingredient sufficient to provide a therapeutic or prophylactic benefit in the treatment or prevention of a disease or to delay or minimize symptoms associated with a disease. Further, a therapeutically effective amount with respect to acompound 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. Used in connection with a compound of the invention, 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.

[0037] 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). In one embodiment, a patient is a human, such as a human infant, child, adolescent or adult.Benefits of the Invention

[0038] There are relatively limited small molecule treatment options for TH2 inflammation-associated conditions and corticosteroids remain the mainstay for TH2 inflammation-associated conditions. Therapeutic effects and benefits of the invention as observed in the Examples are discussed in this section.

[0039] 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.

[0040] In 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. It is also noteworthy to mention 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.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. Thus, beyond the usual allergic TH2 inflammation-associated condition, 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. Further, as persistent TH2 I can lead to TH2 inflammation-associated conditions, CD38 inhibitors can be administered in a subject as prevention, for example in combination therapies with corticosteroids or antihistamines. As a broad TH2 anti- inflammatory, CD38 inhibitors can be used for conditions such as allergy, for example in a nasal spray. In addition, chronic TH2 conditions like CRS, where a nasal spray is also commonly used, a CD38 inhibitor is envisionedadministered alongside a corticosteroid.

[0041] 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.

[0042] Considering that blockade of CD38 enzymatic activity leads to reducing cADPR thereby affecting calcium signaling which have pleiotropic effects on TH2 signaling, including but not limited to inflammation, secretion of TH2 inflammatory mediators, chemotaxis, immune, epithelial and subepithelial cells and tissues, it is considered that CD38 is an etiological agent of TH2 inflammation-associated conditions. In conclusion, CD38 inhibitors demonstrate beneficial effects at least on inflammation, epithelial dysfunction and tissue remodeling in subjects with TH2 inflammation-associated conditions.TH2 Inflammation and TH2 Inflammation-Associated Conditions

[0043] TH2 inflammation (TH2 I) as used herein 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. 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.

[0044] Herein, the term “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.

[0045] The TH2 inflammation-associated condition can be chronic or acute (present acute manifestations). In embodiments, the TH2 inflammation-associated condition is associated with acute signs and symptoms. In preferred embodiments, the TH2 inflammation-associated condition is chronic. In embodiments, the CD38 inhibitor is used to prevent TH2 inflammation from becoming a chronic TH2 inflammation-associated condition.

[0046] In embodiments, 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 triggersand allergens; allergic bronchopulmonary aspergillosis; another allergic condition such as allergic bronchopulmonary aspergillosis (ABPA) and allergic conjunctivitis; eosinophilia; eosinophilic esophagitis; eosinophilic granulomatosis with polyangiitis (eGPA); hypereosinophilic syndrome (HES) including chronic eosinophilic leukemia, idiopathic HES, parasitic infestations, allergic reactions, or a HES secondary to an underlying condition such as helminth infections or eGPA; Chronic Obstructive Pulmonary Disease (COPD), preferably in subjects with elevated eosinophil counts and altered gene and protein expression of several TH2 markers; aspirin-exacerbated respiratory disease; Crohn’s disease; ulcerative colitis (UC); rheumatoid arthritis; lupus erythematosus including Systemic Lupus Erythematosus (SLE); and urticaria.

[0047] In preferred embodiments, the TH2 inflammation-associated condition is allergy, chronic rhinosinusitis (CRS), asthma, atopic dermatitis or eosinophilic esophagitis. In more preferred embodiments, the TH2 inflammation- associated condition is allergy. In most preferred embodiments, the TH2 inflammation-associated condition is chronic rhinosinusitis (CRS), including CRSsNP and CRSwNP, preferably CRSwNP. In alternative preferred embodiments, the TH2 inflammation-associated condition is COPD. In alternative preferred embodiments, the TH2 inflammation- associated condition is rheumatoid arthritis. In alternative preferred embodiments, the TH2 inflammation-associated condition is Systemic Lupus Erythematosus (SLE). In alternative preferred embodiments, the TH2 inflammation- associated condition is ulcerative colitis (UC).

[0048] In embodiments, 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. 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. In embodiments, 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. In embodiments, reducing TH2 inflammation with a CD38 inhibitor is used for preventing TH2 inflammation from developing into a chronic TH2 inflammation-associated condition.

[0049] In embodiments, the TH2 inflammation-associated condition is TH2 inflammation-associated fibrogenesis or TH2 inflammation-associated fibrosis. Herein, “TH2 inflammation-associated fibrogenesis” refers to the process of forming fibrous tissue, particularly the early or active phase of tissue remodeling. Herein, “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.

[0050] In embodiments, the TH2 inflammation-associated condition is TH2 inflammation-associated tissue remodeling. Herein, “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. Inembodiments, reducing TH2 inflammation-associated tissue remodeling includes:• reducing fibrosis, preferably the deposition of collagen and / or• reducing tissue hyperresponsiveness.

[0051] In embodiments, the TH2 inflammation-associated condition is TH2 inflammation-associated epithelial dysfunction. Herein, “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:• decreasing hypersecretion, preferably by goblet cells,• decreasing epithelial cell hyperplasia, preferably goblet cell hyperplasia, and / or• decreasing epithelial thickness.CD38 Inhibitors

[0052] Herein, the term "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.

[0053] Herein, 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.

[0054] The term “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.

[0055] The term “CD38-mediated NAD catabolism” as used herein 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.

[0056] In embodiments, the CD38 inhibitor is a small molecule. The term "small molecule" as used herein 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.

[0057] The CD38 inhibitor used in the present invention can be any CD38 inhibitor known to the skilled person.

[0058] In preferred embodiments, 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:Haffner et al., Synthesis, and Biological Evaluation of Thiazoloquin(az)olin(on)es as Potent CD38 Inhibitors. J Med Chem. 2015 Apr 23;58(8):3548-71 .Boslett et al., 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,Lagu et al. An Orally Bioavailable Enzymatic Inhibitor of CD38, MK-0159, Protects Against Ischemia Reperfusion Injury in the Murine Heart, J. Med. Chem. 2022, 65, 13, 9418-9446Doyle K, Roberts M, Harvey J, Hewer R, Zebisch M, Rangel V, et al. A Covalent Binding Mode of a Pyrazole- Based CD38 Inhibitor. Helv Chim Acta. 2023 Sep;106(9):e202300080.- WO 2016 / 087975, WO 2021 / 087087, WO 2021 / 021986, WO 2022 / 165114, WO 2022 / 228496, WO 2021 / 207186, WO 2024 / 226685, WO 2023 / 084206, WO 2024 / 236315, WO 2024 / 236316, WO 2023 / 227867, WO 2022 / 077034, and WO 2023 / 235880, all of which being incorporated herein by reference in their entirety.

[0059] In embodiments, the CD38 inhibitor is:1. a 6- th i azoloq u i nolin-2-one of formula (I), including those of formula (II);2. an indole-7-carboxamide of formula (III);3. a cyclohexy l-5-(th i azol-5-y I)- 1 h-indole-7-carboxamide of formula (IV);4. a heterobicyclic amide of formula (V);5. a quinoline or azaquinoline of formula (VI);6. a pyridazine or pyrimidine of formula (VII);7. a pyrazine or pyrimidine carboxamide of formula (VIII);8. a tricyclic fused imidazole of formula (IXa) or (IXb),9. a N-(4-aminocyclohexyl)pyrimidine-4-carboxamide of formula (X),10. a 1 , 3-th iazoles and 1 , 2,4-thi adi azole of formula (XI),11. a 3-carbonyl imidazo[1 ,5-a]pyridine of formula (XII),12. a pyrazole of formula (Xllla), (Xlllb), or (Xlllc),13. a heterobicyclic amide of formula (XIV),14. a heteroaryl amide of formula (XV) or (XV*), or15. a picolinamide and pyrimidine carboxamide of formula (XVI), or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[0060] Herein, 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.

[0061] CD38 inhibitors, or their pharmaceutically acceptable salts 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. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

[0062] The term “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.

[0063] In this description, 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, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3- hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, embonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate,stearate, subacetate, succinate, sulfate, sulfosaliculate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts. A pharmaceutically acceptable salt can have more than one charged atom in its structure. In this instance the pharmaceutically acceptable salt can have multiple counterions. Thus, a pharmaceutically acceptable salt can have one or more charged atoms and / or one or more counterions.

[0064] Herein, “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. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series; “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985; and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which are hereby incorporated by reference in their entirety.

[0065] In preferred embodiments, the CD38 inhibitor is:• 4-((-4-(2-Methoxyethoxy)cyclohexyl)amino)-1 -methy l-6-(th i azol-5-y l)qui nol i n-2( 1 H)one, corresponding to compound 78c of Haffner 2015 and Bosslet 2019,• 1 -Methyl-4-((tetrahydro-2Hpyran-4-yl)amino)-6-(thiazol-5-yl)quinolin-2(1 H)-one, corresponding to compound 78b of Haffner 2015,• 4-(((1 r,4r)-4-(2-Methoxyethoxy)cyclohexyl)amino)-1 , 8-dimethyl-6-(thi azol-5-y l)quinolin2( 1 H)-one, corresponding to compound 79c of Haffner 2015,• 4-(((1 r,4r)-4-Methoxycyclohexyl)amino)-1 , 8-dimethyl-6-(th i azol-5-y l)qui nolin-2( 1 H)-one, corresponding to compounds 79d of Haffner 2015,• 5-(1 H-imidazol-1 -yl)-N-(4-(2-methoxyethoxy)cyclohexyl)-1H-indole-7-carboxamide (corresponding to Example 5 of WO 2016 / 087975),• N-(4-(2-methoxyethoxy)cyclohexyl)-6-(thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-4-carboxamide, corresponding to compound MK-0159 of Lagu 2022 and WO 2021 / 087087,• 2-(1 H-lmidazol-1 -yl)-N-(4-(2-methoxyethoxy)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, corresponding to compound RBN013209 of WO 2021 / 021986,5-(1 H-i m id azol-1 -yl)-N-((1 r, 4r)-4-((2, 2, 2-trifl uoroethy l)am i no)cyclohexy I)- 1 H-py razolo[3, 4-c]py rid i ne-7-carboxamide, corresponding to Example 115 of WO 2021 / 021986,• N-((1 r,4r)-4-(2-hydroxypropan-2-yl)cyclohexyl)-5-(1 H-imidazol-1-yl)-1 H-pyrazolo[4,3-d]pyrimidine-7- carboxamide, corresponding to Example 182 of WO 2021 / 021986.• 5-(1 H -i m id azol-1 -yl)-N-((1 r, 4r)-4-((3, 3, 3-trifl uoropropy l)ami no)cyclohexy I)- 1 H-py razolo[3, 4-c]py ridi ne-7- carboxamide, corresponding to Example 189 of WO 2021 / 021986,• 5-(1H-midazol-1 -yI)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)-1H-pyrazolo[4,3-d]pyrimidine-7- carboxamide, corresponding to Example 191 of WO 2021 / 021986,• N-((1 r,4r)-4-((2,2-difluoropropyl)amino)cyclohexyl)-5-(1H-midazol-1 -yI)-1 H-pyrazolo[3,4-c]pyridine-7- carboxamide, corresponding to Example 193 of WO 2021 / 021986,• N-((1 r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-5-(1H-midazol-1 -yI)-1H-pyrazolo [3,4-c] pyridine-7- carboxamide, corresponding to Example 195 of WO 2021 / 021986,• 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 WO 2022 / 165114,• 2-(1H-midazol-1 -yI)-N-(2-(2-methoxyethoxy)pyrimidin-5-yl)-6-(trifluoromethyl) pyrimidine-4-carboxamide, corresponding to Compound 1 of WO / 2022 / 228496,• 2-(1H-midazol-1 -yI)-N-(4-(2-methoxyethoxy)cyclohexyl)-6-methylpyrimidine-4-carboxamide, corresponding to Example 35 of WO 2021 / 207186,• 6-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(1-methyl-1 H-pyrazol-4-yl)picolinamide, corresponding to Example 12 of 2021 / 207186,• 4-amino-6-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide, corresponding to Example 15 of 2021 / 207186,• 4, 6-di(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide, corresponding to Example 16 of 2021 / 207186,• 6-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(thiazol-5-yl)picolinamide, corresponding to Example 17 of 2021 / 207186,• 4-chloro-6-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-picolinamide, corresponding to Example 18 of 2021 / 207186,• 2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1 -methyl-1 H-pyrazol-4-yl)pyrimidine-4- carboxamide, corresponding to Example 27 of 2021 / 207186,• N-((1 r,4r)-4-(difluoromethoxy)cyclohexyl)-2-(1H-midazol-1 -yI)-6-methylpyrimidine-4-carboxamide, corresponding to Example 42 of 2021 / 207186,• 6-(fluoromethyl)-2-(1 H-imidazol-1-yl)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide, corresponding to Example 51 of 2021 / 207186,• 2-(1 H-i m id azol-1 -yl)-N-((1 s,4s)-4-(2-methoxyethoxy)cyclohexyl)-6-methylpyrimidine-4-carboxamide, corresponding to Example 60 of 2021 / 207186,• (R)-N-(Tetrahydro-2H-pyran-3-yl)-5,6-dihydrobenzo[f]imidazo[1,5-d][1 ,4]oxazepine-10-carboxamide, corresponding to Compound 1A of WO 2024 / 226685,• (R)-N-(1 ,1-Dioxidotetrahydrothiophen-3-yl)-5,6-dihydrobenzo[f]imidazo[1,5-d][1 ,4]oxazepine-10- carboxamide, corresponding to Compound 2A of WO 2024 / 226685,• N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10- carboxamide, corresponding to Compound 3A of WO 2024 / 226685,• N-(1-(Methylsulfonyl)piperidin-4-yl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10-carboxamide, corresponding to Compound 4A of WO 2024 / 226685,• (R)-N-(1 ,1-Dioxidotetrahydrothiophen-3-yl)-4-oxo-4,5-dihydroimidazo[1 ,5-a]quinoxaline-8-carboxamide, corresponding to compound 12A of WO 2024 / 226685,• 2-(1 H-imidazol-1-yl)-6-methyl-N-((1 r,4r)-4-((2,2,2- trifluoroethyl)amino)cyclohexyl)pyrimidine-4-carboxamide, corresponding to Example 1 of WO 2023 / 084206,• N-((1 r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-2-(1 H- imidazol-1-yl)-6-methyl-pyrimidine-4-carboxamide, corresponding to Example 2 of WO 2023 / 084206,• 6-cyclopropyl-N-((1 r,4r)-4-((2,2- difluoroethyl)amino)cyclohexyl)-2-(1 H-imidazol-1-yl)pyrimidine-4- carboxamide, corresponding to Example 3 of WO 2023 / 084206,• N-((1 r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-2-(1 H- imidazol-1-yl)-6-methyl-pyrimidine-4-carboxamide corresponding to Example 10 of WO 2023 / 084206,• 2-(1 H-i m id azol-1 -yl)-6-methy l-N -(( 1 r,4r)-4-(( 1 , 1 , 1 -trifl uoro-2- methylpropan-2- yl)amino)cyclohexyl)pyrimidine-4-carboxamide, corresponding to Example 21 of WO 2023 / 084206,• 4-(1 -methyl-1H-imidazol-5-yl)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)thiazole-2-carboxamide, , corresponding to Example 1 of WO 2024 / 236315,• 3-(1 -methyl-1H-imidazol-5-yl)-N-((1 r,4r)-4-((2, 2, 2-trifluoroethyl)amino)cyclohexyl)-1 , 2, 4-thiadiazole-5- carboxamide, corresponding to Example 2 of WO 2024 / 236315,• 2-(1-methyl-1 H-imidazol-5-yl)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)thiazole-4-carboxamide, corresponding to Example 4 of WO 2024 / 236315,N-((1 r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-4-(1 -methyl-1H-imidazol-5-yl)thiazole-2-carboxamide, corresponding to Example 9 of WO 2024 / 236315,• 1 -(1 H-i m id azol- 1 -yl)-N-((1 r, 4r)-4-((2, 2, 2-trifl uoroethy l)am i no)cyclohexy l)i m idazo[ 1 , 5-a]py rid ine-3- carboxamide, corresponding to Example 1 of WO 2024 / 236316,• N-((1 r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-1-(1H-midazol-1 -yI)imidazo[1 ,5-a]pyridine-3- carboxamide, corresponding to Example 2 of WO 2024 / 236316,• 4-{[(1 r,4r)-4-(2-Methoxyethoxy)cyclohexyl]amino}-1-methyl-6-[1-(oxan-2-yl)-1 H-pyrazol-4-yl]quinolin-2(1 H)- one, corresponding to Compound 11 of Doyle 2023,• 4-{[(1 r,4r)-4-(2-Methoxyethoxy)cyclohexyl]amino}-1 -methyl-6-(1 H-pyrazol-4yl)quinolin-2(1 H)-one, Compound corresponding to Compound 12 of Doyle 2023,• 8-{[(1 r,4r)-4-Hydroxy-4-methylcyclohexyl]amino}2-(1 H-imidazol-1-yl)-5-methylpyrido[3,2-d]pyrimidin-6(5H)- one, corresponding to Compound 13 of Doyle 2023,• 2-(1 H-lmidazol-1 -yl)-5-methyl-8-[(oxan-4-yl)amino]pyrido[3,2-d]pyrimidin-6(5H)-one, corresponding to Compound 14 of Doyle 2023,• 2-(1 H-imidazol-1-yl)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)pyrido[2,3-d]pyrimidine-4- carboxamide, corresponding to Example 4 of WO 2023 / 227867,• N-((1 r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-2-(1H-midazol-1 -yI)pyrrolo[2,1-f][1 , 2, 4]triazine-4- carboxamide, corresponding to Example 12 of WO 2023 / 227867,• N-((1s,4r)-4-((S)-3-fluoropyrrolidin-1-yl)cyclohexyl)-2-(1H-midazol-1 -yI)pyrrolo[2,1-f][1 , 2, 4]triazine-4- carboxamide, corresponding to Example 13 of WO 2023 / 227867,• N-(( 1 r, 4r)-4-(( R)-3-f I uoropy rrol id i n- 1 -yl)cyclohexyl)-2-( 1 H-imidazol-1 -y I) py rrolo[2, 1 -f][1 , 2, 4]tri azi ne-4- carboxamide, corresponding to Example 14 of WO 2023 / 227867,• 8-(1H-midazol-1 -yI)-N-((1 r, 4r)-4-((2, 2, 2-trifl uoroethy l)am i no)cyclohexyl)i m idazo[ 1 ,2-a]pyrazine-6- carboxamide, corresponding to Example 19 of WO 2023 / 227867,• 8-(1H-midazol-1 -yI)-N-((1 r, 4r)-4-((2, 2, 2-trifl uoroethy l)am i no)cyclohexy l)-[ 1 , 2, 4]tri azolo[1 ,5-a]pyrazine-6- carboxamide, corresponding to Example 20 of WO 2023 / 227867,• 4-(1H-midazol-1 -yI)-N-((1r,4r)-4-((2, 2, 2-trifluoroethyl)amino)cyclohexyl)pyrazolo[1 ,5-a]pyrazine-6- carboxamide, corresponding to Example 21 of WO 2023 / 227867,• 2-(1 H-imidazol-1-yl)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)pyrrolo[2, 1-f][1 ,2,4]triazine-4- carboxamide, corresponding to Example 29 of WO 2023 / 227867,• N-((1 r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-8-(1H-midazol-1 -yI)imidazo[1 ,2-a]pyrazine-6- carboxamide, corresponding to Example 41 of WO 2023 / 227867,N-((1 r,4r)-4-(3,3-difluoroazetidin-1-yl)cyclohexyl)-8-(1H-midazol-1 -yI)-[1, 2, 4]triazolo[1,5-a]pyrazine-6- carboxamide, corresponding to Example 45 of WO 2023 / 227867,• N-((1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-8-(1 H-imidazol-1-yl)-[1 ,2,4]triazolo[i,5-a]pyrazine-6- carboxamide, corresponding to Example 48 of WO 2023 / 227867,• 4-((cyclopropyl)oxy)-6-(1H-midazol-1 -yI)-N-(2-(trifluoromethyl)pyridin-4-yl)picolinamide, corresponding to Compound 32 of WO 2022 / 077034,• 6-(1H-midazol-1 -yI)-4-methoxy-N-(2-(trifluoromethyl)pyridin-4-yl)picolinamide, corresponding to Compound 35 of WO 2022 / 077034,• 2-(1H-midazol-1 -yI)-6-methoxyethoxy-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide, corresponding to Compound 39 of WO 2022 / 077034, or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[0066] In embodiments, the CD38 inhibitor comprises a thiazole, imidazole, pyrazole, or pyridazole group, preferably a thiazole or imidazole group, and more preferably a thiazole group.

[0067] In embodiments, the CD38 inhibitor comprises a 4-(2-methoxyethoxy)cyclohexyl)amino) group, preferably a trans-4-(2-methoxyethoxy)cyclohexyl)amino) group.

[0068] In embodiments, the CD38 inhibitor comprises a trans-4-(2-methoxyethoxy)cyclohexyl)amino) group and an imidazole group or a thiazole group, preferably a thiazole group.

[0069] In embodiments, 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 2019.6-thiazoloquinolin-2-ones of formulas (I) and (I I), including compound 78b, 78c, 79c, and 79d

[0070] In embodiments, 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.

[0071] In embodiments, the CD38 inhibitor is of formula (I):wherein:R1represents H, alkyl (preferably methyl), O-alkyl (preferably O-methyl), or haloalkyl (preferably CF3),R2represents H or alkyl (preferably methyl or ethyl),R3represents:H; alkyl (preferably C1-4 alkyl), unsubstituted or substituted with one or more OR12, wherein R12is H or alkyl (preferably methyl); cycloalkyl (preferably C3-6cycloalkyl), unsubstituted or substituted with one or more alkyl (preferably methyl), heterocycloalkyl (preferably y-lactam), -OR14, wherein R14is H or alkyl (preferably methyl), -OR15-OR16, wherein R15alkyl (preferably ethyl), and wherein R16is H or alkyl (preferably methyl), -CO-NHR11, wherein R11is H or alkyl (preferably methyl or ethyl), -COOH, or - SO2-alkyl (preferably SO2-methyl); heterocycloalkyl (preferably y-lactam, tetrafuranyl, pyranyl, or piperidinyl), unsubsituted or substituted with one or more alkylamide (preferably formamide); aryl (preferably phenyl or pyridyl), unsubstituted or substituted with one or more halogen atoms, alkyl (preferably methyl), haloalkyl (preferably CF3), -SO2-NH2, -N HSO2-alkyl, wherein the alkyl is preferably methyl, -SO2-alkyl, wherein the alkyl is preferably methyl, -CO-NH2, or aryl (preferably oxazole or imidazole); or heteroalkyl (preferably thiopyran), unsubstituted or substituted with =O; andR4represents H, -OH, alkyl (preferably methyl), haloalkyl (preferably CF3), or =O, or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[0072] In embodiments the CD38 inhibitor is of formula (I) is of formula (II):wherein:R1represents H, alkyl (preferably methyl), O-alkyl (preferably O-methyl), or haloalkyl (preferably CF3),R2represents H or alkyl (preferably methyl or ethyl), andR3represents:H; alkyl (preferably C1-4 alkyl), unsubstituted or substituted with one or more OR12, wherein R12is H or alkyl (preferably methyl); cycloalkyl (preferably C3-6cycloalkyl), unsubstituted or substituted with one or more alkyl (preferably methyl), heterocycloalkyl (preferably y-lactam), -OR14, wherein R14is H or alkyl (preferably methyl), -OR15-OR16, wherein R15alkyl (preferably ethyl), and wherein R16is H or alkyl (preferably methyl), -CO-NHR11, wherein R11is H or alkyl (preferably methyl or ethyl), -COOH, or - SO2-alkyl (preferably SO2-methyl); heterocycloalkyl (preferably y-lactam, tetrafuranyl, pyranyl, or piperidinyl), unsubsituted or substituted with one or more alkylamide (preferably formamide); aryl (preferably phenyl or pyridyl), unsubstituted or substituted with one or more halogen atoms, alkyl (preferably methyl), haloalkyl (preferably CF3), -SO2-NH2, -N HSO2-alkyl, wherein the alkyl is preferably methyl, -SO2-alkyl, wherein the alkyl is preferably methyl, -CO-NH2, or aryl (preferably oxazole or imidazole); or heteroalkyl (preferably thiopyran), unsubstituted or substituted with =O, or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[0073] In preferred embodiments, the CD38 inhibitor is of formula (II), wherein:R1represents H or alkyl (preferably methyl),R2represents H or alkyl (preferably methyl or ethyl), andR3represents cycloalkyl (preferably C3-6cycloalkyl), unsubstituted or substituted with one or more -OR14, wherein R14is H or alkyl (preferably methyl), -OR15-OR16, wherein R15alkyl (preferably ethyl), and wherein R16is H or alkyl (preferably methyl), -CO-NHR11, wherein R11is H or alkyl (preferably methyl or ethyl); orheterocycloalkyl (preferably pyranyl), preferably unsubstituted, or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[0074] In more preferred embodiments, the CD38 inhibitor is of formula (II), wherein:R1represents H,R2represents alkyl (preferably methyl or ethyl), andR3represents cycloalkyl substituted with -OR15-OR16, wherein R15represents alkyl (preferably ethyl), and wherein R16represents H or alkyl (preferably methyl), or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[0075] In embodiments, the CD38 inhibitor is:1) (1s,4s)-N-Methyl-4-((2-oxo-6-(thiazol-5-yl)-1 ,2-dihydroquinolin-4yl)amino)cyclohexanecarboxamide (76a),2) (1 r,4r)-N-Methyl-4-((8-methyl-2-oxo-6-(thiazol-5-yl)-1 ,2-dihydroquinolin-4yl)amino)cyclohexanecarboxamide (77a),3) (1 r,4r)-N-Methyl-4-((1-methyl-2-oxo-6-(thiazol-5-yl)-1 ,2-dihydroquinolin-4yl)amino)cyclohexanecarboxamide (78a),4) (1 r,4r)-4-((1 ,8-Dimethyl-2-oxo-6-(thiazol-5-yl)-1,2-dihydroquinolin-4-yl)amino)- Nmethylcyclohexanecarboxamide (79a),5) (1 r,4r)-4-((1-Ethyl-2-oxo-6-(thiazol-5-yl)-1 ,2-dihydroquinolin-4-yl)amino)-Nmethylcyclohexanecarboxamide (80a),6) 4-((Tetrahydro-2H-pyran-4-yl)amino)-6-(thiazol-5-yl)quinolin-2(1 H)-one (76b),7) 8-Methyl-4-((tetrahydro-2H-pyran-4-yl)amino)-6-(thiazol-5-yl)quinolin-2( 1 H)-one (77b),8) 1 -M ethy l-4-((tetrahydro-2 H py ran-4-y I) am i no)-6-(th i azol-5-y l)q ui noli n-2( 1 H)-one (78b),9) 1,8-Dimethyl-4-((tetrahydro-2H-pyran-4-yl)amino)-6-(thiazol-5-yl)quinolin-2(1 H)-one (79b),10) 4-(((1s,4s)-4-(2-Methoxyethoxy)cyclohexyl)amino)-6-(thiazol-5-yl)quinolin-2(1 H)-one (76c),11) 4-(((1s,4s)-4-(2-Methoxyethoxy)cyclohexyl)amino)-8-methyl-6-(thiazol-5-yl)quinolin-2(1 H)one (77c)12) 4-(((1 r,4r)-4-(2-Methoxyethoxy)cyclohexyl)amino)-1-methyl-6-(thiazol-5-yl)quinolin-2(1 H)one (78c),13) 4-(((1 r,4r)-4-(2-Methoxyethoxy)cyclohexyl)amino)-1 ,8-dimethyl-6-(thiazol-5-yl)quinolin2(1 H)-one (79c),14) 1 -Ethyl-4-(((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)amino)-6-(thiazol-5-yl)quinolin-2(1 H)one (80b),15) 4-(((1s,4s)-4-Methoxycyclohexyl)amino)-8-methyl-6-(thiazol-5-yl)quinolin-2(1 H)-one (77d),16) 4-(((1 r,4r)-4-Methoxycyclohexyl)amino)-1-methyl-6-(thiazol-5-yl)quinolin-2(1 H)-one (78d),17) 4-(((1 r,4r)-4-Methoxycyclohexyl)amino)-1 ,8-dimethyl-6-(thiazol-5-yl)quinolin-2(1 H)-one (79d),18) 4-(((1 s,4s)-4-Hydroxycyclohexyl)amino)-1 -methyl-6-(thiazol-5-yl)quinolin-2(1 H)-one trifluoroacetic acid salt (78e), or19) 4-Amino-1 -methyl-6-(thiazol-5-yl)quinolin-2(1 H)-one (78f), or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[0076] In preferred embodiments, 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 Haffner 2015 and Bosslet 2019, or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[0077] In most preferred embodiments, 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. lndole-7-carboxamides of formula (I II), including 5-(1 H-imidazol- 1 -yl)-N-(4-(2-methoxyethoxy)cyclohexyl)-1 H-indole-7-carboxamide

[0078] In embodiments, the CD38 inhibitor is an indole-7-carboxamide as described in WO 2016 / 087975, incorporated herein by reference.

[0079] In preferred embodiments, the indole-7-carboxamide is of formula (III):wherein Q is 0, NH, N(H)C(O), or C(O)N(H);R1is Ci.5alkylS(O)2CH3, or C1-6alkyl, wherein said alkyl can comprise straight-chain portions, branched chain portions, cycloalkyl portions, and wherein said C1-6alkyl is optionally substituted by one OH or OCH3and wherein said C1-6alkyl is optionally further substituted by 1 to 3 fluorine atoms; andR2is H, C1-3alkyl, or halogen, or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[0080] Preferably, R2is H or Cl. Most preferably, R2is H.

[0081] Preferably, the indole-7-carboxamide of formula III have the trans orientation on the cyclohexyl ring depicted below :

[0082] In embodiments, the CD38 inhibitor is:20) 5-(1 H-lmidazol-1 -yl)-N-((1 r,4r)-4-((3,3,3-trifluoro-2-hydroxy-2-methylpropyl)amino)cyclohexyl)-1H-indole-7- carboxamide, Example 1;21 ) 5-(1 H-lmidazol-1 -yl)-N-((1 r,4r)-4-(((R)-1 ,1,1 -trifluoro-3-hydroxy-2-methylpropan-2-yl)amino)cyclohexyl)-1H- indole-7-carboxamide, Example 2;22) N-((1 r,4r)-4-(2-Hydroxy-2-methylpropoxy)cyclohexyl)-5-(1H-midazol-1 -yI)-3-isopropyl-1H-indole-7- carboxamide, Example 3;23) 5-(1 H-lmidazol-1-yl)-N-((1s,4s)-4-(methylcarbamoyl)cyclohexyl)-1H-indole-7-carboxamide, Example 4;24) 5-(1H-midazol-1 -yI)-N-((1 s,4s)-4-(2-methoxyethoxy)cyclohexyl)-1H-indole-7-carboxamide, Example 5;25) N-((1 r,4r)-4-(2-Hydroxy-2-methylpropoxy)cyclohexyl)-5-(1H-midazol-1 -yI)-1H-indole-7-carboxamide, Example 6;26) N-((1 r,4r)-4-(2-Hydroxypropoxy)cyclohexyl)-5-(1H-midazol-1 -yI)-1H-indole-7-carboxamide, Example 7;27) 3-Chloro-N-((1r,4r)-4-(2-hydroxypropoxy)cyclohexyl)-5-(1H-midazol-1 -yI)-1H-indole-7-carboxamide, Example 8;28) 5-(1 H-lmidazol-1-yl)-N-(1 r,4r)-4-(3,3,3-trifluoro-2-hydroxy-2-methylpropoxy)cyclohexyl)-1H-indole-7- carboxamide, Example 9;29) 5-(1 H-lmidazol-1-yl)-N-((1 r,4r)-4-((3,3,3-trifluoro-2-hydroxy-2-methylpropyl)amino)cyclohexyl)-1H-indole-7- carboxamide, Example 10;30) 5-(1 H-lmidazol-1-yl)-N-((1 r,4r)-4-(3,3,3-trifluoro-2-hydroxy-2-methylpropanamido)cyclohexyl)-1H-indole-7- carboxamide, Example 11 ;31) N-((1 r,4r)-4-((2,2-Difluoroethyl)amino)cyclohexyl)-5-(1H-midazol-1 -yI)-1H-indole-7-carboxamide, Example 12;32) 3-Chloro-N-((1 r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-5-(1H-midazol-1 -yI)-1H-indole-7-carboxamide, Example 13;33) N-((1 r,4r)-4-(2-Hydroxy-3-methylbutoxy)cyclohexyl)-5-(1H-midazol-1 -yI)-1 H-indole-7-carboxamide, Example 14;34) N-((1 r,4r)-4-(2-Cyclopropyl-2-hydroxypropoxy)cyclohexyl)-5-(1H-midazol-1 -yI)-1 H-indole-7-carboxamide, Example 15; or35) 5-(1 H-lmidazol-1-yl)-N-((1r,4r)-4-(((R)-1-(methylsulfonyl)propan-2-yl)amino)cyclohexyl)-1H-indole-7- carboxamide, Example 16; or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[0083] In most preferred embodiments, 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.Cyclohexyl-5-(thiazol-5-yl)- 1 h-indole-7-carboxamides of formula (IV), including MK-0159

[0084] In embodiments, 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. An Orally Bioavailable Enzymatic Inhibitor of CD38, MK-0159, Protects Against Ischemia Reperfusion Injury in the Murine Heart, J. Med. Chem. 2022, 65, 13, 9418-9446 and WO 2021 / 087087, both of which being incorporated by reference herein.

[0085] In embodiments, 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;X1is CR1Aand X2is NR5A, when bond a is a double bond and bond b is a single bond; or X1is NR1Band X2is CR5B, when bond a is a single bond and bond b is a double bond;R1Ais H, C1-4alkyl, NO2, CN, CONRaRb, CH2NRaRb, (CHRc)mOH, C1-4haloalkyl, CHO, COO-Ra, or halo;Ra, Rb, and Rcare each independently H or C1-4alkyl;R1Bis H or C1-4alkyl optionally substituted with 3-5 membered monocyclic heterocyclyl or hydroxy;R5Ais H or C1-4alkyl;R5Bis H, halo, CN, C1-4alkyl, C1-4haloalkyl, NHRbor CONHRc;R2is 5-membered heteroaryl;R3is C1-4alkyl, C3-6cycloalkyl, bridged C7-12cycloalkyl, 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 Rxgroups, wherein Rxis halo, 3 to 6- membered heterocyclyl, C1-4alkyl, C1-4haloalkyl, C1-4hydroxyalkyl, SO2Me or ORd;Rdis H or C1-4alkyl optionally substituted with C1-4alkoxy;R4is H, halo, CN, C1-4alkyl, C1-4haloalkyl, NHReor CONHRf;Reand Rfare each independently H or C1-4alkyl;R6is H or C1-4alkyl; n is O or 1 ; and m is 1, 2 or 3, provided that, when R1Ais H or C1-4alkyl; and R2is, then n is 1; and provided that when A1 is N, X1is N and R1Bis C1-4alkyl, then n is 1 ; and, in an alternative, when A1 is N; X1is N; R1Bis C1-4alkyl; and R3is an optionally substituted phenyl, then n is 1 , or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[0086] In preferred embodiments, A1 and A2 are CH.

[0087] In preferred embodiments, R2is

[0088] In preferred embodiments, n is 0.

[0089] In preferred embodiments, R3is, wherein Y is O, NH, SO2, CH2or CHRX, and p is 0 or 1.

[0090] In preferred embodiments, R3is

[0091] In preferred embodiments, Rx is C1-4hydroxy alkyl or ORd, preferably wherein Rd is H or C1-4alkyl substituted with C1-4alkoxy.

[0092] In preferred embodiments, Rx is OH, OCH2CH2OMe or OCH2CH2CH2OMe.

[0093] In embodiments, the CD38 inhibitor is:

[0094] N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-(thiazol-5-yl)-1H-indole-7-carboxamide, Example 1 ;36) N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-(1 H-pyrazol-1-yl)-1H-indole-7-carboxamide, Example 2;37) N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-(1 H-1,2,4-triazol-l-yl)-1H-indole-7-carboxamide, Example 3;38) N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-(5H-tetrazol-5-yl)-1H-indole-7-carboxamide, Example 4;39) N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-(thiazol-4-yl)-1H-indole-7-carboxamide, Example 5;40) 5-(1 H-imidazol-2-yl)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-indole-7-carboxamide, Example 6;41) N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-(1 H-pyrazol-4-yl)-1 H-indole-7-carboxamide, Example 7;42) 3-(1 -hydroxyethyl)-5-(1 H-imidazol-1-yl)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1 H-indole-7- carboxamide, Example 8;43) 3-((S)-1 -hydroxyethyl)-5-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1 H-indole-7- carboxamide, Example 9;44) 3-((R)-1-hydroxyethyl)-5-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1 H-indole-7- carboxamide, Example 10;45) 5-(1 H-imidazol-1-yl)-7-(((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)carbamoyl)-1 H-indole-3-carboxylic acid, Example 11 ;46) 5-(1 H-imidazol-1-yl)-N7-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-N3-methyl-1 H-indole-3,7-dicarboxamide, Example 12;47) 5-(1 H-imidazol-1-yl)-N7-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-N3,N3-dimethyl-1 H-indole-3,7- dicarboxamide, Example 13;48) 5-(1H-midazol-1 -yI)-N-((1 r, 4r)-4-(2-methoxyethoxy)cyclohexyl)-3-n i tro- 1 H-indole-7-carboxamide, Example 14;49) 3-formyl-5-( 1 H-imidazol-1 -yl)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1 H-indole-7-carboxamide, Example 15;50) 3-((dimethylamino)methyl)-5-(1 H-imidazol-1-yl)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1 H-indole-7- carboxamide, Example 16;51) 3-(aminomethyl)-5-(1H-midazol-1 -yI)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1 H-indole-7-carboxamide, Example 17;52) 3-(hydroxymethyl)-5-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1 H-indole-7-carboxamide, Example 18;53) 5-(1 H-imidazol-1-yl)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-3-(trifluoromethyl)-1 H-indole-7-carboxamide, Example 19;54) 3-cyano-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-(thiazol-5-yl)-1H-indole-7-carboxamide, Example 20;55) 3-cyano-5-(1H-midazol-1 -yI)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1 H-indole-7-carboxamide, Example 21 ;56) 5-(1H-midazol-1 -yI)-3-iodo-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-indole-7-carboxamide, Example 22;57) 5-(1 H-imidazol-1-yl)-N7-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1 H-indole-3,7-dicarboxamide, Example 23;58) N-(1 ,1-dioxidotetrahydro-2H-thiopyran-4-yl)-6-(thiazol-5-yl)-1H-indole-4-carboxamide, Example 24;59) N-(2-fluoro-6-(trifluoromethyl)benzyl)-6-(thiazol-5-yl)-1H-indole-4-carboxamide, Example 25;60) N-(2-(methylsulfonyl)ethyl)-6-(thiazol-5-yl)-1H-indole-4-carboxamide, Example 26;61) N-((tetrahydro-2H-pyran-4-yl)methyl)-6-(thiazol-5-yl)-1H-indole-4-carboxamide, Example 27;62) N-((1 r,3s,5R,7S)-3-hydroxyadamantan-l-yl)-6-(thiazol-5-yl)-1H-indole-4-carboxamide, Example 28;63) N-(( 1 r,4r)-4-(2-hyd roxypropan-2-yl)cyclohexy l)-6-(thi azol-5-y l)-1H-indole-4-carboxamide, Example 29;64) N-((lr, 3r)-3-(2-methoxyethoxy)cyclobutyl)-6-(thi azol-5-y l)-1H-indole-4-carboxamide, Example 30;65) N-((IR,3R)-3-hydroxycyclopentyl)-6-(thiazol-5-yl)-1H-indole-4-carboxamide, Example 31 ;66) N-((1 s,3s)-3-(2-methoxyethoxy)cyclobutyl)-6-(thiazol-5-yl)-1H-indole-4-carboxamide, Example 32;67) N-(4-morpholi nobenzyl)-6-(thi azol-5-yl)- 1 H-indole-4-carboxamide, Example 33;68) N-(Trans-3-(2-methoxyethoxy)cyclopentyl)-6-(thiazol-5-yl)-1H-indole-4- carboxamide, Example 34;69) N-(piperidin-4-yl)-6-(thiazol-5-yl)-1H-indole-4-carboxamide hydrochloride, Example 35;70) N-(3-hydroxy-3-methylcyclobutyl)-6-(thiazol-5-yl)-1H-indole-4-carboxamide, Example 36;71) N-((1 r,4r)-4-(3-methoxypropoxy)cyclohexyl)-6-(thiazol-5-yl)-1 H-indole-4-carboxamide, Example 37;72) N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(thiazol-5-yl)-1H-indole-4-carboxamide, Example 38;73) N-(1 -(2-fluorophenyl)ethyl)-6-(thiazol-5-yl)-1H-indole-4-carboxamide, Example 39;74) N-((IR,2S)-2-methylcyclohexyl)-6-(thiazol-5-yl)-1H-indole-4-carboxamide, Example 40;75) N-((1 r,4r)-4-hydroxycyclohexyl)-6-(thiazol-5-yl)-1H-indole-4-carboxamide, Example 41;76) N-(1-methoxy-2-methylpropan-2-yl)-6-(thiazol-5-yl)-1 H-indole-4-carboxamide, Example 42;77) N-(2-hydroxy-2-methy Ipropy l)-6-(th i azol-5-yl)- 1 H-indole-4-carboxamide, Example 43;78) N-(adamantan-1-yl)-6-(thiazol-5-yl)-1 H-indole-4-carboxamide, Example 44;79) N-(tetrahydro-2H-pyran-4-yl)-6-(thiazol-5-yl)-1H-indole-4-carboxamide, Example 45;80) N-((1 r,3r)-3-hydroxycyclobutyl)-6-(thiazol-5-yl)-1H-indole-4-carboxamide, Example 46;81) N-cyclohexyl-6-(thiazol-5-yl)-1H-indole-4-carboxamide, Example 47;82) N-((1 s,4s)-4-(2-methoxyethoxy)cyclohexyl)-6-(thiazol-5-yl)-1H-indole-4-carboxamide, Example 48;83) methyl5-(1H-midazol-1 -yI)-7-(((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)carbamoyl)-1 H-indole-3-carboxylate, Example 49;84) N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-l-(oxetan-3-ylmethyl)-6-(thiazol-5-yl)-1 H-indole-4-carboxamide, Example 50;85) N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-l-methy l-6-(thi azol-5-y l)-1H-indole-4-carboxamide, Example 51 ;86) 1 -isopropyl-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(thiazol-5-yl)-1H-indole-4-carboxamide, Example 52;87) 1 -(2-hydroxy-2-methyl propy l)-N-(( 1 r, 4r)-4-(2-methoxyethoxy)cyclohexy l)-6-(thi azol-5-y I)- 1 H -i ndole-4- carboxamide, Example 53;88) 5-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1 -methyl-1 H-indole-7-carboxamide, Example 54;89) 7-fluoro-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(thiazol-5-yl)-1H-indole-4-carboxamide, Example 55;90) 3-cyano-6-(1H-midazol-1 -yI)-N-(( 1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-indole-4-carboxamide, Example 56;91) N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-3-methyl-6-(thiazol-5-yl)-1H-indole-4-carboxamide, Example 57;92) N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(thiazol-5-yl)-1 H-pyrrolo[2,3-b]pyridine-4-carboxamide, Example 58;93) 5-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide, Example 59; or94) N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-(thiazol-5-yl)-1 H-pyrrolo[3,2-bipyridine-7-carboxamide, Example 60; or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[0095] In most preferred embodiment, 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

[0096] In embodiments, the CD38 inhibitor is a heterobicyclic amide as described in WO 2021 / 021986, incorporated herein by reference.

[0097] In embodiments, the CD38 inhibitor is of formula (V):wherein:V is N or CRV, wherein Rvis H, halo, or C1-4alkyl;W is N or CRW, wherein Rwis H, halo, or C1-4alkyl;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 C1-4alkyl; each RNis independently selected from H, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, wherein said C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3'7cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of RNare each optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from Cy, Cy-C1-4alkyl, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd; each RA, RB, and Rcis independently selected from H, halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C2-6aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, wherein said alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of RA, RB, and Rcare each optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from Cy, Cy-C1-4alkyl, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd;L is a C1-4alkylene linker; n is O or 1 ;Q is H, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10haloalkyl, C6-10aryl, C3-14cycloalkyl, 5-14 membered heteroaryl, or 4-14 membered heterocycloalkyl, wherein said C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10haloalkyl, C6-10aryl, C3-14cycloalkyl, 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 Cy1, Cy1- C1-4alkyl, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(=NRe1)NRc1Rd1, NRc1C(=NRe1)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein Q is other than H when n is 0; each Cy is independently selected from C6-10aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted by 1 , 2, 3, or 4 substituents independently selected from halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl-C1-4alkyl, C3-7cycloalkyl-C1-4alkyl, 5- 10 membered heteroaryl- C1-4alkyl, 4-10 membered heterocycloalkyl-C1-4alkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcRd, NRcC(O)Rb,NRcC(O)ORa, NRcC(O)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd; each Cy1is independently selected from C6-10aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted by 1 , 2, 3, or 4 substituents independently selected from halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl, C3-7cycloalkyl-C1-4alkyl, 5-10 membered heteroaryl-C1-4alkyl, 4-10 membered heterocycloalkyl-C1-4alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2; each Ra, Rb, Rc, Rd, Ra1, Rb1, Rc1, Rd1, Ra2, Rb2, Rc2, and Rd2is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl, C3-7cycloalkyl-C1-4alkyl, 5-10 membered heteroaryl-C1-4alkyl, 4-10 membered heterocycloalkyl-C1-4alkyl, wherein said C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C-1-4 alkyl, C3-7cycloalkyl-C1-4alkyl, 5-10 membered heteroaryl-C1-4alkyl, 4-10 membered heterocycloalkyl-C-1-4 alkyl of Ra, Rb, Rc, Rd, Ra1, Rb1, Rc1, Rd1, Ra2, Rb2, Rc2, and Rd2is optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from Cy2, Cy2-C1-4alkyl, halo, C1-4alkyl, C1-4haloalkyl, C1-6haloalkyl, C2-6alkenyl, C2.6 alkynyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, and S(O)2NRc3Rd3; or Rcand Rdtogether with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1 , 2, or 3 substituents independently selected from halo, C1-4alkyl, C1-4haloalkyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, and S(O)2NRc3Rd3; or Rc1and Rd1together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1 , 2, or 3 substituents independently selected from halo, C1-4alkyl, C1-4haloalkyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, and S(O)2NRc3Rd3; or Rc2and Rd2together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1 , 2, or 3 substituents independently selected from halo, C1-4alkyl, C1-4haloalkyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, S(O)Rb3,S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, and S(O)2NRc3Rd3; each Cy2is C6-10aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, each optionally substituted by 1 , 2, 3, or 4 substituents independently selected from halo, C1-4alkyl, C1-4haloalkyl, C1-6haloalkyl, C2.6alkenyl, C2.6alkynyl, CN, 0Ra3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, 0C(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, and S(O)2NRc3Rd3; each Ra3, Rb3, Rc3, and Rd3 is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C-i- 4 alkyl, C3-7cycloalkyl-C1-4alkyl, 5-10 membered heteroaryl-C1-4alkyl, and 4-10 membered heterocycloalkyl- C1-4alkyl, wherein said C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl, C3-7cycloalkyl-C1-4alkyl, 5-10 membered heteroaryl-C1-4alkyl, and 4-10 membered heterocycloalkyl-C1-4alkyl of Ra3, Rb3, Rc3, and Rd3 are each optionally substituted with 1 , 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6alkyl, C1-6alkylamino, di(C1-6alkyl)amino, C1-6alkoxy, C1-6haloalkyl, and C1-6haloalkoxy; each Re, Re1, Re2, and Re3is independently selected from H, C1-4alkyl, and CN; wherein one or more ring-forming C or N atoms of any aforementioned heterocycloalkyl group is optionally substituted by an oxo (=O) group; wherein one or more ring-forming S atoms of any aforementioned heterocycloalkyl group is optionally substituted by one or two oxo (=O) groups; and with the proviso that when:V is CH;W is CH; the moiety represented byn is O; andQ is cyclohexyl optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from Cy1, Cy1- C1-4alkyl, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(=NRe1)NRc1Rd1, NRc1C(=NRe1)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1;then Ring A is other than:or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[0098] In preferred embodiments, V is N.

[0099] In preferred embodiments, W is N or CH, preferably N.

[0100] In preferred embodiments, the moiety represented by

[0102] In preferred embodiments, Ring A is a 5-membered heteroaryl group having 2 ring-forming N heteroatoms, ,preferably

[0103] In preferred embodiments, each RNis H.

[0104] In preferred embodiments, each RA, and RBis H.

[0105] In preferred embodiments, n is 0.

[0106] In preferred embodiments, Q is a C3-14cycloalkyl (preferably cyclohexyl) substituted with ORa1, NRc1Rd1, or - C(CH3)2-OH.

[0107] In preferred embodiments, each Ra1is C1-6alkyl (preferably ethyl) substituted with ORa3.

[0108] In preferred embodiments, each Rc1is H. In preferred embodiments, each Rd1is C1-6alkyl (preferably ethyl or propyl) substituted with halogen. In preferred embodiments, each Ra3is independently C1-6alkyl, preferably methyl.

[0109] In embodiments, the CD38 inhibitor is:

[0110] 5-(1 H-lmidazol-1-yl)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-benzo[d]imidazole-7-carboxamide, Example 1;96) N-(2-Fluoro-6-(trifluoromethyl)benzyl)-5-(1 H-imidazol-1-yl)-1 H-benzo[d]imidazole-7-carboxamide, Example 2;97) N-[[2-Fluoro-6-(trifluoromethyl)phenyl]methyl]-6-thiazol-5-yl-3H-benzimidazole-4-carboxamide, Example 3;98) N-((1r,4r)-4-(2-Methoxyethoxy)cyclohexyl)-5-(thiazol-5-yl)-1H-benzo[d]imidazole-7-carboxamide, Example 4;99) N-(2-Fluoro-6-(trifluoromethyl)benzyl)-5-(1H-midazol-1 -yI)-1H-indole-7-carboxamide, Example 5;100) N-((1r,4r)-4-(2-Methoxy ethoxy)cyclohexyl)-5-(thiazol-5-yl)-1H-indole-7-carboxamide, Example 6;101) 2-(1 H-lmidazol-1 -yl)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 7;102) 5-(1 H-lmidazol-1 -yl)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1 H-indazole-7-carboxamide, Example 8:103) 5-(1 H-lmidazol-1 -yl)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-methyl-1 H-indole-7-carboxamide, Example 9;104) 5-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1 H-pyrrolo[3,2-bipyridine-7-carboxamide, Example 10;105) N-(2-Fluoro-6-(trifluoromethyl)benzyl)-2-methyl-5-(thiazol-5-yl)-1H-indole-7-carboxamide, Example 11 ;106) 5-(1 H-lmidazol-1 -yl)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1 H-pyrrolo[2,3-c]pyridine-7-carboxamide, Example 12;107) N-((1r,4r)-4-(2-Methoxyethoxy)cyclohexyl)-2-methyl-5-(thiazol-5-yl)-1 H-benzo[d]imidazole-7-carboxamide, Example 13;108) 2-(1 H-lmidazol-1 -yl)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-7H-purine-6-carboxamide, Example 14;109) N-(2-Fluoro-6-(trifluoromethyl)benzyl)-5-(1H-midazol-1 -yI)-1 H-pyrazolo[4,3-bipyridine-7-carboxamide, Example 15;110) 5-(1 H-lmidazol-1 -yl)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1 H-pyrazolo[3,4-c]pyridine-7-carboxamide, Example 16;111) N-((1r,4r)-4-(2-Methoxyethoxy)cyclohexyl)-5-(thiazol-5-yl)-1H-pyrazolo[4.3-bipyridine-7-carboxamide, Example 17;112) 2-(1 H-lmidazol-1 -yl)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)thieno[3,2-d]pyrimidine-4-carboxamide, Example 18;113) 2-(Aminomethyl)-5-(1H-midazol-1 -yI)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1 H-indole-7-carboxamide, Example 19;114) N-(2-FI uoro-6-(trifl uoromethy l)benzy l)-2-(th i azol-5-y l)th ieno[3 ,2-d]py rim idi ne-4-carboxamide, Example 20;115) N-((1r,4r)-4-(2-Methoxyethoxy)cyclohexyl)-5-(thiazol-5-yl)-1 H-pyrazolo[3,4-c]pyridine-7-carboxamide, Example 21 ;116) 2-(1 H-lmidazol-1 -yl)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-methyl-5H-pyrrolo[3,2-d]pyrimidine-4- carboxamide, Example 22;117) 5-(1 H-lmidazol-1 -yl)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-pyrazolo[4,3-d]pyrimidine-7- carboxamide, Example 23;118) 5-(1 H-lmidazol-1 -yl)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)thieno|3.2-bipyridine-7-carboxamide, Example 24;119) 5-(1 H-lmidazol-1 -yl)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)thiazolo|4.5-d]pyrimidine-7-carboxamide, Example 25;120) 6-(1 H-lmidazol-1 -yl)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-3H-imidazo[4,5-c]pyridine-4-carboxamide, Example 26;121) 2-(1 H-lmidazol-1 -yl)-N-(tetrahydro-2H-pyran-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 27;122) (S)-2-(1 H-lmidazol-1 -yl)-N-(tetrahydro-2H-pyran-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 28a;123) (R)-2-(1H-midazol-1 -yI)-N-(tetrahydro-2H-pyran-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 28b;124) 4-Fluoro-5-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1 H-indole-7-carboxamide, Example 29;125) 5-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-methyl-1H-benzo[d]imidazole-7- carboxamide, Example 30;126) N-(2-Fluoro-6-(trifluoromethyl)benzyl)-5-(thiazol-5-yl)-1H-indole-7-carboxamide, Example 31;127) N-(( 1 r,4r)-4-(2-Methoxy ethoxy)cyclohexyl)-2-(thiazol-5-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 32;128) N-(2-Fluoro-6-(trifluoromethyl)benzyl)-6-(thiazol-5-yl)-3l-imidazo[4,5-c]pyridine-4-carboxamide, Example 33;129) N-((1r, 4r)-4-(2-Methoxy ethoxy)cyclohexyl)-2-(2-methyl-1H-imidazol-1 -yl)-5H-pyrrolo[3,2-d]pyrimidine-4- carboxamide, Example 34;130) N-((1r,4r)-4-(2-Methoxyethoxy)cyclohexyl)-2-(2H-1 ,2,3-triazol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-4- carboxamide, Example 35;131) 4r)-4-(2-Methoxyethoxy)cyclohexyl)-2-(5-methyl-1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4- carboxamide, Example 36;132) N-((1 r, 4r)-4-(2-methoxy ethoxy)cyclohexyl)-2-(4-methyl-1H-imidazol-1 -yl)-5H-pyrrolo[3,2-d]pyrimidine-4- carboxamide, Example 37;133) 2-(1 H-lmidazol-4-yl)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 38;134) 2-(1 H-lmidazol-1 -yl)-N-((1s,4s)-4-(trifluoromethyl)cyclohexyl)-5H-pyrrolo[3, 2- d]pyrimidine-4-carboxamide,Example 39a;135) 2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(trifluoromethyl)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 39b;136) 5-(1 H-lmidazol-1-yl)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)benzo[d]isothiazole-7-carboxamide, Example 41;137) N-(2-Fluoro-6-(trifluoromethyl)benzyl)-5-(1H-midazol-1 -yI)-2-methyl-1 H-benzo[d]imidazole-7-carboxamide, Example 42;138) N-(2-Fluoro-6-(trifluoromethyl)benzyl)-2-(thiazol-5-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 43;139) N-(2-Fluoro-6-(trifluoromethyl)benzyl)-5-(1H-midazol-1 -yI)-1 H-pyrrolo[3,2-bipyridine-7-carboxamide, Example 44;140) N-((1r,4r)-4-(2-Methoxyethoxy)cyclohexyl)-2-methyl-5-(thiazol-5-yl)-1H-indole-7-carboxamide, Example 45;141) N-(2-Fluoro-6-(trifluoromethyl)benzyl)-2-(1H-midazol-1 -yI)-7H-purine-6-carboxamide, Example 46;142) N-((1r,4r)-4-(2-Methoxyethoxy)cyclohexyl)-6-(thiazol-5-yl)-3H-imidazo[4,5-c]pyridine-4-carboxamide, Example 47;143) N-(2-Fluoro-6-(trifluoromethyl)benzyl)-5-(1H-midazol-1 -yI)-1 H-pyrazolo[3,4-c]pyridine-7-carboxamide, Example 48;144) N-(2-Fluoro-6-(trifluoromethyl)benzyl)-2-(1H-midazol-1 -yI)thieno[3,2-d]pyrimidine-4-carboxamide, Example 49;145) N-((1r,4r)-4-(2-Methoxyethoxy)cyclohexyl)-2-(thiazol-5-yl)thieno[3,2-d]pyrimidine-4-carboxamide, Example 50;146) N-(2-Fluoro-6-(trifluoromethyl)benzyl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 51 ;147) 2-(1 H-lmidazol-1 -yl)-N-(1 -(2,2,2-trifluoroethyl)piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 52;148) 2-(1 H-lmidazol-1 -yl)-N-(1-(2-methoxyethyl)piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 53;149) 2-(1 H-lmidazol-1 -yl)-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 54;150) 2-(1 H-lmidazol-1 -yl)-N-(1 -(3, 3, 3-trifluoropropyl)piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 55;151) 2-(1 H-lmidazol-1 -yl)-N-((1 r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4- carboxamide, Example 56;152) 2-(1 H-lmidazol-1 -yl)-N-((1 r,4r)-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4- carboxamide, Example 57;153) 2-(1 H-lmidazol-1 -yl)-N-((1 r,4r)-4-methoxycyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 58;154) N-cyclohexyl-2-(1 H-lmidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 59;155) 2-(1 H-lmidazol-1 -yl)-N-(1-methylpiperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 60;156) N-(1 ,1-Dioxidotetrahydro-2H-thiopyran-4-yl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4- carboxamide, Example 61;157) 2-(1 H-lmidazol-1 -yl)-N-(tetrahydro-2H-pyran-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 62;158) 2-(1 H-lmidazol-1 -yl)-N-(4-(2-methoxyethoxy)phenyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 63;159) N-(1-Acetylpiperidin-4-yl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 64;160) 2-(1 H-lmidazol-1 -yl)-N-((1 r,3r)-3-(2-methoxyethoxy)cyclobutyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 65;161) 2-(1 H-lmidazol-1 -yl)-N-((1 r,3r)-3-methoxycyclobutyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 66;162) 2-(1 H-lmidazol-1 -yl)-N-(1 -(3, 3, 3-trifluoropropyl)pyrrolidin-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 67;163) 2-(1 H-lmidazol-1 -yl)-N-(1 -(2, 2, 2-trifluoroethyl)pyrrolidin-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 68;164) 2-(1 H-lmidazol-1 -yl)-N-((1s,4s)-4-(2-methoxyethoxy)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 69;165) 2-(1 H-lmidazol-1 -yl)-N-methyl-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 70;166) 2-(1 H-lmidazol-1 -yl)-N-((1 r,4r)-4-(2-(methylamino)ethoxy)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4- carboxamide, Example 71 ;167) N-((1 r,4r)-4-(2-(Dimethylamino)ethoxy)cyclohexyl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4- carboxamide, Example 72;168) 2-(1 H-lmidazol-1 -yl)-N-(pyrrolidin-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 73;169) 2-(1 H-lmidazol-1 -yl)-N-(1-methylpynOlidin-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 74;170) 2-(1 H-lmidazol-1 -yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 75;171) 2-(1 H-lmidazol-1 -yl)-N-(1 -(oxetan-3-yl)piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 76;172) N-Cyclobutyl-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 77;173) N-(Cyclohexylmethyl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 78;174) N-Benzyl-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 79;175) 2-(1 H-lmidazol-1 -yl)-N-((1 r,4r)-4-(2-(methylamino)-2-oxoethoxy)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4- carboxamide, Example 80;176) 2-(1 H-lmidazol-1 -yl)-N-(pyridin-2-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 81 ;177) 2-(1 H-lmidazol-1 -yl)-N-phenyl-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 82;178) 2-(1 H-lmidazol-1 -yl)-N-(pyridin-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 83;179) 2-(1 H-lmidazol-1 -yl)-N-(5-methoxypyridin-2-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 84;180) 2-(1 H-lmidazol-1 -yl)-N-(6-methoxypyridin-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 85;181) 2-(1 H-lmidazol-1 -yl)-N-(1 H-pyrazol-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 86;182) N-(4-Chlorophenyl)-2-( 1 H-imidazol-1 -yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 87;183) N-(3-Chlorophenyl)-2-( 1 H-imidazol-1 -yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 88;184) N-(2-Chlorophenyl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 89;185) N-Cyclopentyl-2-(1 H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 90;186) 2-(1 H-lmidazol-1 -yl)-N-(tetrahydrofuran-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 91 ;187) N-Cycloheptyl-2-(1 H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 92;188) 2-(1 H-lmidazol-1 -yl)-N-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 93;189) 2-(1 H-lmidazol-1 -yl)-N-(1-methyl-1 H-pyrazol-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 94;190) 2-(1 H-lmidazol-1 -yl)-N-(1-methyl-1H-imidazol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 95;191) N-(3-Chloro-4-fluorophenyl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 96;192) 2-(1 H-lmidazol-1 -yl)-N-((1 r,4r)-4-(2-morpholinoethoxy)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4- carboxamide, Example 97;193) 2-(1 H-lmidazol-1 -yl)-N-(1 H-pyrazol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 98;194) 2-(1 H-lmidazol-1 -yl)-N-(1 -methyl-1H-pyrazol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 99;195) 2-(1 H-lmidazol-1 -yl)-N-(3-(2-methoxyethoxy)phenyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 100;196) 2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4- carboxamide, Example 101 ;197) 2-(1H-midazol-1 -yI)-N-((1s,4s)-4-((2, 2, 2-trifluoroethyl)amino)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4- carboxamide, Example 102;198) 2-(1H-midazol-1 -yI)-N-((1 r, 4r)-4-((3, 3, 3-trifl uoropropy l)ami no)cyclohexy l)-5 H-py rrolo[3, 2-d]py ri m id i ne-4- carboxamide, Example 103;199) N-((1 r,4r)-4-(cyanomethoxy)cyclohexyl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 104;200) N-((1 r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4- carboxamide, Example 105;201) N-((1 s,4s)-4-((2,2-difluoroethyl)amino)cyclohexyl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4- carboxamide, Example 106;202) N-(4,4-difluorocyclohexyl)-5-(1H-midazol-1 -yI)-1 H-pyrazolo[3,4-c]pyridine-7-carboxamide, Example 107;203) 2-(1 H-imidazol-1-yl)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-4- carboxamide, Example 108;204) N-((1 r,4r)-4-(2-hydroxypropan-2-yl)cyclohexyl)-5-(1H-midazol-1 -yI)-1 H-pyrazolo[3,4-c]pyridine-7- carboxamide, Example 109;205) 2-(1 H-imidazol-1-yl)-N-((1 r,4r)-4-(methyl(3,3,3-trifluoropropyl)amino)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine- 4-carboxamide, Example 110;206) 2-(1 H-imidazol-1-yl)-N-((1 s,4s)-4-(methyl(3,3,3-trifluoropropyl)amino)cyclohexyl)-5H-pyrrolo[3,2- d]pyrimidine-4-carboxamide, Example 111 ;207) 2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(methyl(2, 2, 2-trifluoroethyl)amino)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine- 4-carboxamide, Example 112;208) 2-(1H-midazol-1 -yI)-N-((1 s,4s)-4-(methy I (2, 2, 2-trif I uoroethy l)ami no)cyclohexy l)-5 H-py rrolo[3, 2-d]py ri m idi ne- 4-carboxamide, Example 113;209) N-((1 r,4r)-4-(acetamidomethyl)cyclohexyl)-2-(1 H-imidazol-1-yl)-5H-pyrrc>lo[3,2-d]pyrimidine-4-carboxamide, Example 114;210) 5-(1H-midazol-1 -yI)-N-((1 r, 4r)-4-((2, 2, 2-trifl uoroethy l)am i no)cyclohexy I)- 1 H-py razolo[3, 4-c]py rid i ne-7- carboxamide, Example 115;211) 5-(1H-midazol-1 -yI)-N-((1s,4s)-4-((2, 2, 2-trifluoroethyl)amino)cyclohexyl)-1H-pyrazolo[3,4-c]pyridine-7- carboxamide, Example 116;212) N-(4,4-difluorocyclohexyl)-2-(1 H-imidazol-1-yl)-8-methyl-7H-purine-6-carboxamide, Example 117;213) N-[4-( 1 -cyano-1 -methy l-ethy l)pheny l]-2-i mid azol-1 -yl-5 H-py rrolo[3, 2-d]py rim idi ne-4-carboxam ide , Example 118;214) N-((1 R,4r)-4-((R)-2-hydroxy-3-methylbutoxy)cyclohexyl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4- carboxamide, Example 119a;215) N-((1s,4r)-4-((S)-2-hydroxy-3-methylbutoxy)cyclohexyl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4- carboxamide, Example 119b;216) N-((1s,4s)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)-2-(1 H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4- carboxamide, Example 120a;217) N-((1r,4r)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4- carboxamide, Example 120b;218) 2-(1H-midazol-1 -yI)-N-((1 r, 4r)-4-(trif I uoromethy I Jcyclohexy I) th ieno[3,2-d]pyri m id i ne-4-carboxam ide, Example 121;219) 2-(1H-midazol-1 -yI)-N-((1 s,4s)-4-(trif I uoromethy l)cyclohexyl)th ieno[3,2-d]pyri m id i ne-4-carboxam ide, Example 122;220) N-((3S,4R)-3-fluoropiperidin-4-yl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 123a;221) N-((3R,4R)-3-fluoropiperidin-4-yl)-2-(1H-midazol-1 -yI)-5H-pyrrolo [3 ,2-d]pyrimidine-4-carboxamide, Example 123b;222) 2-(1H-midazol-1 -yI)-N-((1 S , 3S)-3-(2-methoxyethoxy)cyclohexyl)-5 H-py rrolo[3, 2-d]pyri mid i ne-4- carboxamide, Example 124a;223) 2-(1H-midazol-1 -yI)-N-((1 S ,3 R)-3-(2-methoxyethoxy)cyclohexy l)-5 H-py rrolo[3, 2-d]py ri mid i ne-4- carboxamide, Example 124b;224) N-((1 R,4r)-4-((R)-2-hydroxypropoxy)cyclohexyl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4- carboxamide, Example 125a;225) N-((1 R,4r)-4-((S)-2-hydroxypropoxy)cyclohexyl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4- carboxamide, Example 125b;226) N-((1 R,4r)-4-((R)-2-hydroxy-2,3-dimethylbutoxy)cyclohexyl)-2-(1 H-imidazol-1 -yl)-5H-pyrrolo[3, 2- d]pyrimidine-4-carboxamide, Example 126a;227) N-((1 R,4r)-4-((S)-2-hydroxy-2,3-dimethylbutoxy)cyclohexyl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3, 2- d]pyrimidine-4-carboxamide, Example 126b;228) 2-(1H-midazol-1 -yI)-N-((1 R,4r)-4-((R)-3, 3, 3-trifluoro-2-hydroxy-2-methylpropanamido)cyclohexyl)-5H- pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 127a;229) 2-(1H-midazol-1 -yI)-N-((1 R,4r)-4-((S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamido)cyclohexyl)-5H- pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 127b;230) 2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methoxy-4-methylcyclohexyl)-5H-pyrrc>lo[3,2-d]pyrimidine-4-carboxamide, Example 128a;231) 2-(1H-midazol-1 -yI)-N-((1s,4s)-4-methoxy-4-methylcyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 128b;232) N-(5-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidie-4-carboxamide, Example 129;233) N-(4-cyanophenyl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 130;234) N-(3-fluoro-4-(2-methoxyethoxy)phenyl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 131 ;235) 2-(1H-midazol-1 -yI)-N-(1-(methoxymethyl)-1 H-pyrazol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 132;236) N-((1 r,4r)-4-(2-(2-(dimethylamino)ethoxy)ethox)cyclohexyl)-2-(1 H-imidazol-1 -yl)-5H-pyrrolo[3,2-d]pyrimidine- 4-carboxamide, Example 133;237) N-(5-chloropyridin-2-yl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 134;238) 2-(1H-midazol-1 -yI)-N-(4-methyltetrahydro-2H-pyran-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 135;239) 2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methoxycyclohexyl)thieno[3,2-d]pyrimidine-4-carboxamide, Example 136;240) N-(6-chloropyridin-3-yl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 137;241) 2-(1H-midazol-1 -yI)-N-(pyridin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 138;242) N-((1r,4r)-4-(2-hydroxypropan-2-yl)cyclohexyl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4- carboxamide, Example 139;243) N-(2-chloropyridin-4-yl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 140;244) N-(5-chloropyridin-3-yl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 141;245) N-(4-chloropyridin-2-yl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 142;246) 2-(1H-midazol-1 -yI)-N-(1-(2-morpholinoacetyl)piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 143;247) N-(6-chloropyridin-2-yl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 144;248) 2-(1H-midazol-1 -yI)-N-(6-(2-morpholinoethoxy)pyridin-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 145;249) N-((1 r,4r)-4-(2-(dimethylamino)-2-oxoethoxy)cyclohexyl)-2-(1 H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4- carboxamide, Example 146;250) 2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(trifluoromethyl)cyclohexyl)-7H-purine-6-carboxamide, Example 147;251) N-((1r,4r)-4-cyanocyclohexyl)-2-(1 H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 148;252) N-(4,4-difluorocyclohexyl)-2-(1 H-imidazol-1-yl)thieno[3,2-d]pyrimidine-4-carboxamide, Example 149;253) 2-(1H-midazol-1 -yI)-N-(pyrimidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 150;254) N-(6-(2-(dimethylamino)ethoxy)pyridin-3-yl)-2-(1H-midazol-1 -yI)thieno[3,2-d]pyrimidine-4-carboxamide, Example 151 ;255) N-(4,4-difluorocyclohexyl)-2-(1 H-imidazol-1-yl)-7H-purine-6-carboxamide, Example 152;256) 2-(1H-midazol-1 -yI)-N-(pyrimidin-5-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 153;257) 2-(1H-midazol-1 -yI)-N-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 154;258) 2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-morpholinocyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 155;259) N-(5-chloro-6-(2-morpholinoethoxy)pyridin-3-yl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4- carboxamide, Example 156;260) N-(2-(4,4-difluorocyclohexyl)ethyl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 157;261) 2-(1H-midazol-1 -yI)-N-(6-(4-morpholinopiperidin-1 -yl)pyridin-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4- carboxamide, Example 158;262) N-(4,4-difluorocyclohexyl)-5-(1H-midazol-1 -yI)-1H-pyrazolo[4,3-d]pyrimidine-7-carboxamide, Example 159;263) 5-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(trifluoromethyl)cyclohexyl)-1 H-pyrazolo[4,3-d]pyrimidine-7-carboxamide, Example 160;264) 5-(1H-midazol-1 -yI)-N-((1s,4s)-4-(trifluoromethyl)cyclohexyl)-1 H-pyrazolo[4,3-d]pyrimidine-7-carboxamide, Example 161 ;265) 2-(1H-midazol-1 -yI)-N-(isoxazol-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 162;266) 2-(1H-midazol-1 -yI)-N-(2-(2-methoxyethyl)-l, 2, 3, 4-tetrahydroisoquinolin-7-yl)-5H-pyrrolo[3,2-d]pyrimidine-4- carboxamide, Example 163;267) 2-(1H-midazol-1 -yI)-N-(1 -phenylcyclopropyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 164;268) 2-(1H-midazol-1 -yI)-N-(2-(2-methoxyethoxy)pyrimidin-5-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide,Example 165;269) N-(((1 r,4r)-4-cyanocyclohexyl)methyl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 166;270) 2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(trifluoromethoxy)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 167;271) N-((1r,4r)-4-fluorocyclohexyl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 168;272) 2-(1H-midazol-1 -yI)-N-((1 s,4s)-4-morpholinocyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 169;273) 2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(methylcarbamoyl)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 170;274) 5-(1H-midazol-1 -yI)-N-((1 r, 4r)-4-(trif I uoromethy I)cyclohexyl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide, Example 171 ;275) N-(2-acetyl-2-azabicyclo[2.2.1]heptan-5-yl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 172;276) N-(4,4-difluorocyclohexyl)-2-(1 H-imidazol-1-yl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 173;277) N-((1 r,4r)-4-(hydroxymethyl)cyclohexyl)-2-(1 H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 174;278) N-((1s,4s)-4-hydroxy-4-methylcyclohexyl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 175;279) N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 176;280) N-((1r,4r)-4-hydroxycyclohexyl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 177;281) N-((1 r,4r)-4-(l,l-dioxidoisothiazolidin-2-yl)cyclohexyl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4- carboxamide, Example 178;282) 2-(1H-midazol-1 -yI)-N-(2-(2-methoxyethyl)-l, 2, 3, 4-tetrahydroisoquinolin-6-yl)-5H-pyrrolo[3,2-d]pyrimidine-4- carboxamide, Example 179;283) N-((1 r,4r)-4-((3,3-difluoropropyl)amino)cyclohexyl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4- carboxamide, Example 180;284) N-((1 s,4s)-4-((3,3-difluoropropyl)amino)cyclohexyl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 181 ;285) N-((1 r,4r)-4-(2-hydroxypropan-2-yl)cyclohexyl)-5-(1H-midazol-1 -yI)-1H-pyrazolo[4,3-d]pyrimidine-7- carboxamide, Example 182;286) 5-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methoxycyclohexyl)-1H-pyrazolo[4,3-d]pyrimidine-7-carboxamide, Example 183;287) N-((1r,4r)-4-(2-hydroxypropan-2-yl)cyclohexyl)-2-(1H-midazol-1 -yI)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-4- carboxamide, Example 184;288) N-((1 r,4r)-4-(cyanomethyl)cyclohexyl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 185;289) N-((1s,4s)-4-hydroxycyclohexyl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine- 4-carboxamide, Example 186;290) 2-(1H-midazol-1 -yI)-N-((1 r, 4r)-4-(2-methoxy propan-2-y I )cyclohexyl)-5 H-py rrolo[3, 2-d]py ri m id i ne-4- carboxamide, Example 187;291) 5-(1H-midazol-1 -yI)-N-((1s,4s)-4-((3, 3, 3-trifluoropropyl)amino)cyclohexyl)-1 H- pyrazolo[3,4-c]pyridine-7- carboxamide, Example 188;292) 5-(1H-midazol-1 -yI)-N-((1 r, 4r)-4-((3, 3, 3-trifl uoropropy l)ami no)cyclohexy I)- 1 H-py razolo[3, 4-c]py rid i ne-7- carboxamide, Example 189;293) N-(6-(3-(dimethylamino)prop-1 -yn-1-yl)pyridin-3-yl)-2-(1 H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4- carboxamide, Example 190;294) 5-(1H-midazol-1 -yI)-N-((1r,4r)-4-((2, 2, 2-trifluoroethyl)amino)cyclohexyl)-1H-pyrazolo[4,3-d]pyrimidine-7- carboxamide, Example 191 ;295) N-((IS,4r)-4-((S)-1-hydroxyethyl)cyclohexyl)-5-(1H-midazol-1 -yI)-1 H-pyrazolo[3,4-c]pyridine-7-carboxamide, Example 192a;296) N-((1 R,4r)-4-((R)-1-hydroxyethyl)cyclohexyl)-5-(1H-midazol-1 -yI)-1H-pyrazolo[3,4-c]pyridine-7- carboxamide, Example 192b;297) N-((1 r,4r)-4-((2,2-difluoropropyl)amino)cyclohexyl)-5-(1H-midazol-1 -yI)-1 H-pyrazolo[3,4-c]pyridine-7- carboxamide, Example 193;298) N-((1 s,4s)-4-((2,2-difluoropropyl)amino)cyclohexyl)-5-(1H-midazol-1 -yI)-1 H-pyrazolo[3,4-c]pyridine-7- carboxamide, Example 194;299) N-((1 r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-5-(1H-midazol-1 -yI)-1 H-pyrazolo[3,4-c]pyridine-7- carboxamide, Example 195;300) 5-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-methyl-2H-pyrazolo[3,4-c]pyridine-7-carboxamide, Example 196;301) 5-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1 -methyl-1H-pyrazolo[3,4-c]pyridine-7- carboxamide, Example 197;302) 5-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)thieno[2,3-c]pyridine-7-carboxamide, Example 198;303) 5-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-(methylamino)-2-oxoethyl)cyclohexyl)-1 H-pyrazolo[3,4-c]pyridine-7- carboxamide, Example 199;304) N-((1 r,4r)-4-(2-hydroxyethyl)cyclohexyl)-2-(1 H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 200;305) N-((1 r,4r)-4-(2-(dimethylamino)-2-oxoethoxy)cyclohexyl)-5-(1H-midazol-1 -yI)-1 H-pyrazolo[4,3-d]pyrimidine- 7-carboxamide, Example 201;306) N-((1 r,4r)-4-(2-(dimethylamino)-2-oxoethoxy)cyclohexyl)-5-(1H-midazol-1 -yI)-1 H-pyrazolo[3,4-c]pyridine-7- carboxamide, Example 202;307) 5-(1H-midazol-1 -yI)-N-(6-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)-1 H-pyrazolo[3,4-c]pyridine-7-carboxamide, Example 203;308) N-((1 r,4r)-4-(3,3-difluoroazetidin-1-yl)cyclohexyl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4- carboxamide, Example 204;309) N-(4-cyanophenyl)-5-(1H-midazol-1 -yI)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide, Example 205;310) N-((1 r,4r)-4-(2,2-difluoroethylamino)cyclohexyl)-5-(1H-midazol-1 -yI)-1H-pyrazolo[4,3-d]pyrimidine-7- carboxamide, Example 206;311) N-((1s,4r)-4-((S)-2-hydroxypropoxy)cyclohexyl)-5-(1H-midazol-1 -yI)-1 H-pyrazolo[3,4-c]pyridine-7- carboxamide, Example 207;312) N-((1 r,4r)-4-((R)-2-hydroxypropoxy)cyclohexyl)-5-(1H-midazol-1 -yI)-1H-pyrazolo[3,4-c]pyridine-7- carboxamide, Example 208;313) N-((1 r,4r)-4-(acetamidomethyl)cyclohexyl)-5-(1H-midazol-1 -yI)-1 H-pyrazolo[3,4-c]pyridine-7-carboxamide, Example 209;314) N-((1 r,4r)-4-(2-hydroxypropan-2-yl)cyclohexyl)-2-(1 H-imidazol-1-yl)thieno[3,2-d]pyrimidine-4-carboxamide, Example 210;315) 2-(1H-midazol-1 -yI)-N-(isoindolin-5-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 211;316) N-((1 r,4r)-4-(4-cyanophenoxy)cyclohexyl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 212;317) 2-(1H-midazol-1 -yI)-N-((1r,4r)-4-(methylsulfonyl)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide,Example 213;318) N-((1 r,4r)-4-(cyanomethoxy)cyclohexyl)-5-(1 H-imidazol-1-yl)-1H-pyrazolo[4,3-d]pyrimidine-7-carboxamide, Example 214;319) N-((1 r,4r)-4-(cyanomethoxy)cyclohexyl)-5-(1 H-imidazol-1-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide, Example 215;320) 2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(oxetan-3-ylamino)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, Example 216;321 ) 5-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(methylcarbamoyl)cyclohexyl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide, Example 217;322) 5-(1H-midazol-1 -yI)-N-((1 r, 4r)-4-(methyl (2, 2, 2-trif I uoroethy I) am i no)cyclohexy I)- 1 H -py razolo[3, 4-c]pyrid ine-7- carboxamide, Example 218;323) N-((1 r,4r)-4-(cyanomethyl)cyclohexyl)-5-(1H-midazol-1 -yI)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide, Example 219;324) 2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2, 2, 2-trifluoroethylamino)cyclohexyl)thieno[3,2-d]pyrimidine-4- carboxamide, Example 220;325) N-((1 r,4r)-4-(2,2-difluoroethylamino)cyclohexyl)-2-(1H-midazol-1 -yI)thieno[3,2-d]pyrimidine-4-carboxamide, Example 221 ;326) 2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-((3, 3, 3-trifluoropropyl)amino)cyclohexyl)thieno[3,2-d]pyrimidine-4- carboxamide, Example 222;327) N-(6-(2-(dimethylamino)ethoxy)pyridin-3-yl)-5-(1H-midazol-1 -yI)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide, Example 223;328) 5-(1 H-imidazol-1-yl)-N-(6-(piperazin-1 -yl)pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide, Example 224;329) N-((1 r,4r)-4-(hydroxymethyl)cyclohexyl)-5-(1H-midazol-1 -yI)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide, Example 225;330) N-((1s,4s)-4-hydroxy-4-methylcyclohexyl)-5-(1H-midazol-1 -yI)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide, Example 226;331 ) N-((1 r,4r)-4-(3,3-difluoroazetidin-1 -yl)cyclohexyl)-5-(1H-midazol-1 -yI)-1H-pyrazolo[3,4-c]pyridine-7- carboxamide, Example 227;332) N-((1 r,4r)-4-(1-hydroxycyclopropyl)cyclohexyl)-5-(1H-midazol-1 -yI)-1H-pyrazolo[3,4-c]pyridine-7- carboxamide, Example 228;333) 5-(1H-midazol-1 -yI)-N-(6-(trifl uoromethy I) pyridi n-3-y l)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide, Example229;334) N-(6-(2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethoxy)pyridin-3-yl)-5-(1 H-imidazol-1 -yl)-1 H-pyrazolo[3,4- c]pyridine-7-carboxamide, Example 230;335) 5-(1H-midazol-1 -yI)-N-(6-(2,2,2-trifl uoroethoxy)py rid in-3-y l)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide, Example 231 ;336) N-((1 r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-5-(1H-midazol-1 -yI)-1 H-pyrazolo[3,4-c]pyridine-7- carboxamide, Example 232;337) 5-(1H-midazol-1 -yI)-N-((1 r, 4r)-4-(oxetan-3-y I am i no)cyclohexy l)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide, Example 233;338) 5-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(3-(trifluoromethyl)azetidin-1-yl)cyclohexyl)-1 H-pyrazolo[3,4-c]pyridine-7- carboxamide, Example 234;339) N-((1 r,4r)-4-((2,2-difluoropropyl)amino)cyclohexyl)-2-(1H-midazol-1 -yI)-5H-pyrrolo[3,2-d]pyrimidine-4- carboxamide, Example 235;340) 5-( 1 H-imidazol-1 -yl)-N-(isoindolin-5-yl)-1H-pyrazolo[3,4-c] pyridine-7-carboxamide, Example 236;341) N-(2-acetylisoindolin-5-yl)-5-(1H-midazol-1 -yI)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide, Example 237;342) N-((1 r,4r)-4-(1-hydroxycyclopropyl)cyclohexyl)-5-(1H-midazol-1 -yI)-1H-pyrazolo[4,3-d]pyrimidine-7- carboxamide, Example 238;343) 5-(1 H-imidazol-1-yl)-N-((1s,4s)-4-methyl-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)-1 H-pyrazolo[3,4- c]pyridine-7-carboxamide, Example 239;344) 5-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methyl-4-((2, 2, 2-trifluoroethyl)amino)cyclohexyl)-1 H-pyrazolo[3, 4- c]pyridine-7-carboxamide, Example 240;345) 5-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(3-(trifluoromethyl)azetidin-1-yl)cyclohexyl)-1 H-pyrazolo[4,3-d]pyrimidine-7- carboxamide, Example 241 ;346) 5-(1H-midazol-1 -yI)-N-((1 r, 4r)-4-(methylcarbamoy l)cyclohexy I)- 1 H-py razolo[4,3-d]py ri m id i ne-7- carboxamide, Example 242;347) N-((1 r,4r)-4-(acetamidomethyl)cyclohexyl)-5-(1H-midazol-1 -yI)-1H-pyrazolo[4,3-d]pyrimidine-7- carboxamide, Example 243;348) N-((1 r,4r)-4-((2,2-difluoropropyl)amino)cyclohexyl)-5-(1H-midazol-1 -yI)-1H-pyrazolo[4,3-d]pyrimidine-7- carboxamide, Example 244;349) N-(3,3-difluoropropyl)-5-(1H-midazol-1 -yI)-1 H-pyrazolo[3,4-c]pyridine-7-carboxamide, Example 245;350) N-((1 r,4r)-4-((2,2-difluoropropyl)amino)cyclohexyl)-2-(1H-midazol-1 -yI)thieno[3,2-d]pyrimidine-4- carboxamide, Example 246;351 ) 5-(1H-midazol-1 -yI)-N-((1 s,4s)-4-methyl-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)-1H-pyrazolo[3,4- c]pyridine-7-carboxamide, Example 247;352) 5-(1H-midazol-1 -yI)-N-((1 r, 4r)-4-(methyl (2, 2, 2-trif I uoroethy I) am i no)cyclohexy l)-1 H -py razolo[4, 3-d]py ri m idi ne- 7-carboxamide, Example 248;353) 5-(1H-midazol-1 -yI)-N-((1 r, 4r)-4-(3, 3, 3-trifl uoropropoxy)cyclohexyl)-1H-py razolo[3 ,4-c]py ridine-7- carboxamide, Example 249;354) 5-(1H-midazol-1 -yI)-N-((1 r, 4r)-4-(((2, 2,2-trifl uoroethy l)ami no) methyl)cyclohexyl)- 1 H -py razolo[3 , 4-c]py ridi ne- 7-carboxamide, Example 250;355) 5-(1H-midazol-1 -yI)-N-((1s,4s)-4-(2,2,2-trifluoroethoxy)cyclohexyl)-1H-pyrazolo[3,4-c]pyridine-7- carboxamide, Example 251 ;356) 5-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2, 2, 2-trifluoroethoxy)cyclohexyl)-1H-pyrazolo[3,4-c]pyridine-7- carboxamide, Example 252;357) N-((1 r,4r)-4-((1 , 1 -difluoro-2-methylpropan-2-yl)amino)cyclohexyl)-5-(1H-midazol-1 -yI)-1H-pyrazolo [3,4-c] pyridine-7-carboxamide, Example 253;358) N-((1 s,4s)-4-(( 1 , 1 -d if I uoro-2-methy I propan-2-y I) am i no)cycl ohexy l)-5-( 1 H-imidazol-1 -yl)-1H-pyrazolo[3,4- c]pyridine-7-carboxamide, Example 254;359) N-((1 r,4r)-4-(3,3-difluoroazetidin-1 -yl)cyclohexyl)-5-(1H-midazol-1 -yI)-1H-pyrazolo[4,3-d]pyrimidine-7- carboxamide, Example 255;360) N-((1 s,4s)-4-(3-fluoro-3-methylazetidin-1-yl)cyclohexyl)-5-(1H-midazol-1 -yI)-1H-pyrazolo[4,3-d]pyrimidine-7- carboxamide, Example 256;361 ) N-((1 r,4r)-4-(3-fluoro-3-methylazetidin-1 -yl)cyclohexyl)-5-(1H-midazol-1 -yI)-1H-pyrazolo[4,3-d]pyrimidine-7- carboxamide, Example 257;362) N-((1 r,4r)-4-(3-cyano-3-methylazetidin-1-yl)cyclohexyl)-51-(1H-midazol-1 -yl)-1H-pyrazolo[3,4-c]pyridine-7- carboxamide, Example 258;363) N-((1 s,4s)-4-(3-cyano-3-methylazetidin-1 -yl)cyclohexyl)-5-(1H-midazol-1 -yI)-1H-pyrazolo[3,4-c]pyridine-7- carboxamide, Example 259;364) N-((1 r,4r)-4-(2-hydroxypropan-2-yl)cyclohexyl)-5-(1H-midazol-1 -yI)thieno[2,3-c]pyridine-7-carboxamide, Example 260;365) N-((1 r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-5-(1H-midazol-1 -yI)thieno[2,3-c]pyridine-7-carboxamide, Example 261 ;366) N-((1 r,4r)-4-((2,2-difluoropropyl)amino)cyclohexyl)-5-(1H-midazol-1 -yI)thieno[2,3-c]pyridine-7-carboxamide, Example 262;367) N-((1r,4r)-4-(1-hydroxycyclopropyl)cyclohexyl)-5-(1 H-imidazol-1-yl)thieno[2,3-c]pyridine-7-carboxamide, Example 263;368) N-((1 R,4r)-4-((R)-1-hydroxyethyl)cyclohexyl)-5-(1H-midazol-1 -yI)thieno[2,3-c]pyridine-7-carboxamide, Example 264a;369) N-((1s,4r)-4-((S)-1 -hydroxyethyl)cyclohexyl)-5-(1H-midazol-1 -yI)thieno[2,3-c]pyridine-7-carboxamide, Example 264b;370) N-((1r,3r)-3-(2-hydroxypropan-2-yl)cyclobutyl)-5-(1H-midazol-1 -yI)-1 H-pyrazolo[4,3-d]pyrimidine-7- carboxamide, Example 265;371) N-((1 r,3r)-3-(2-hydroxypropan-2-yl)cyclobutyl)-5-(1H-midazol-1 -yI)-1H-pyrazolo[3,4-c]pyridine-7- carboxamide, Example 266;372) N-((1 r,4r)-4-((R)-1-hydroxyethyl)cyclohexyl)-2-(1H-midazol-1 -yI)thieno[3,2-d]pyrimidine-4-carboxamide, Example 267a;373) N-((1s,4r)-4-((S)-1-hydroxyethyl)cyclohexyl)-2-(1H-midazol-1 -yI)thieno[3,2-d]pyrimidine-4-carboxamide, Example 267b;374) 2-(1H-midazol-1 -yI)-N-((1 r, 4r)-4-(2-methoxyethoxy)cyclohexyl)-7-methy I-5 H-py rrolo[3,2-d]pyri m idi ne-4- carboxamide, Example 268;375) N-((1 r,4r)-4-(3-cyanoazetidin-1-yl)cyclohexyl)-5-(1H-midazol-1 -yI)-1 H-pyrazolo[3,4-c]pyridine-7- carboxamide, Example 269;376) 5-(1H-midazol-1 -yI)-N-((1r,4r)-4-((2, 2, 2-trifluoroethyl)amino)cyclohexyl)thieno[2,3-c]pyridine-7-carboxamide, Example 270;377) 5-(1H-midazol-1 -yI)-N-((1 r, 4r)-4-(((2, 2, 2-trif I uoroethy l)ami no) methyl)cyclohexyl)-1 H-pyrazolo[4,3- d]pyrimidine-7-carboxamide, Example 271 ;378) 2-(1H-midazol-1 -yI)-N-((1 r, 4r)-4-(( 1 ,1 ,1 -trifl uoro-2-methy I propan-2-yl) ami no)cyclohexy l)-5H-py rrolo[3, 2- d]pyrimidine-4-carboxamide, Example 272;379) N-((1 r,4r)-4-((l,l-difluoro-2-methylpropan-2-yl)amino)cyclohexyl)-2-(1 H-imidazol-1-yl)-5H-pyrrolo[3,2- d]pyrimidine-4-carboxamide, Example 273;380) 5-(1H-midazol-1 -yI)-N-((1 s,4s)-4-methyl-4-((2,2, 2-trif luoroethy I) am i no)cyclohexy I)- 1 H-pyrazolo[4,3- d]pyrimidine-7-carboxamide, Example 274;381 ) 5-(1H-midazol-1 -yI)-N-((1 r, 4r)-4-methyl-4-((2, 2, 2-trif luoroethyl)am i no)cyclohexy l)-1 H-pyrazolo[4,3- d]pyrimidine-7-carboxamide, Example 275;382) 5-(1H-midazol-1 -yI)-N-((1 r, 4r)-4-(( 1 ,1 ,1 -trifl uoro-2-methyl propan-2-y l)ami no)cyclohexy I)- 1 H-pyrazolo[4,3- d]pyrimidine-7-carboxamide, Example 276; or383) 5-(1 H-i m id azol- 1 -yl)-N-((1 s,4s')-4-((1 , 1 , 1 -trifluoro-2-methylpropan-2-yl)amino)cyclohexyl)-1 H-pyrazolo[4,3- d]pyrimidine-7-carboxamide, Example 277; or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[0111] In most preferred embodiments, 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.

[0112] In other preferred embodiments, 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 (Example 195), 5-(1H-midazol-1 -yI)-N-((1 r,4r)-4-((3, 3, 3-trifluoropropyl)amino)cyclohexyl)-1 H-pyrazolo[3,4-c]pyridine-7-carboxamide (Example 189), N-((1 r,4r)-4-((2,2-difluoropropyl)amino)cyclohexyl)-5-(1 H-imidazol-1 -yl)-1 H- pyrazolo[3,4-c]pyridine-7-carboxamide (Example 193), or N-((1 r,4r)-4-(2-hydroxypropan-2-yl)cyclohexyl)-5-(1 H- imidazol-1-yl)-1 H-pyrazolo[4,3-d]pyrimidine-7-carboxamide (Example 182) of WO 2021 / 021986, or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.Quinolines and azaquinolines of formula (VI), including 2-(1 H-imidazol-1 -yl)-8-((4-(2-methoxyethoxy)cyclohexyl)amino)-5-methylpyrido[3,2-d]pyrimidin- 6(5H)-one (Example 7)

[0113] In embodiments, the CD38 inhibitor is a quinoline or azaquinoline as described in WO 2022 / 165114, incorporated by reference herein.

[0114] In embodiments, the CD38 inhibitor is of formula (VI):(VI), wherein:X3is CR3or N;X4is CR4or 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 C1-4alkyl;L is a C1-4alkylene linker; n is O or 1 ;Q is H, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10haloalkyl, C6-10aryl, C3-14cycloalkyl, 5-14 membered heteroaryl, or 4-14 membered heterocycloalkyl, wherein said C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10haloalkyl, C6-10aryl, C3-14cycloalkyl, 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 Cy1, Cy1-C1-4alkyl, halo, C1-6alkyl, C2.6alkenyl, C2.6alkynyl, C1-6haloalkyl, CN, N02, 0Ra, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd, wherein said C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted by 1 , 2, or 3 substituents independently selected from Cy1, CN, N02, 0Ra, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd; each Cy1is independently selected from C6-10aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted by 1 , 2, 3, or 4 substituents independently selected from halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl-C1-4alkyl, C3-7cycloalkyl-C1-4alkyl, 5- 10 membered heteroaryl-C1-4alkyl, 4-10 membered heterocycloalkyl-C1-4alkyl, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(=NRe1)NRc1Rd1, NRc1C(=NRe1)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1;R1is C1-6alkyl;R2, R3, and R4are each independently selected from H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl- C1-4alkyl, C3-7cycloalkyl-C1-4alkyl, 5-10 membered heteroaryl-C1-4alkyl, 4-10 membered heterocycloalkyl- C1-4alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRC2Rd2, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl, C3-7cycloalkyl-C1-4alkyl, 5-10 membered heteroaryl-C1-4alkyl, and 4-10 membered heterocycloalkyl-C1-4alkyl of R2, R3, and R4are each optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRC2Rd2; each Ra, Rb, Rc, Rd, Ra1, Rb1, Rc1, Rd1, Ra2, Rb2, Rc2, and Rd2is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl, C3-7cycloalkyl-C1-4alkyl, 5-10 membered heteroaryl-C1-4alkyl, and 4- 10 membered heterocycloalkyl-C1-4alkyl, wherein said C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, Ce- io aryl, C3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl, C3-7cycloalkyl-C1-4alkyl, 5-10 membered heteroaryl-C1-4alkyl, and 4-10 membered heterocycloalkyl-C1-4alkyl of Ra, Rb, Rc, Rd, Ra1, Rb1, Rc1, Rd1, Ra2, Rb2, Rc2, and Rd2is optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from halo, C1-4alkyl, C1-4haloalkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRC3Rd3; or Rc and Rd together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1 , 2, or 3 substituents independently selected from halo, C1-4alkyl, C1-4haloalkyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRC3Rd3; or Rc1and Rd1together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1 , 2, or 3 substituents independently selected from halo, C1-4alkyl, C1-4haloalkyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRC3Rd3;

[0115] or Rc2and Rd2together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1 , 2, or 3 substituents independently selected from halo, C1-4alkyl, C1-4haloalkyl,CN, 0Ra3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRC3Rd3; each Ra3, Rb3, Rc3, and Rd3is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-7cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein said C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-7cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1 , 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, and C1-6haloalkoxy; and each Re, Re1, Re2, and Re3is independently selected from H, C1-4alkyl, and CN; wherein when X3is CR3and X4is CR4, then Ring A is not or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[0116] In embodiments, X3is N.

[0117] In embodiments, X4is N.

[0118] In embodiments, R1is C1-6alkyl, preferably methyl.

[0119] In embodiments, R2is H.

[0120] In embodiments, A is a 5-membered heteroaryl group having 2 ring-forming N heteroatoms, preferably

[0121] In embodiments, n is O.

[0122] In embodiments, Q is C3-14cycloalkyl (preferably cyclohexyl) substituted with ORa.

[0123] In embodiments, Rais C1-6alkyl substituted with ORa3.

[0124] In embodiments, Ra3is C1-6alkyl, preferably methyl.

[0125] In embodiments, the CD38 inhibitor is:385) 6-(1 H-imidazol-1 -yl)-4-(((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)amino)-1 -methylquinolin-2(1 H)-one, Example 1 ;386) 6-(1 H-imidazol-1 -yl)-1-methyl-4-(((1 r,4r)-4-(oxetan-3-ylamino)cyclohexyl)amino)quinolin-2(1 H)-one, Example 2;387) 6-(1 H-imidazol-1 -yl)-4-(((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)amino)-1 -methyl-1 ,5-naphthyridin-2(1 H)-one,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;389) 4-((( 1 r, 4r)-4-(2-hyd roxy propan-2-y l)cyclohexy l)ami no)-6-( 1 H-i m idazol- 1 -yl)-1 -methyl- 1 , 7-naph thy ridi n-2( 1 H)- one, Example 5;390) 6-(1H-midazol-1 -yI)-4-(((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)amino)-1-methyl-1 ,7-naphthyridin-2(1 H)-one, Example 6;391) 2-(1H-midazol-1 -yI)-8-(((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)amino)-5-methylpyrido[3,2-d]pyrimidin-6(5H)- one, Example 7;392) 8-(((1 r,4r)-4-(2-hydroxypropan-2-yl)cyclohexyl)amino)-2-(1H-midazol-1 -yI)-5-methylpyrido[3,2-d]pyrimidin- 6(5H)-one, Example 8;393) 2-(1H-midazol-1 -yI)-5-methyl-8-((4-(trifluoromethyl)phenyl)amino)pyrido[3,2-d]pyrimidin-6(5H)-one, Example 9;394) 2-(1H-midazol-1 -yI)-5-methyl-8-((6-(2-morpholinoethoxy)pyridin-3-yl)amino)pyrido[3,2-d]pyrimidin-6(5H)- one, Example 10;395) 6-(1H-midazol-1 -yI)-1-methyl-4-(((1 r,4r)-4-((2, 2, 2-trifluoroethyl)amino)cyclohexyl)amino)quinolin-2(1 H)-one, Example 11 ;396) 4-(((1 r,4r)-4-(2-hydroxypropan-2-yl)cyclohexyl)amino)-6-(1H-midazol-1 -yI)-1-methylquinolin-2(1 H)-one, Example 12;397) 6-(1H-midazol-1 -yI)-1 -methyl-4-((1 -(methylsulfonyl)piperidin-4-yl)amino)quinolin-2(1 H)-one, Example 13;398) 2-(((1 r,4r)-4-((6-(1H-midazol-1 -yI)-1-methyl-2-oxo-1 ,2-dihydroquinolin-4-yl)amino)cyclohexyl)oxy)-N,N- dimethylacetamide, Example 14;399) 6-(1H-midazol-1 -yI)-1-methyl-4-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)amino)quinolin-2(1 H)-one, Example 15;400) 4-(((1 r,4r)-4-((2,2-difluoropropyl)amino)cyclohexyl)amino)-6-(1H-midazol-1 -yI)-1-methylquinolin-2(1 H)-one, Example 16;401) 4-((6-(2-(dimethylamino)ethoxy)pyridin-3-yl)amino)-6-(1H-midazol-1 -yI)-1 -methylquinolin-2(1 H)-one, Example 17;402) 6-(1H-midazol-1 -yI)-1-methyl-4-(((1 r,4r)-4-(2-(pyrrolidin-1 -yl)ethoxy)cyclohexyl)amino)quinolin-2(1 H)-one, Example 18;403) 8-(((1 r,4r)-4-((2,2-difluoropropyl)amino)cyclohexyl)amino)-2-(1H-midazol-1 -yI)-5-methylpyrido[3, 2- d]pyrimidin-6(5H)-one, Example 19;404) 8-(1 s,4r)-4-((S)-1-hydroxyethyl)cyclohexyl)amino)-2-(1H-midazol-1 -yI)-5-methylpyrido[3,2-d]pyrimidin-6(5H)-one, Example 20;405) 2-(((1 r,4r)-4-((2-(1 H-imidazol-1-yl)-5-methyl-6-oxo-5,6-dihydropyrido[3,2-d]pyrimidin-8- yl)amino)cyclohexyl)oxy)-N,N-dimethylacetamide, Example 21 ;406) 4-((2-( 1 H-imidazol-1 -y l)-5-methy l-6-oxo-5, 6-d i hydropy rido[3,2-d]py rim idi n-8-y I) am ino) benzoni tri le, Example 22;407) 2-(1H-midazol-1 -yI)-5-methyl-8-(((1 r,4r)-4-((2, 2, 2-trifluoroethyl)amino)cyclohexyl)amino)pyrido[3, 2- d]pyrimidin-6(5H)-one, Example 23;408) 2-(1H-midazol-1 -yI)-8-(((1r,4r)-4-methoxycyclohexyl)amino)-5-methylpyrido[3,2-d]pyrimidin-6(5H)-one, Example 24;409) 2-(1H-midazol-1 -yI)-5-methy l-8-((6-(2-(py rrolid i n-1 -y l)ethoxy) py rid in-3-y l)am i no) py rido[3,2-d]py ri mid i n- 6(5H)-one, Example 25;410) 8-((4,4-difluorocyclohexyl)amino)-2-(1 H-imidazol-1-yl)-5-methylpyrido[3,2-d]pyrimidin-6(5H)-one, Example 26;411) 8-(((1 r,4r)-4-(1-hydroxycyclopropyl)cyclohexyl)amino)-2-(1H-midazol-1 -yI)-5-methylpyrido[3,2-d]pyrimidin- 6(5H)-one, Example 27; or412) 8-(((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)amino)-5-methyl-2-(thiazol-5-yl)pyrido[3,2-d]pyrimidin-6(5H)-one, Example 28; or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[0126] In most preferred embodiments, 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.Pyridazine or pyrimidine of formula (VII), including 2-(1 H-imidazol- 1 -yl)-N-(2- (2-methoxyethoxy)pyrimidin-5-yl)-6-(trifluoromethyl) pyrimidine-4- carboxamide (Compound 1)

[0127] In embodiments, the CD38 inhibitor is a pyridazine or pyrimidine compound as described in WO 2022 / 228496, incorporated by reference herein.

[0128] In embodiment, the CD38 inhibitor is of formula (VII):whereinAi 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 C1-6alkyl optionally substituted with 1 , 2 or 3 halogen;A2 is optionally having one or two carbonatoms replaced with nitrogen; wherein A2 is optionally substituted with 0 or 1 -OH; -CN; halogen; C1-6alkyl optionally substituted with 1 , 2 or 3 halogen; C2-6alkynyl; C1-6alkoxy; C3-6cycloalkoxy, in which the cycloalkyl optionally has one carbon atom replaced with 0 or S; -NR1R2, in which each of R1 and R2 independently is H, C1-6alkyl, -C(O)C1-6is a 5 or 6 membered saturated or unsaturated heterocycle containing 1 to3 heteroatoms selected from the group consisting of N, 0 and S, and optionally substituted with 1-2 C1-6alkyl;A3 is selected from the group consisting ofC1-6alkyl; -(CHR3)n-C3-8cycloalkyl, in which the C3-8cycloalkyl optionally has one or two carbon atoms replaced with N, 0 or S, n is 0, 1 or 2, and R3 is H orC1-6alkyl; orin which the phenyl optionally has one or two carbon atoms replaced withN, 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; -OCH2CH2OCH3; -CO-C1-6alkyl; halogen; C1-6alkyl optionally substituted with 1-3 halogen, methoxy or hydroxy; C1-6alkoxy optionally substituted with NH2, dimethylamino, hydroxy or carboxy; C3-6cycloalkoxy; or C3-8cycloalkyl, in which the C3-8cycloalkyl optionally has one or two carbon atoms replaced with N, 0 or S and is optionally substituted with 1-3 halogen, C1-6alkyl, C1-6alkyl or hydroxy; andR is H or C1-6alkyl; or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[0129] In embodiments, A1 is a 5 membered unsaturated monocyclic heterocycle containing two N heteroatoms(preferablyPreferably A1 is unsubstituted.

[0130] In embodiments, A2 ishaving two carbon atoms replaced with nitrogen, preferablyPreferably, A2 is substituted C1-6alkyl optionally substituted with 1 , 2 or 3 halogen (preferably -CF3).

[0131] In embodiments, A3in which the phenyl has one or two carbon atoms replaced with N(preferably), and k is 0. Preferably, A3 is optionally substituted with -OCH2CH2OCH3.

[0132] In embodiments, R is H.

[0133] In embodiments, the CD38 inhibitor is:413) 4,6-di(1H-midazol-1 -yI)-N-((1 r,4r)-4-methoxycyclohexyl)picolinamide;414) 6-chloro-4-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methoxycyclohexyl)picolinamide;415) 4-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methoxycyclohexyl)-6-oxo-1,6-dihydropyridine-2-carboxamide:416) 6-(1H-midazol-1 -yI)-4-methoxy-N-((1r,4r)-4-methoxycyclohexyl)picolinamide;417) 4-hydroxy-6-(1H-midazol-1 -yI)-N-((1r,4r)-4-methoxycyclohexyl)picolinamide;418) 2-acetamido-N-((1r,4r)-4-methoxycyclohexyl)-5-(thiazol-5-yl)benzamide;419) 2-amino-N-((1r,4r)-4-methoxycyclohexyl)-5-(thiazol-5-yl)benzamide;420) 2-fluoro-N-((1r,4r)-4-methoxycyclohexyl)-3-(thiazol-5-yl)benzamide;421 ) N-((1 r,4r)-4-methoxycyclohexyl)-6-(thiazol-5-yl)pyrazine-2-carboxamide;422) 3-amino-6-(1 H-imidazol-1-yl)-N-((1 r,4r)-4-methoxycyclohexyl)pyridazine-4-carboxamide;423) 6-(1 H-imidazol-1-yl)-N-((1 r,4r)-4-methoxycyclohexyl)pyrazine-2-carboxamide;424) N-((1 r,4r)-4-methoxycyclohexyl)-6-(thiazol-5-yl)picolinamide;425) N-((1 r,4r)-4-methoxycyclohexyl)-6-(1 H-pyrazol-5-yl)pyrazine-2-carboxamide;426) N-((1 r,4r)-4-methoxycyclohexyl)-6-(1 H-pyrazol-4-y1)pyrazine-2-carboxamide;427) 6-(isoxazol-4-yl)-N-((1 r,4r)-4-methoxycyclohexyl)pyrazine-2-carboxamide;428) N-((1 r,4r)-4-methoxycyclohexyl)-6-(pyridin-4-yl)pyrazine-2-carboxamide;429) 6-(isoxazol-5-yl)-N-((1 r,4r)-4-methoxycyclohexyl)picolinamide;430) N-((1 r,4r)-4-methoxycyclohexyl)-6-(4H-1 ,2,4-triazol-4-yl)pyrazine-2-carboxamide;431) N-((1 r,4r)-4-methoxycyclohexyl)-6-(1,3,4-oxadiazol-2-yl)pyrazine-2-carboxamide;432) 5-amino-6-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methoxycyclohexyl)picolinamide;433) 2-amino-6-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methoxycyclohexyl)pyrimidine-4-carboxamide;434) 6-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methoxycyclohexyl)-2-(methylamino)pyrimidine-4-carboxamide;435) 6-(dimethylamino)-2-(1 H-imidazol-1-yl)-N-((1r,4r)-4-methoxycyclohexyl)pyrimidine-4-carboxamide;436) 2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methoxycyclohexyl)-6-(methylamino)pyrimidine-4-carboxamide;437) 6-amino-2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methoxycyclohexyl)pyrimidine-4-carboxamide;438) 2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methoxycyclohexyl)-6-(piperidin-1-yl)pyrimidine-4-carboxamide;439) 3-amino-N-((1r,4r)-4-methoxycyclohexyl)-6-(thiazol-5-yl)pyrazine-2-carboxamide;440) 5-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methoxycyclohexyl)pyridazine-3-carboxamide;441) N-cyclohexyl-6-(1 H-imidazol-1-yl)pyrazine-2-carboxamide;442) 6-(1H-midazol-1 -yI)-N-isopropylpyrazine-2-carboxamide;443) 6-(1H-midazol-1 -yI)-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide:;444) 6-(1H-midazol-1 -yI)-N-(piperidin-4-yl)pyrazine-2-carboxamide;445) N-(tert-butyl)-6-(1 H-imidazol-1-yl)pyrazine-2-carboxamide;446) 6-(1H-midazol-1 -yI)-N-phenylpyrazine-2-carboxamide;447) 6-(1H-midazol-1 -yI)-N-(1-methylpiperidin-4-yl)pyrazine-2-carboxamide;448) N-(cyclohexylmethyl)-6-(1 H-imidazol-1-y1)pyrazine-2-carboxamide;449) N-benzyl-6-(1H-midazol-1 -yI)pyrazine-2-carboxamide;450) N-(1-cyclohexylethyl)-6-(1 H-imidazol-1-yl)pyrazine-2-carboxamide;451) N-(1-acetylpiperidin-4-yl)-6-(1H-midazol-1 -yI)pyrazine-2-carboxamide:452) 3-amino-6-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methoxycyclohexyl)pyrazine-2-carboxamide;453) 3-amino-N-cyclohexyl-6-(1H-midazol-1 -yI)pyrazine-2-carboxamide;454) 3-(dimethylamino)-6-(1 H-imidazol-1-y1)-N-((1 r,4r)-4-methoxycyclohexyl)pyrazine-2-carboxamide;455) 6-(1 H-imidazol-1-yl)-N-((1 r,4r)-4-methoxycyclohexyl)-3-(methylamino)pyrazine-2-carboxamide;456) 4-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methoxycyclohexyl)-6-methylpicolinamide;457) 4-chloro-6-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methoxycyclohexyl)picolinamide;458) 6-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methoxycyclohexyl)-4-methylpicolinamide;459) 6-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methoxycyclohexyl)-4-(trifluoromethyl)picolinamide;460) 5-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methoxycyclohexyl)nicotinamide;461) 2-amino-5-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methoxycyclohexyl)nicotinamide;462) 3-amino-6-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methoxycyclohexyl)picolinamide:463) 3-amino-N-cyclohexyl-6-(1 H-imidazol-1 -y I) picol in amide;464) 2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methoxycyclohexyl)isonicotinamide;465) 4-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methoxycyclohexyl)picolinamide;466) 6-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methoxycyclohexyl)pyrimidine-4-carboxamide;467) N-cyclooctyl-2-(1H-midazol-1 -yI)pyrimidine-4-carboxamide;468) 2-(1H-midazol-1 -yI)-N-(pyridin-3-yl)pyrimidine-4-carboxamide;469) 3-hydroxy-6-(1H-midazol-1 -yI)-N-((1r,4r)-4-methoxycyclohexyl)pyrazine-2-carboxamide;470) 2-hydroxy-5-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methoxycyclohexyl)nicotinamide;471) 5-amino-2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methoxycyclohexyl)isonicotinamide;472) N-((1r,4r)-4-methoxycyclohexyl)-6-(1 H-1 ,2,4-triazol-1-yl)pyrazine-2-carboxamide;473) 3-hydroxy-6-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methoxycyclohexyl)picolinamide;474) N-cyclohexyl-2-(1H-midazol-1 -yI)pyrimidine-4-carboxamide;475) 4-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methoxycyclohexyl)pyrimidine-2-carboxamide;476) 6-(1H-midazol-1 -yI)-5-methoxy-N-((1r,4r)-4-methoxycyclohexyl)picolinamide;477) 3-chloro-6-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methoxycyclohexyl)picolinamide;478) 6-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methoxycyclohexyl)-5-methylpicolinamide;479) 5-chloro-6-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methoxycyclohexyl)picolinamide;480) N-cyclohexyl-6-(4-methyl-1H-imidazol-1 -yl)pyrazine-2-carboxamide;481 ) N-cyclohexyl-6-(5-methyl-1H-imidazol-1 -yl)pyrazine-2-carboxamide;482) N-cyclohexyl-6-(2-methyl-1H-imidazol-1 -yl)pyrazine-2-carboxamide;483) 2-(1H-midazol-1 -yI)-N-phenylpyrimidine-4-carboxamide;484) 2-(1H-midazol-1 -yI)-N-(o-tolyl)pyrimidine-4-carboxamide;485) N-(2-fl uoropheny l)-2-( 1 H-imidazol-1 -yl)pyrimidine-4-carboxamide;486) N-(2-chlorophenyl)-2-(1H-midazol-1 -yI)pyrimidine-4-carboxamide;487) 2-(1H-midazol-1 -yI)-N-(2-methoxyphenyl)pyrimidine-4-carboxamide;488) 2-(1H-midazol-1 -yI)-N-(p-tolyl)pyrimidine-4-carboxamide;489) N-(4-fl uoropheny l)-2-( 1 H-imidazol-1 -yl)pyrimidine-4-carboxamide;490) N-(4-chlorophenyl)-2-(1H-midazol-1 -yI)pyrimidine-4-carboxamide;491) 2-(1H-midazol-1 -yI)-N-(4-(trifluoromethyl)phenyl)pyrimidine-4-carboxamide;492) N-(4-cyanophenyl)-2-(1 H-imidazol-1-yl)pyrimidine-4-carboxamide;493) 2-(1H-midazol-1 -yI)-N-(m-tolyl)pyrimidine-4-carboxamide:494) N-(3-fl uoropheny l)-2-( 1 H-imidazol-1 -yl)pyrimidine-4-carboxamide;495) N-(3-chlorophenyl)-2-(1 H-imidazol-1-yl)pyrimidine-4-carboxamide:496) 2-(1 H-imidazol-1 -y l)-N-(th i azol-5-y I) py ri m id i ne-4-carboxamide;497) N-cyclopentyl-2-(1 H-imidazol-1-yl)pyrimidine-4-carboxamide;498) N-cycloheptyl-2-(1 H-imidazol-1-yl)pyrimidine-4-carboxamide;499) 2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methoxycyclohexyl)-6-methylpyrimidine-4-carboxamide;500) N-((1r,4r)-4-methoxycyclohexyl)-2-(1 H-pyrazol-1-yl)pyrimidine-4-carboxamide;501 ) N-(3-fl uoropheny l)-2-( 1 H-imidazol-1 -yl)-6-(piperidi n-1 -yl)pyrimidine-4-carboxamide;502) N-(3-fl uoropheny l)-2-( 1 H-pyrazol-1 -yl)pyrimidine-4-carboxamide;503) 2-(1H-midazol-1 -yI)-N-((1 r, 4r)-4-methoxycyclohexyl)-6-(trifluoromethyl)pyrimidine-4- carboxamide;504) 6-cyclobutoxy-2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methoxycyclohexyl)pyrimidine-4-carboxamide;505) 2-(1H-midazol-1 -yI)-6-methoxy-N-((1r,4r)-4-methoxycyclohexyl)pyrimidine-4-carboxamide;506) 6-cyano-2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methoxycyclohexyl)pyrimidine-4-carboxamide;507) 2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide;508) N-(4,4-dimethylcyclohexyl)-2-(1 H-imidazol-1-yl)pyrimidine-4-carboxamide;509) 2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methylcyclohexyl)pyrimidine-4-carboxamide;510) N-(4,4-difluorocyclohexyl)-2-(1 H-imidazol-1-yl)pyrimidine-4-carboxamide;511) 2-(1 H-imidazol-1 -y1 )-N-(pyridin-4-yl)pyrimidine-4-carboxamide;512) 2-(1H-midazol-1 -yI)-N-(pyridin-2-y1)pyrimidine-4-carboxamide;513) 2-(1H-midazol-1 -yI)-N-((1s,4s)-4-methylcyclohexyl)pyrimidine-4-carboxamide;514) N-(3-fluorophenyl)-2-(1 H-imidazol-1-vl)-6-morpholinopyrimidine-4-carboxamide;515) N-(3-fluorophenyl)-2-(1H-midazol-1 -yI)-5-(piperidin-1-yl)pyrimidine-4-carboxamide;516) N-(3-fluorophenyl)-2-(1 H-pyrazol-5-yl)pyrimidine-4-carboxamide;517) N-(3-fluorophenyl)-2-(1H-midazol-1 -yI)-N-methyl-6-(piperidin-1 -yl)pyrimidine-4-carboxamide;518) N-(2,6-difluorophenyl)-2-(1H-midazol-1 -yI)-6-(piperidin-1 -yl)pyrimidine-4-carboxamide;519) N-benzyl-2-(1H-midazol-1 -yI)-6-(piperidin-1 -yl)pyrimidine-4-carboxamide;520) N-(3-fl uoropheny l)-2-( 1 H-imidazol-1 -yl)-6-(py rrolidi n-1 -y1 )pyrimidine-4-carboxamide;521) 6-cyclobutoxy-N-(3-fluorophenyl)-2-(1 H-imidazol-1-yl)pyrimidine-4-carboxamide;522) N-(3-fl uoropheny l)-2-( 1 H-imidazol-1 -yl)-6-(oxetan-3-yloxy)pyrimidine-4-carboxamide;523) N-(3-fl uoropheny l)-2-( 1 H-imidazol-1 -yl)-6-(trifl uoromethyl) pyrim id i ne-4-carboxamide;524) N-(3-chlorophenyl)-2-(1H-midazol-1 -yI)-6-(trifluoromethyl)pyrimidine-4-carboxamide;525) N-(3,4-d if I uoropheny l)-2-( 1 H-imidazol-1 -yl)pyrimidine-4-carboxamide;526) N-(3,5-d if I uoropheny l)-2-( 1 H-imidazol-1 -yl)pyrimidine-4-carboxamide;527) N-(4-ch loro-3-f I uoropheny l)-2-( 1 H-i m idazol- 1 -yl)pyrimidine-4-carboxamide;528) 4-(4,4-dimethylpiperidin-1 -yl)-N-(3-fluorophenyl)-6-(1H-midazol-1 -yI)picolinamide:529) N-(3-fl uoropheny l)-6-( 1 H-imidazol-1 -yl)-4-(piperidi n-1 -yl) picol in am ide;530) N-cyclohexyl-6-(1H-midazol-1 -yI)-4-(piperidin-1 -yl)picolinamide;531 ) N-(3-fl uoropheny l)-6-( 1 H-imidazol-1 -yl)-4-isopropy I picoli n amide;532) N-(3-fl uoropheny l)-2-( 1 H-imidazol-1 -yl)-6-isopropy I py ri mid i ne-4-carboxam ide;533) N-(3-fl uoropheny l)-6-( 1 H-imidazol-1 -yl)-4-(trifl uoromethyl) picol i n amide;534) N-(3,4-difluorophenyl)-2-(1H-midazol-1 -yI)-6-(trifluoromethyl)pyrimidine-4-carboxamide;535) N-(2, 5-d if I uoropheny l)-2-( 1 H-imidazol-1 -yl)-6-(piperidin-1 -yl)pyrimidine-4-carboxamide:536) N-(2-ch loro-5-fl uorophenyl)-2-( 1 H-imidazol-1 -yl)-6-(piperid i n-1 -yl)pyrimidine-4-carboxamide;537) N-(5-fluoro-2-methylphenyl)-2-(1H-midazol-1 -yI)-6-(piperidin-1-yl)pyrimidine-4-carboxamide;538) N-(4,4-dimethylcyclohexyl)-2-(1 H-imidazol-1-yl)-6-(trifluoromethyl)pyrimidine-4-carboxamide;539) 2-(1H-midazol-1 -yI)-N-(1-methylcyclohexyl)-6-(trifluoromethyl)pyrimidine-4-carboxamide;540) N-cyclohexyl-2-(1H-midazol-1 -yI)-6-(trifluoromethyl)pyrimidine-4-carboxamide;541) N-(tert-butyl)-2-(1H-midazol-1 -yI)-6-(trifluoromethyl)pyrimidine-4-carboxamide;542) N-(4,4-dimethylcyclohexyl)-2-(1 H-imidazol-1-yl)-6-(piperidin-1 -yl)pyrimidine-4-carboxamide;543) 2-(1H-midazol-1 -yI)-N-(1-methylcyclohexyl)-6-(piperidin-1 -yl)pyrimidine-4-carboxamide;544) N-cyclohexyl-2-(1H-midazol-1 -yI)-6-(piperidin-1 -yl)pyrimidine-4-carboxamide;545) N-(tert-butyl)-2-(1 H-imidazol-1-yl)-6-(piperidin-1 -yl)pyrimidine-4-carboxamide;546) 2-(1H-midazol-1 -yI)-N-((1r,4r)-4-methylcyclohexyl)-6-(trifluoromethyl)pyrimidine-4-carboxamide;547) 2-(1H-midazol-1 -yI)-N-((1r,4r)-4-methylcyclohexyl)-6-(piperidin-1-yl)pyrimidine-4-carboxamide;548) 2-(1H-midazol-1 -yI)-N-((1r,4r)-4-methylcyclohexyl)-6-morpholinopyrimidine-4-carboxamide;549) 6-cyclobutoxy-2-(1 H-imidazol-1-yl)-N-((1 r,4r)-4-methylcyclohexyl)pyrimidine-4-carboxamide;550) 2-(1 H-imidazol-1-yl)-N-((1r,4r)-4-methylcyclohexyl)-6-(oxetan-3-yloxy)pyrimidine-4-carboxamide;551) 6-(1 H-imidazol-1-yl)-N-((1r,4r)-4-methoxycyclohexyl)-3-(trifluoromethyl)picolinamide;552) 6-(1 H-imidazol-1-yl)-N-((1r,4r)-4-methoxycyclohexyl)-5-(trifluoromethyl)picolinamide;553) N-((1 r,4r)-4-methoxycyclohexyl)-2-(4-(trifluoromethyl)-1H-imidazol-1 -yl)pyrimidine-4-carboxamide;554) N-((1r,4r)-4-methoxycyclohexyl)-2-(2-(trifluoromethyl)-1 H-imidazol-1-yl)pyrimidine-4-carboxamide;555) N-((1 r,4r)-4-methoxycyclohexyl)-6-(4-(trifluoromethyl)-1H-imidazol-1-yl)picolinamide;556) N-((1 r,4r)-4-methoxycyclohexyl)-6-(2-(trifluoromethyl)-1H-imidazol-1-yl)picolinamide;557) 2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(trifluoromethyl)pyrimidine-4-carboxamide;558) 6-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methylcyclohexyl)-4-(trifluoromethyl)picolinamide;559) N-(3-fl uoropheny l)-6-( 1 H-imidazol-1 -yl)-3-(trifl uoromethyl) picol i n amide;560) N-(3-fl uoropheny l)-6-( 1 H-imidazol-1 -yl)-5-(trifl uoromethyl) picol i n amide;561) 2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methoxycyclohexyl)-5-(trifluoromethyl)pyrimidine-4-carboxamide;562) 2-(1H-midazol-1 -yI)-N-(piperidin-4-yl)-6-(trifluoromethyl)pyrimidine-4-carboxamide hydrochloride;563) 2-(1H-midazol-1 -yI)-N-(tetrahydro-2H-pyran-4-yl)-6-(trifluoromethyl)pyrimidine-4-carboxamide;564) N-(6-cyanopyridin-3-yl)-2-(1 H-imidazol-1 -y1 )-6-(trifluoromethyl)pyrimidine-4-carboxamide;565) N-(4-cyanophenyl)-2-(1 H-imidazol-1-yl)-6-(trifluoromethyl)pyrimidine-4-carboxamide;566) 2-(1H-midazol-1 -yI)-N-(pyridin-3-yl)-6-(trifluoromethyl)pyrimidine-4-carboxamide;567) N-(5-fluoropyridin-3-yl)-2-(1H-midazol-1 -yI)-6-(trifluoromethyl)pyrimidine-4-carboxamide;568) 2-(1H-midazol-1 -yI)-N-(pyridin-4-yl)-6-(trifluoromethyl)pyrimidine-4-carboxamide;569) N-(5-cyanopyridin-3-yl)-2-(1H-midazol-1 -yI)-6-(trifluoromethyl)pyrimidine-4-carboxamide;570) 2-(1 H-imidazol-1 -y l)-N-(py ri m idi n-5-y l)-6-(trif I uoromethy l)py rim id i ne-4-carboxam ide;571) 2-(1H-midazol-1 -yI)-N-(pyridazin-4-yl)-6-(trifluoromethyl)pyrimidine-4-carboxamide;572) N-(4-fl uoropheny l)-2-( 1 H-imidazol-1 -yl)-6-(trifl uoromethyl) py rim id i ne-4-carboxamide :573) N-(3,4-difluorophenyl)-2-(1H-midazol-1 -yI)-6-(trifluoromethyl)pyrimidine-4-carboxamide;574) N-(3,5-difluorophenyl)-2-(1H-midazol-1 -yI)-6-(trifluoromethyl)pyrimidine-4-carboxamide;575) N-(3-fluoro-5-(piperazin-1-yl)phenyl)-2-(1H-midazol-1 -yI)-6-(trifluoromethyl)pyrimidine-4-carboxamide;576) N-(3-fluoro-5-morpholinophenyl)-2-(1 H-imidazol-1-yl)-6-(trifluoromethyl)pyrimidine-4-carboxamide;577) 2-(1H-midazol-1 -yI)-N-(3-morpholinophenyl)-6-(trifluoromethyl)pyrimidine-4-carboxamide;578) (S)-N-(3-fluoro-5-(3-hydroxypyrrolidin-1 -yl)phenyl)-2-(1H-midazol-1 -yI)-6-(trifluoromethyl)pyrimidine-4- carboxamide;579) N-(3-fluoro-5-(2-methoxypropan-2-yl)phenyl)-2-(1 H-imidazol-1-yl)-6-(trifluoromethyl)pyrimidine4-carboxamide;580) N-(3-fluoro-4-(2-hydroxypropan-2-yl)phenyl)-2-(1 H-imidazol-1-yl)-6-(trifluoromethyl)pyrimidine4-carboxamide;581) N-(3-(2-(dimethylamino)ethoxy)-5-fluorophenyl)-2-(1H-midazol-1 -yI)-6-(trifluoromethyl)pyrimidine-4- carboxamide;582) N-(3-fluoro-5-(2-methoxyethoxy)phenyl)-2-(1 H-imidazol-1-yl)-6-(trifluoromethyl)pyrimidine-4-carboxamide;583) 2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methoxycyclohexyl)-6-(pyridin-4-yl)pyrimidine-4-carboxamide;584) 2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methoxycyclohexyl)-6-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4- carboxamide;585) 6-cyano-N-(3-fluorophenyl)-2-(1H-midazol-1 -yI)pyrimidine-4-carboxamide;586) 6-cyano-2-(1H-midazol-1 -yI)-N-(pyridin-3-yl)pyrimidine-4-carboxamide;587) 6-cyano-N-(4-fluorophenyl)-2-(1H-midazol-1 -yI)pyrimidine-4-carboxamide;588) 2-(1H-midazol-1 -yI)-N-(2-(2-methoxyethoxy)pyrimidin-5-yl)-6-(trifluoromethyl)pyrimidine-4-carboxamide;589) 6-cyano-2-(1H-midazol-1 -yI)-N-(pyrimidin-5-yl)pyrimidine-4-carboxamide;590) 6-(1H-midazol-1 -yI)-N-(pyridin-4-yl)-4-(trifluoromethyl)picolinamide;591) 6-(1H-midazol-1 -yI)-N-(pyridin-3-yl)-4-(trifluoromethyl)picolinamide;592) 6-(1H-midazol-1 -yI)-N-(py ri m idi n-5-y l)-4-(trif I uoromethy l)picol i namide;593) N-(2-(2-hydroxyethoxy)pyrimidin-5-yl)-2-(1H-midazol-1 -yI)-6-(trifluoromethyl)pyrimidine-4-carboxamide;594) 2-((5-(2-(1H-midazol-1 -yI)-6-(trifluoromethyl)pyrimidine-4-carboxamido)pyrimidin-2-yl)oxy)acetic acid; or595) N-(2-hydroxypyrimidin-5-yl)-2-(1H-midazol-1 -yI)-6-(trifluoromethyl)pyrimidine-4-carboxamide; or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[0134] In most preferred embodiments, 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.Pyrazine or pyrimidine carboxamide of formula (VI II), including 2-(1 H- imidazol- 1 -yl)-N-(4-(2-methoxyethoxy)cyclohexyl)-6-methyl pyrimid ine-4- carboxamide (Example 35)

[0135] In embodiments, the CD38 inhibitor is a pyrazine or pyrimidine carboxamide as described in WO 2021 / 207186, which is incorporated herein by reference.

[0136] In embodiments, the CD38 inhibitor is of formula (VIII):wherein:X1and X2are independently CH or N, provided that X1and X2are not both CH;Cy is C3-7cycloal kyl optionally substituted with an oxo group or with one or two Rxgroups, wherein Rxis halo, C1-4alkyl, C1-4haloalkyl, C1-4hydroxyalkyl, -NHSO2C1-C4 alkyl, or -SO2C1-C4alkyl;R1is -H, -NRaRb, halo, -CN, -C(=O)NH2, -COOH, C1-4alkyl, C1-4haloalkyl, C1-4hydroxyalkyl, C2-4alkenyl, C1-4alkoxy, C1-4alkoxyalkyl, C1-4alkylthio, C1-4alkylsulfone, C1-4alkoxyalkylthio, C1-4haloalkylthio, C1-4haloalkoxy, C3-4cycloalkyl, or a 5-membered heteroaryl, wherein the 5-membered heteroaryl is optionally substituted with one, two or three C1-4alkyl groups;R2is a 5-membered heteroaryl optionally substituted with one, two or three deuterium or C1-4alkyl groups;Rdis H, C1-4haloalkyl, C1-4hydroxyalkyl, or C1-4alkyl optionally substituted with C1-4alkoxy;Raand Rbindependently are -H or C1-4alkyl; and n is 0 or 1 , or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[0137] In embodiments, X1and X2are N. In embodiments, Xi is CH and X2 is N. In embodiments, R1is C1-4alkyl (preferably methyl), halo (preferably Cl), C1-4haloalkyl (preferably -CH2F), a 5-membered heteroaryl (preferably), or -NRaRb, wherein Raand Rbare -H. In embodiments, R2is a 5-membered heteroaryl(preferablyIn embodiments, Cy is cyclohexyl. In embodiments, Rdis C1-4alkyl (preferably ethyl) substituted with C1-4alkoxy (preferably methoxy); or C1-4haloalkyl (preferably -CHF2). In embodiments, n is 1.

[0138] In embodiments, the CD38 inhibitor is:

[0139] N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-(thiazol-5-yl)-6-(1 H-imidazol-1-yl)isonicotinamide, Example 1 ;596) N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2,6-di(thiazol-5-yl)isonicotinamide, Example 2;597) N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-(1 -methyl-1H-pyrazol-4-yl)-6-(thiazol-5-yl)isonicotinamide, Example 3;598) N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-(thiazol-5-yl)-6-(trifluoromethyl)isonicotinamide, Example 4;599) N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2,6-di(thiazol-5-yl)pyrimidine-4-carboxamide, Example 5;600) N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1 -methyl-1H-pyrazol-4-yl)-2-(thiazol-5-yl)pyrimidine-4- carboxamide, Example 6;601) N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(methylthio)-2-(thiazol-5-yl)pyrimidine-4-carboxamide, Example 7;602) N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(1-methyl-1H-pyrazol-4-yl)-6-(thiazol-5-yl)picolinamide, Example 8;603) N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(thiazol-5-yl)picolinamide, Example 9;604) 4-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(thiazol-5-yl)picolinamide, Example 10;605) 6-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide, Example 11 ;606) 6-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(1-methyl-1 H-pyrazol-4-yl)picolinamide, Example 12;607) 6-(1H-midazol-1 -yI)-4-(1-isopropyl-1H-pyrazol-4-yl)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide, Example 13;608) 6-(1 H-imidazol-1-yl)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(1 ,3,5-trimethyl-1 H-pyrazol-4- yl)picolinamide, Example 14;609) 4-amino-6-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide, Example 15;610) 4, 6-di(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide, Example 16;611) 6-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(thiazol-5-yl)picolinamide, Example 17;612) 4-chloro-6-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-picolinamide, Example 18;613) 6-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(trifluoromethyl)picolinamide, Example 19;614) 4-fluoro-6-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide, Example 20;615) 2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)isonicotinamide, Example 21 ;616) 2, 6-di(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)isonicotinamide, Example 22;617) 2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1-methyl-1 H-pyrazol-4-yl)isonicotinamide, Example 23;618) 2-(1-ethyl-1 H-pyrazol-4-yl)-6-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)isonicotinamide, Example 24;619) 2-(1 H-imidazol-1-yl)-6-(1-isopropyl-1 H-pyrazol-4-yl)-N-((1 r,4r)-4-(2- methoxyethoxy)cyclohexyl)isonicotinamide, Example 25;620) 2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1-methyl-1 H-pyrazol-3-yl)isonicotinamide, Example 26;621) 2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1-methyl-1 H-pyrazol-4-yl)pyrimidine-4- carboxamide, Example 27;622) 2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide, Example 28;623) 6-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-methylpicolinamide, Example 29;624) 4-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1-methyl-1 H-pyrazol-4-yl)picolinamide, Example 30;625) N-((1 r,4r)-4-hydroxycyclohexyl)-6-(1H-midazol-1 -yI)picolinamide, Example 31 ;626) N-cyclohexyl-6-(1 H-imidazol-1-yl)picolinamide, Example 32;627) 6-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methoxycyclohexyl)picolinamide, Example 33;628) N-((1 r,4r)-4-hydroxycyclohexyl)-2-(1H-midazol-1 -yI)pyrimidine-4-carboxamide, Example 34;629) 2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-methylpyrimidine-4-carboxamide, Example 35;630) 2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(trifluoromethyl)pyrimidine-4-carboxamide, Example 36;631) 6-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(methylthio)picolinamide, Example 37;632) 4-(1-Hydroxyethyl)-6-(1H-midazol-1 -yI)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide, Example 38;633) 6-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(methylsulfonyl)picolinamide, Example 39;634) 4-(2-Hydroxypropan-2-yl)-6-(1H-midazol-1 -yI)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide, Example 40;635) N-((1r,4r)-4-(difluoromethoxy)cyclohexyl)-2-(1H-midazol-1 -yI)pyrimidine-4-carboxamide, Example 41 ;636) N-((1r,4r)-4-(difluoromethoxy)cyclohexyl)-2-(1H-midazol-1 -yI)-6-methylpyrimidine-4-carboxamide, Example 42;637) 4-Cyano-6-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide, Example 43;638) N-((1r,4r)-4-(2-hydroxyethoxy)cyclohexyl)-2-(1 H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide, Example 44;639) 2-(1H-midazol-1 -yI)-N-(4-(2-methoxyethoxy)cyclohexyl)-6-carboxyl-pyrimidine-4-carboxamide, Example 45;640) 2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-methylisonicotinamide, Example 46;641) 6-cyano-2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide, Example 47;642) 2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4,6-dicarboxamide, Example 48;643) 6-(hydroxymethyl)-2-(1 H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide, Example 49;644) 2-(1 H-imidazol-1 -yl-d3)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-methylpyrimidine-4-carboxamide, Example 50;645) 6-(fluoromethyl)-2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide, Example 51 ;646) 6-(Difluoromethyl)-2-(1 H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide, Example 52;647) N-((1r,4r)-4-(ethylsulfonamido)cyclohexyl)-2-(1 H-imidazol-1-yl)pyrimidine-4-carboxamide, Example 53;648) 2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methoxy-4-methylcyclohexyl)pyrimidine-4-carboxamide, Example 54;649) N-((1 s,4s)-4-hydroxy-4-methylcyclohexyl)-2-(1H-midazol-1 -yI)pyrimidine-4-carboxamide, Example 55;650) 6-cyclopropyl-2-(1 H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl) pyrimidine-4-carboxamide,Example 56;651) 6-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-vinylpicolinamide, Example 57;652) N-((1r,4r)-4-ethoxycyclohexyl)-2-(1H-midazol-1 -yI)pyrimidine-4-carboxamide, Example 58;653) 4-(difluoromethyl)-6-(1 H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide, Example 59;654) 2-(1H-midazol-1 -yI)-N-((1s,4s)-4-(2-methoxyethoxy)cyclohexyl)-6-methylpyrimidine-4-carboxamide, Example 60;655) 2-(1H-midazol-1 -yI)-N-((1 r, 4r)-4-(2-methoxy-2-methylpropoxy)cyclohexyl)-6-methylpyrimidine-4- carboxamide, Example 61 ;656) 6-(1H-midazol-1 -yI)-4-methoxy-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide, Example 62;657) 2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-methoxycyclohexyl)pyrimidine-4-carboxamide, Example 63;658) N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-2-(1H-midazol-1 -yI)pyrimidine-4-carboxamide, Example 64; or659) 2-(1H-midazol-1 -yI)-N-((1 r,3r)-3-(2-methoxyethoxy)cyclobutyl)pyrimidine-4-carboxamide, Example 65; or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[0140] In most preferred embodiments, the CD38 inhibitor is 2-(1H-midazol-1 -yI)-N-(4-(2- methoxyethoxy)cyclohexyl)-6-methylpyrimidine-4-carboxamide, corresponding to Example 35 of WO 2021 / 207186, and which is of formula:or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[0141] In other most preferred embodiments, the CD38 inhibitor can also be 2-(1 H-imidazol-1-yl)-N-((1s,4s)-4-(2- methoxyethoxy)cyclohexyl)-6-methylpyrimidine-4-carboxamide (Example 60), 6-(fluoromethyl)-2-(1 H-imidazol-1 -yl)- N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide (Example 51), 4-amino-6-(1 H-imidazol-1 -yl)-N- ((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide (Example 15), 4-chloro-6-(1 H-imidazol-1 -yl)-N-((1 r,4r)-4-(2- methoxyethoxy)cyclohexyl)-picolinamide (Example 18), 6-(1 H-imidazol-1-yl)-N-((1r,4r)-4-(2- methoxyethoxy)cyclohexyl)-4-(thiazol-5-yl)picolinamide (Example 17), 4, 6-di(1 H-imidazol-1 -yl)-N-((1 r, 4r)-4-(2- methoxyethoxy)cyclohexyl)picolinamide (Example 16), N-((1 r,4r)-4-(difluoromethoxy)cyclohexyl)-2-(1 H-imidazol-1 -yl)- 6-methylpyrimidine-4-carboxamide (Example 42), 6-(1H-midazol-1 -yI)-N-((1 r, 4r)-4-(2-methoxyethoxy)cyclohexyl)-4- (1-methyl-1H-pyrazol-4-yl)picolinamide (Example 12), or 2-(1H-midazol-1 -yI)-N-((1 r, 4r)-4-(2- methoxyethoxy)cyclohexyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-4-carboxamide (Example 27) of WO2021 / 207186, or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.Tricyclic fused imidazole of formula (IX), including compounds 1 A, 2A, 3A, 4A, and 12A of WO 2024 / 226685

[0142] In embodiments, the CD38 inhibitor is a tricyclic fused imidazole as described in WO 2024 / 226685, incorporated herein by reference.

[0143] In preferred embodiments, the CD38 inhibitor is of formula (IX):wherein Z is selected from, wherein t represents the point of connection between Z and the imidazole ring;X is selected from 0 and S;Y is selected from -N(R10)2, -OR10, and -SR10;A is selected from N and OR18;D is selected from N and OR19;R4is selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6aminoalkyl, C1-6cyanoalkyl, C1-6alkoxyalkyl, C1-6alkyl-N(R20)2, C3-5cycloalkyl, and 3- to 6-membered heterocycle;R5is selected from hydrogen and C1-6alkyl;R6is selected from hydrogen, C1-6alkyl, halogen, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6aminoalkyl, C1-6cyanoalkyl, C1-6alkoxyalkyl, C1-6alkyl-N(R20 )2, C4-6cycloalkyl, and 3- to 6-membered heterocycloalkyl; R7is selected from C3-C12 carbocycle and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more R8; each R8is independently selected from halogen, -N(R20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, - S(O)N(R20)2, -S(O)R20(=N R20), -NR20S(O)2R20, -C(O)N(R20)2, -C(=N R20)N(R20)2, -C(O)NR20OR20, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, - N(R20)C(O)O R20, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R R20), -CN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NO2, -NH2, oxo, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, C1-6hydroxyalkyl, C1-6aminoalkyl, C1-6cyanoalkyl, and C1-6alkoxyalkyl;R9is selected from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6cyanoalkyl, C1-C6alkoxyalkyl, C1-C6alkyl-N(R20)2, C3-6carbocycle and 4- to 6-membered heterocycle, wherein the C3-6carbocycle and 4- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, oxo, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6cyanoalkyl, C1-C6alkoxyalkyl, C1-C6alkyl-N(R20)2, C2-10alkenyl, and C2-10alkynyl; each R10is independently selected from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6cyanoalkyl, C1-C6alkoxyalkyl, and C1-C6alkyl- N(R20)2;R17is selected from hydrogen, halogen, -N (R2°)2, -OR29, -SR29, -S(O)2( R29), -S(O)2N(R29)2, -S(O) N(R29)2, - S(O)R29(=N R29), -NR29S(O)2R29, -C(O)N(R29)2, -C(=NR29)N(R29)2, - C(O)NR29OR29, -N(R29)C(O)R29, - N(R29)C(O)N(R29)2, -N(R29)C(O)O R29, -C(O)R29, - C(O)O R29, -OC(O) R29, -OC(O)N(R29)2, -NO2, -CN, C1-6alkyl-N(R29)2, C1-6aminoalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocycle and 5- to 12-membered heterocycle;R18is selected from hydrogen, halogen, -OH, -CN, -NO2, -NH2, -NHC1-10alkyl, -N(C1-10alkyl)2, -O-C1-10alkyl, C1-C6alkyl, and C1-C6haloalkyl; R19is selected from hydrogen, halogen, -OH, -CN, -NO2, -NH2, -N HC1-10alkyl, -N(C1-10alkyl)2, -O-C1-10alkyl, C1-C6alkyl, and C1-C6haloalkyl; andR29is independently selected at each occurrence from hydrogen; C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, - NO2, -NH2, C1-10alkyl, - C1-10haloalkyl, -0- C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle, or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[0144] Preferably, Z isPreferably, X is 0. Preferably, R9is hydrogen. Preferably, R17is hydrogen.Preferably, A is CR18. Preferably, R18is hydrogen. Preferably, D is CR19. Preferably, R19is hydrogen. Preferably, R4is hydrogen. Preferably, R5is selected from hydrogen. Preferably, R6hydrogen. Preferably, R7is a 5- to 15- membered heterocycle (preferably «

[0145] In alternative embodiments, the CD38 inhibitor is of formula (IXb):(IXb) wherein:Z is selected from, wherein t represents the point of connection between Z andis selected from -0-, -NR9-, -S-, and -SO2-; each R50is independently selected from hydrogen, halogen, C1-C6alkyl; or come together to form ; each R51is independently selected from hydrogen, halogen, andC1-C6alkyl; k is selected from 1 and 2; A is selected from N and CRis;is selected from an optionally substituted imidazole, wherein the imidazole is optionally substituted with one or more R14; D is selected from N and CR19; R5is selected from hydrogen and C1-6alkyl;R7is selected from hydrogen; and C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-C14carbocycle and 5- to 15- membered heterocycle, each of which are optionally substituted with one or more R8; each R8is independently selected from halogen, -N(R20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, - S(O)N(R20)2, -S(O)R20(=N R20), -NR20S(O)2R20, -C(O)N(R20)2, -C(=N R20)N(R20)2, -C(O)NR20OR20, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, - N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2-NO2, =O, =N(R20), =NO(R20), -CN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-C12carbocycle, and 4- to 12-membered heterocycle, wherein the C1-6alkyl is optionally substituted with one or more R8* , and wherein the C3-C12carbocycle and 4- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -CN, -N02, -NH2, oxo, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6cyanoalkyl, and C1-C6alkoxyalkyl; each R8* is independently selected from 4- to 12-membered heterocycle, wherein the 4- to 12- membered heterocycle is optionally substituted with one or more substituents selected from halogen, -OH, -CN, -N02, - NH2, OXO, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6cyanoalkyl, and C1-C6alkoxyalkyl;R9is selected from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6cyanoalkyl, C1-C6alkoxyalkyl, C1-C6alkyl-N(R20)2, C3-6carbocycle and 4- to 6-membered heterocycle, wherein the C3-6carbocycle and 4- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, oxo, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6cyanoalkyl, C1-C6alkoxyalkyl, C1-C6alkyl-N(R20)2, C2-10alkenyl, C2-10alkynyl; each R14is independently selected from halogen, -OH, -CN, -NO2, -NH2, -NHC1-10alkyl, -N(C1-10alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle;R17is selected from hydrogen, halogen, -N(R20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, - S(O) N(R2°)2, - S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, - C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, -CN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocycle, and 5- to 12-membered heterocycle;R18is selected from hydrogen, halogen, -OH, -CN, -NO2, -NH2, -NHC1-10alkyl, -N(C1-10alkyl)2, -O-C1-10alkyl, C1-C6alkyl, and C1-C6haloalkyl;R19is selected from hydrogen, halogen, -OH, -CN, -NO2, -NH2, -NHC1-10alkyl, -N(C1-10alkyl)2, -O-C1-10alkyl, C1-C6alkyl, and C1-C6haloalkyl; andR20is independently selected at each occurrence from hydrogen; C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, - NO2, -NH2, -S(O)2(C1-6alkyl), C1-10alkyl, - C1- 10haloalkyl, -O-C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle, or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[0146] Preferably, Y is -O-. Preferably, each R50is hydrogen. Preferably, each R51is hydrogen. Preferably, k is 2.Preferably, A is selected from N and CRis. Preferably, is imidazole. Preferably, D is selected CR19.Preferably, R19is hydrogen. Preferably, R5is hydrogen Preferably, R17is hydrogen. . Preferably, R7is• C3-C14 carbocycle (preferably cyclohexyl) substituted with -OR20, wherein R20is preferably C1-6alkyl (preferably ethyl) substituted with -O-C1-10alkyl, preferably methoxy, or• a 5- to 15-membered heterocycle, preferably piperidinyl substituted with -S(O)2(R20), wherein R20is preferably C1-6alkyl (preferably methyl); or tetrahydropyranyl, or tetrahydrothiophenyl.

[0147] In embodiments, the CD38 inhibitor is:661) (R)-N-(Tetrahydro-2H-pyran-3-yl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10-carboxamide, compound 1A;662) ( R)-N-( 1 , 1 -Dioxidotetrahyd rothiophen-3-y l)-5 ,6-d i hyd robenzo[f]l i midazo[ 1 ,5-d][1 ,4]oxazepine-10-carboxamide, compound 2A;663) N-((1r,4r)-4-(2-Methoxyethoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10-carboxamide, compound 3A;664) N-(1-(Methylsulfonyl)piperidin-4-yl)-5,6-dihydrobenzo[f]imidazo[1,5-d][1 ,4]oxazepine-10-carboxamide, compound 4A;665) N-(4, 4-D ifl uorocyclohexy l)-5, 6-d i hydrobenzo[f]im idazo[ 1 ,5-d][1 ,4]oxazepine-10-carboxamide, compound 5A;666) (S)-N-(2,3-Di hyd ro- 1 H-inden-1 -y l)-5, 6-di hydrobenzoff li m idazo[ 1 , 5-d][ 1 ,4]oxazepine-10-carboxamide, compound 6A;667) N -( Benzo[d]thi azol-5-y l)-5, 6-di hydrobenzo[f]i m idazo[1 , 5-d][ 1 ,4]oxazepine-10-carboxamide, compound 7A;668) N-(2,3-Dihydrobenzo[b][1 ,4]dioxin-6-yl)-5,6-dihydrobenzo[f]imidazo[1,5-d][1 ,4]oxazepine-10-carboxamide, compound 8A;669) N -(2, 3-D i hyd robenzof uran-5-y l)-5, 6-d i hyd robenzo[f]i m idazo[ 1 , 5-d][ 1 ,4]oxazepine-10-carboxamide, compound 9A;670) N-(6-(Trifluoromethyl)pyridin-3-yl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10-carboxamide, compound 10A;671 ) N-((1 r,4r)-4-(2-Methoxyethoxy)cyclohexyl)-4-oxo-4,5-dihydroimidazo[1 ,5-alquinoxaline-8-carboxamide, compound 11 A;672) (R)-N-(1 , 1 -Dioxidotetrahydrothiophen-3-yl)-4-oxo-4,5-dihydroimidazo[1 ,5-a]quinoxaline-8-carboxamide, compound 12A;673) (R)-4-Oxo-N-(tetrahydro-2H-pyran-3-yl)-4,5-dihydroimidazo[1,5-a]quinoxaline8-carboxamide, compound 13A;674) (R)-N-(Tetrahydro-2H-pyran-3-yl)-4,5-dihydrobenzo[b]imidazo[1 ,2-d][1 ,4]oxazepine-9-carboxamide, compound 14A;675) (R)-N-(Tetrahydro-2H-pyran-3-yl)-4,5-dihydrobenzo[b]imidazo[1 ,5-d][1 ,4]oxazepine-9-carboxamide, compound 15A;676) (R)-5-Methyl-4-oxo-N-(tetrahydro-2H-pyran-3-yl)-4,5-dihydroimidazo[1 ,5-a quinoxaline-8-carboxamide, compound 16A;677) N-((1r,4r)-4-(Methylcarbamoyl)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10-carboxamide, compound 17A;678) N-(3-(Methylsulfonyl)phenyl)-5,6-dihydrobenzo[flimidazo[1 ,5-d][1,4]oxazepine10-carboxamide, compound 18A;679) N-(1 , 1-Dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10-carboxamide, compound 19A;680) N-((1r,4r)-4-Methoxycyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1,4]oxazepine-10-carboxamide, compound 20A;681) N-(4-Fluoro-3-(methylsulfonyl)phenyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10-carboxamide, compound 21A;682) N-(5-( M ethy Isu Ifony l)py rid i n-3-y l)-5,6-di hyd robenzo[f]im id azo[ 1 , 5-d][ 1 ,4]oxazepine-10-carboxamide, compound 22A;683) tert-Buty 1 5-(5,6-d ihyd robenzo[f]i m idazo[ 1 ,5-d][ 1 ,4]oxazepine-10-carboxamido)isoindoline-2-carboxylate, compound 23A;684) N -( I soi ndol i n-5-y l)-5, 6-d i hyd robenzo[f]i mid azo[1 , 5-d][ 1 ,4]oxazepine-10-carboxamide hydrochloride, compound 24A;685) N -(2-(M ethy Isulfony I) isoi ndol i n-5-y l)-5, 6-d i hyd robenzo[f]i mid azo[1 , 5-d][ 1 ,4]oxazepine-10-carboxamide, compound 25A;686) (R)-N-(Tetrahydro-2H-pyran-3-yl)-6,7-dihydro-5H-benzo[b]imidazo[5,1-][1 ,5]oxazocine-11 -carboxamide, compound 26A;687) (R)-4-((2-Methoxyethyl)amino)-N-(tetrahydro-2H-pyran-3-yl)imidazo[1 ,5-a]quinoxaline-8-carboxamide, compound 27A;688) ( R)-4-( M ethy I amino)-N -(tetrahydro-2H -py ran-3-y l)imid azo[1 ,5-a]quinoxaline-8-carboxamide, compound 28A;689) N-((1 r,4r)-4-((2-Methoxyethyl)sulfonamido)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1,5-d][1 ,4]oxazepine-10- carboxamide, compound 29A;690) N -(2, 3-D i hyd ro-[ 1 , 41 dioxi no[2,3-b]py ridi n-6-y l)-5, 6-d i hyd robenzo[f]i mid azo[ 1 ,5-d][1 ,4]oxazepine-10- carboxamide, compound 30A;691) N-(2,3-Dihydro-[1 ,4]dioxino[2,3-b]pyridin-7-yl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1,4]oxazepine-10- carboxamide, compound 31A;692) N -(2, 3-Di hydrobenzof uran-6-y l)-5, 6-d i hyd robenzo[f]i m idazo[ 1 , 5-d][ 1 ,4]oxazepine-10-carboxamide, compound 32A;693) N-(1 ,3-Dihydroisobenzofuran-5-yl)-5,6-dihydrobenzo[f]imidazo[1,5-d][1,4]oxazepine-10-carboxamide, compound 33A;694) N-(1 H-Benzo[d]imidazol-6-yl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine10-carboxamide, compound 34A;695) (R)-4-(Dimethylamino)-N-(tetrahydro-2H-pyran-3-yl)imidazo[1 ,5-a]quinoxaline8-carboxamide, compound 35A;696) N-(1 -Methyl-2-oxo-1 ,2-dihydropyridin-4-yl)-5,6-dihydrobenzo[flimidazo[1 ,5-d][1 ,4]oxazepine-10-carboxamide,compound 36A697) N-((1r,4r)-4-(Propylsulfonamido)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10-carboxamide, compound 37A698) (R)-6,6-Dimethyl-N-(tetrahydro-2H-pyran-3-yl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1,4]oxazepine-10- carboxamide, compound 38A;699) N-(Benzo[d]oxazol-6-yl)-5,6-dihydrobenzo[f]imidazo[1 , 5-d][ 1 ,4]oxazepine-10-carboxamide, compound 39A;700) N-(Thi azolo[5 , 4-b]py ridi n-6-yl)-5 , 6-d i hyd robenzo[f]i m id azo[ 1 ,5-d][1 ,4]oxazepine10-carboxamide, compound 40A;701) N-(Benzo[d]thiazol-6-yl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1,4]oxazepine-10-carboxamide, compound 41 A;702) (R)-N-(tetrahydro-2H-pyran-3-yl)-6,7-dihydroimidazo[1 ,5-d]pyrido[3,2-b][1 ,4]oxazepine-2-carboxamide, compound 42A;703) (Z)-N-((R)-Tetrahydro-2H-pyran-3-yl)-5,6-dihydro-1 ,4-(metheno)pyrido[3,2-b][1,4,6]oxadiazonine-10- carboxamide, compound 43A;704) N -(2-Methoxy benzo[d]th i azol-5-y l)-5,6-di hyd robenzo[f]im idazo[ 1 , 5-d][ 1 ,4]oxazepine-10-carboxamide, compound 44A;705) N-(2-(2-Methoxyethoxy)benzo[d]thiazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10- carboxamide, compound 45A;706) 8-Bromo-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1,4]oxazepine-10- carboxamide, compound 46A;707) N -(2-( Methy lami no) benzo[d]thi azol-5-y l)-5, 6-d i hyd robenzo[f]im id azo[1 , 5-d][ 1 ,4]oxazepine-10-carboxamide, compound 47A;708) N -(2-((2-M ethoxyethy l)ami no)benzo[d]th i azol-5-y l)-5,6-d i hyd robenzo[f]i mid azo[ 1 , 5-d][ 1 ,4]oxazepine-10- carboxamide, compound 48A;709) N -(2-(Di methy lam ino) benzo[d]th i azol-5-yl)-5,6-d ihyd robenzo[f]i m idazo[ 1 , 5-d][ 1 ,4]oxazepine-10-carboxamide, compound 49A;710) 8-Cyclopropyl-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10- carboxamide, compound 50A;711) (R)-5,5-Dimethyl-N-(tetrahydro-2H-pyran-3-yl)-5,6-dihydrobenzo[flimidazo[1 ,5-d][1 ,4]oxazepine-10- carboxamide, compound 51A;712) N-((1 r,4r)-4-(T rif I uoromethy l)cyclohexy l)-5, 6-di hydrobenzo[f]i m idazo[ 1 , 5-d][ 1 ,4]oxazepine-10-carboxamide, compound 52A;713) N-((1 r,4r)-4-(2-Methoxyethoxy)cyclohexyl)-8-methyl-5,6-dihydrobenzo[f]imidazo[1 , 5-d][ 1 ,4]oxazepine-10-carboxamide, compound 53A;714) 8-Methoxy-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1,4]oxazepine-10- carboxamide, compound 54A;715) N-((1 r,4r)-4-(2-Methoxyethoxy)cyclohexyl)-8-(trifluoromethyl)-5,6-dihydrobenzo[f]imidazo[1 ,5- d][1 ,4]oxazepine-10-carboxamide, compound 55A;716) N-((1 r,4r)-4-(2-Hydroxyethyl)cyclohexyl)-5,6-dihydrobenzo[flimidazo[1 ,5-d][1 ,4]oxazepine-10-carboxamide, compound 56A;717) 8-Fluoro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1,5-d][1 ,4]oxazepine-10- carboxamide, compound 57A;718) N-((1 r,4r)-4-(2-Hydroxypropan-2-yl)cyclohexyl)-5,6-dihydrobenzo[flimidazo[1 ,5-d][1 ,4]oxazepine-10- carboxamide, compound 58A;719) N-((1 r, 4r)-4-((2-Methoxyethyl)carbamoy l)cyclohexy l)-5, 6-d i hyd robenzo[f]i mid azo[ 1 , 5-d][ 1 ,4]oxazepine-10- carboxamide, compound 59A;720) N-((1r,4r)-4-Acetamidocyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10-carboxamide, compound 60A;721) N-((1 r,4r)-4-((2,2,2-Trifluoroethyl)carbamoyl)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1,4]oxazepine-10- carboxamide, compound 61A;722) N-((1 r,4r)-4-((2,2,2-Trifluoroethyl)amino)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10- carboxamide, compound 62A;723) N-((1 r,4r)-4-((2,2-Difluoroethyl)amino)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1,5-d][1 ,4]oxazepine-10- carboxamide, compound 63A;724) N-((1s,4s)-4-(3,3-Difluoroazetidin-1-yl)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1,5-d][1 ,4]oxazepine-10- carboxamide, compound 64A;725) N-((1 r,4r)-4-(Hydroxymethyl)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10-carboxamide, compound 65A;726) N-(3, 3-D ifl uorocyclopen tyl)-5,6-d i hyd robenzo[f]i mid azo[ 1 , 5-d][ 1 ,4]oxazepine-10-carboxamide, compound 66A;727) N-((1r,4r)-4-(3-Methoxypropanamido)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10- carboxamide, compound 67A;728) 5-M ethy l-N-((R)-tetrahyd ro-2 H-pyran-3-yl)-5, 6-di hyd robenzo[f]i m idazo[1 , 5-d][ 1 ,4]oxazepine-10-carboxamide, compound 68A;729) N-((1s,4s)-4-(3,3-Difluoropyrrolidin-1-yl)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10- carboxamide, compound 69A;730) N-((1 r,4r)-4-(2-Methoxyethoxy)cyclohexyl)-6,7-dihydroimidazo[1 ,5-d]pyrido[3,2-b][1 ,4]oxazepine-2- carboxamide, compound 70A;731 ) N-(( 1 r, 4r)-4-(3, 3-D if I uoropy rrol id i n-1 -yl)cyclohexyl)-5,6-di hyd robenzo[f]i mid azo[ 1 , 5-d][ 1 ,4]oxazepine-10- carboxamide, compound 71 A;732) N-((1r,4r)-4-(3,3-Difluoroazetidin-1-yl)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1,5-d][1 ,4]oxazepine-10- carboxamide, compound 72A;733) N-(4 , 4-Dif I uorocyclohexy l)-8-f luoro-5, 6-d i hyd robenzo[f]i mid azo[ 1 ,5-d][1 ,4]oxazepine-10-carboxamide, compound 73A;734) N-((1r,4r)-4-(((R)-1 ,1 ,1-Trifluoropropan-2-yl)amino)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5- d][1,4]oxazepine-10-carboxamide, compound 74A;735) N-((1s,4s)-4-((Tetrahydrofuran-2-yl)methoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1,4]oxazepine-10- carboxamide, compound 75A;736) N-((1 r,4r)-4-((Tetrahydrofuran-2-yl)methoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10- carboxamide, compound 76A;737) N-((1s,4s)-4-(3,3-Difluoropropoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10- carboxamide, compound 77A;738) N-((1 r,4r)-4-(3,3-Difluoropropoxy)cyclohexyl)-5,6-dihydrobenzo[flimidazo[1,5-d][1,4]oxazepine-10- carboxamide, compound 78A;739) N-((1s,4s)-4-(3-Fluoropropoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10-carboxamide, compound 79A;740) N-((1r,4r)-4-(3-Fluoropropoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1,5-d][1,4]oxazepine-10-carboxamide, compound 80A;741) N-(2-(2-Methoxyethoxy)pyrimidin-5-yl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10-carboxamide, compound 81A;742) N-((1 r,4r)-4-((2,2-Difluorocyclobutyl)amino)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1,5-d][1,4]oxazepine-10- carboxamide, compound 82A;743) N-((1r,4r)-4-((2-Fluoro-2-methylpropyl)amino)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1,5-d][1 ,4]oxazepine-10- carboxamide, compound 83A;744) N-(3,3-Difluorocyclobutyl)-5,6-dihydrobenzo[f]imidazo[1,5-d][1 ,4]oxazepine-10-carboxamide, compound 84A;745) N-((1 r,4r)-4-(3-(Methylsulfonyl)propoxy)cyclohexyl)-5,6-dihydrobenzo[f[imidazo[1 ,5-d][1,4]oxazepine-10- carboxamide, compound 85A;746) N-((1 s,4s)-4-(3-(Methylsulfonyl)propoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10-carboxamide, compound 86A;747) N-((1r,4r)-4-(((S)-1 ,1 , 1 -Trifluoropropan-2-yl)amino)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5- d][1 ,4]oxazepine-10-carboxamide, compound 87A;748) N-((1 r,4r)-4-((1 , 1 , 1 -T rif I uoro-2-methy I propan-2-y l)am i no)cyclohexy l)-5, 6-d i hyd robenzo[f]i midazo[ 1 ,5- d][1 ,4]oxazepine-10-carboxamide, compound 88A;749) N-((1 s,4s)-4-(3,3,3-Trifluoropropoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10- carboxamide, compound 89A;750) N-((1 r,4r)-4-(3,3,3-Trifluoropropoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10- carboxamide, compound 90A;751) 8, 11 -Difluoro-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10- carboxamide, compound 91A;752) (R)-N-(3,3-Difluorocyclopentyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10-carboxamide, compound 92A;753) (S)-N-(3,3-Dif I uorocyclopen tyl)-5, 6-d i hyd robenzo[f]i m id azo[ 1 ,5-d][1 ,4]oxazepine10-carboxamide, compound 93A;754) 8-Chloro-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10- carboxamide, compound 94A;755) 8,9-Difluoro-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10- carboxamide, compound 95A;756) N -(3, 3-D if I uorocyclohexy l)-5, 6-di hyd robenzo[f]im id azo[1 ,5-d][1 ,4]oxazepine-10-carboxamide, compound 96A;757) N-(2,3-Dihydro-[1 ,4]dioxino[2,3-b]pyridin-7-yl)-8-fluoro-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10- carboxamide, compound 97A;758) N -(4-Methy I-3, 4-d ihyd ro-2 H-py rido[3, 2-b][ 1 ,4]oxazi n-7-y l)-5, 6-d i hyd robenzo[f]i mid azo[ 1 , 5-d][ 1 ,4]oxazepine-10- carboxamide, compound 98A;759) N-(2-(3,3-Difluoroazetidin-1-yl)pyrimidin-5-yl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10- carboxamide, compound 99A;760) N-(2-((2,2,2-Trifluoroethyl)amino)pyrimidin-5-yl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10- carboxamide, compound 100A;761) N-(1 -Methyl-2,3-dihydro-1H-pyrido[2,3-b][1 ,4]oxazin-7-yl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10- carboxamide, compound 101 A;762) N -(2-(3-FI uoropropoxy)pyri mid i n-5-y l)-5, 6-di hydrobenzo[f]i m id azo[ 1 ,5-d][1 ,4]oxazepine-10-carboxamide, compound 102A;763) N-(2-(3, 3-D if I uoropropoxy) pyrim id i n-5-y l)-5, 6-d i hyd robenzo[fl i mid azo[ 1 ,5-d][1 ,4]oxazepine-10-carboxamide, compound 103A;764) N-(2-(3, 3, 3-T rif I uoropropoxy)py ri m id i n-5-y l)-5,6-d i hyd robenzo[f]i m id azo[ 1 ,5-d][1 ,4]oxazepine-10-carboxamide, compound 104A;765) N-((1 r,4r)-4-((3,3-Difluoroazetidin-1-yl)methyl)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10- carboxamide, compound 105A;766) N-((1 r,4r)-4-((2-(Methylsulfonyl)ethyl)amino)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10- carboxamide, compound 106A;767) N-((1 r,4r)-4-(3-(T rif I uoromethy l)azetidi n-1 -yl)cyclohexy l)-5, 6-d i hyd robenzo[f]im id azo[ 1 , 5-d][1 ,4]oxazepine-10- carboxamide, compound 107A;768) ( R)-N-(3, 3-Dif I uorocyclopen tyl)-8-f I uoro-5, 6-d i hyd robenzo[f]im id azo[1 , 5-d][ 1 ,4]oxazepine-10-carboxamide, compound 108A;769) N-(2-(2, 2, 2-Trifluoroethoxy)pyrimidin-5-yl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10-carboxamide, compound 109A;770) N-((1 r,4r)-4-((3,3,3-Trifluoropropyl)amino)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10- carboxamide, compound 1 10A;771 ) N-((1 s,4s)-4-((3, 3, 3-T rif I uoropropy I) am i no)cyclohexyl)-5, 6-di hyd robenzo[f]i mid azo[ 1 , 5-d][ 1 ,4]oxazepine-10- carboxamide, compound 111 A;772) (R)-8-Chloro-N-(3,3-difluorocyclopentyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10-carboxamide, compound 1 12A;773) N-((1 r,4r)-4-(3-(Difluoromethyl)azetidin-1-yl)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10- carboxamide, compound 1 13A;774) 8-Fluoro-N-((1 r,4r)-4-(2-hydroxypropan-2-yl)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10- carboxamide, compound 1 14A;775) 8-Fluoro-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine- 10-carboxamide, compound 115A;776) ( R)-N-(3, 3-Dif I uorocyclohexy l)-5, 6-d i hyd robenzo[f]i m id azo[ 1 ,5-d][1 ,4]oxazepine10-carboxamide, compound 1 16A;777) (S)-N-(3, 3-Dif I uorocyclohexy l)-5, 6-d i hyd robenzo[f]i m id azo[1 ,5-d][1 ,4]oxazepine10-carboxamide, compound 1 17A;778) N-((1s,4s)-4-((1-(Trifluoromethyl)cyclopropyl)methoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5- d][1 ,4]oxazepine-10-carboxamide, compound 1 18A;779) N-(4-(2, 2, 2-T rif I uoroethyl)cyclohexyl)-5 , 6-di hyd robenzo[f]i mid azo[ 1 , 5-d][ 1 ,4]oxazepine-10-carboxamide, compound 119A;780) N-((1 r,4r)-4-(3,3,3-Trifluoro-2,2-dimethylpropoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine- 10-carboxamide, compound 120A;781) N-((1s,4s)-4-(3,3,3-Trifluoro-2,2-dimethylpropoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5- d][1 ,4]oxazepine-10-carboxamide, compound 121 A;782) N-((1 r,4r)-4-(2,2,2-Trifluoroethoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10- carboxamide, compound 122A;783) N-((1 s,4s)-4-(2,2,2-Trifluoroethoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10- carboxamide, compound 123A;784) N-(2-(3-(Dif I uoromethy l)azetid i n- 1 -yl) py ri mid i n-5-y l)-5,6-di hyd robenzo[f]i mid azo[ 1 , 5-d][ 1 ,4]oxazepine-10- carboxamide, compound 124A;785) N-(4-Ethy Icyclohexy l)-5, 6-d i hyd robenzo[f]i mid azo[ 1 ,5-d][1 ,4]oxazepine-10-carboxamide, compound 125A;786) N-(4-( 1 -Hyd roxyethyl)cyclohexyl)-5,6-di hyd robenzo[f]im id azo[ 1 , 5-d][ 1 ,4]oxazepine-10-carboxamide, compound 126A;787) N-((1 r,4r)-4-(2-Methoxy-2-methylpropoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10- carboxamide, compound 127A;788) N-((1 s,4s)-4-(2-Methoxy-2-methylpropoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10- carboxamide, compound 128A;789) 8-Ch loro-N-(2, 3-d ihyd ro-[1 , 4]dioxi no[2, 3-b]py ridi n-7-yl)-5, 6-d ihyd robenzo[f]i mid azo[1 , 5-d][ 1 ,4]oxazepine-10- carboxamide, compound 129A;790) (R)-8-Fluoro-N-(tetrahydro-2H-pyran-3-yl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10-carboxamide, compound 130A;791 ) N-((1 r,4r)-4-((2-Hydroxy-2-(trifluoromethyl)butyl)amino)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5- d][1 ,4]oxazepine-10-carboxamide, compound 131 A;792) ( R)-N-( 1 , 1 -Dioxidotetrahyd rothiophen-3-y l)-8-fl uoro-5,6-di hyd robenzo[f]i mid azo[ 1 , 5-d][ 1 ,4]oxazepine-10- carboxamide, compound 132A;793) N-(4-( 1 , 1 , 1 -T rif I uoropropan-2-y I )cyclohexyl)-5,6-di hyd robenzo[f]i m id azo[ 1 ,5-d][1 ,4]oxazepine-10-carboxamide, compound 133A;794) 8-Chloro-N-(3,3-difluorocyclobutyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10-carboxamide, compound 134A;795) N-(3, 3-Dif I uorocyclobu ty l)-8-fl uoro-5, 6-d i hyd robenzo[f]i mid azo[ 1 ,5-d][1 ,4]oxazepine-10-carboxamide,compound 135A; ) N-(3-Fluoro-3-methylcyclobutyl)-5,6-dihydrobenzo[flimidazo[1 ,5-d][1,4]oxazepine-10-carboxamide, compound 136A; ) 8-Chloro-N-(4,4-difluorocyclohexyl)-5,6-dihydrobenzo[f]imidazo[1,5-d][1,4]oxazepine-10-carboxamide, compound 137A; ) 8-Fluoro-N-(3-fluoro-3-methylcyclobutyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10-carboxamide, compound 138A; ) N-(2,2-Difluorocyclobutyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10-carboxamide, compound 139A;) N-(2 , 2-Dif I uorocyclobu ty l)-8-fl uoro-5, 6-d i hyd robenzo[f]i mid azo[ 1 ,5-d][1 ,4]oxazepine-10-carboxamide, compound 140A; ) N-(3 , 3-Di methy Icyclobu tyl)-5, 6-d i hydrobenzo[f]i m idazo[ 1 , 5-d][ 1 ,4]oxazepine-10-carboxamide, compound 141A; ) N-((1r,4r)-4-((1-(Trifluoromethyl)cyclopropyl)methoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5- d][1 ,4]oxazepine-10-carboxamide, compound 142A; ) N-(3, 3-Di methy Icyclobu tyl)-8-fluoro-5, 6-d i hyd robenzo[f]i mid azo[ 1 ,5-d][1 ,4]oxazepine-10-carboxamide, compound 143A; ) N-(3-(Methoxymethyl)-2,3-dihydro-[1 ,4]dioxino[2,3-b]pyridin-7-yl)-5,6-dihydrobenzo[f]imidazo[1 ,5- d][1,4]oxazepine-10-carboxamide, compound 144A; ) N-(2-(Methoxymethyl)-2,3-dihydro-[1 ,4]dioxino[2,3-b]pyridin-7-yl)-5,6-dihydrobenzo[f]imidazo[1 ,5- d][1,4]oxazepine-10-carboxamide, compound 145A; ) N -(4-(M ethy Isulfony I )cyclohexyl)-5, 6-d i hyd robenzo[f]i mid azo[ 1 , 5-d][ 1 ,4]oxazepine-10-carboxamide, compound 146A; ) N-((1 r,4r)-4-((1s,3s)-3-Fluorocyclobutoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1,5-d][1 ,4]oxazepine-10- carboxamide, compound 147A; ) N-((1 r,4r)-4-((1 r,3r)-3-Fluorocyclobutoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1,4]oxazepine-10- carboxamide, compound 148A; ) N-((1 s,4s)-4-((1s,3s)-3-Fluorocyclobutoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10- carboxamide, compound 149A; ) N-((1s,4s)-4-((1 r,3r)-3-Fluorocyclobutoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10- carboxamide, compound 150A; ) N-(3-(T rif I uoromethyl)cyclohexy l)-5, 6-di hyd robenzo[f li m idazo[ 1 , 5-d][ 1 ,4]oxazepine-10-carboxamide, compound 151 A;812) N-((1r,4r)-4-(3,3-Difluorocyclobutoxy)cyclohexyl)-5,6-dihydrobenzo[flimidazo[1 ,5-d][1 ,4]oxazepine-10- carboxamide, compound 152A;813) N-((1s,4s)-4-(3,3-Difluorocyclobutoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10- carboxamide, compound 153A;814) N-(4,4-Difluorocyclohexyl)-8,9-difluoro-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10-carboxamide, compound 154A;815) 8-Fluoro-N-((1r,4r)-4-(2,2,2-trifluoroethoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10- carboxamide, compound 155A;816) 8-Fluoro-N-((1s,4s)-4-(2,2,2-trifluoroethoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10- carboxamide, compound 156A;817) 8-Chloro-N-((1r,4r)-4-(2,2,2-trifluoroethoxy)cyclohexyl)-5,6-dihydrobenzo[flimidazo[1 ,5-d][1 ,4]oxazepine-10- carboxamide, compound 157A;818) 8-Chloro-N-((1s,4s)-4-(2,2,2-trifluoroethoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10- carboxamide, compound 158A;819) 8-Fluoro-N-(spiro[3.3]heptan-2-yl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1,4]oxazepine-10-carboxamide, compound 159A;820) 8-Fluoro-N-(2-oxaspiro[3.3]heptan-6-yl)-5,6-dihydrobenzo[flimidazo[1 ,5-d][1 ,4]oxazepine-10-carboxamide, compound 160A;821) 8-Fluoro-N-(3-(trifluoromethyl)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1,5-d][1,4]oxazepine-10-carboxamide, compound 161 A;822) 8-Fluoro-N-(1-methylcyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10-carboxamide, compound 162A;823) 8-Chloro-N-(1-methylcyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10-carboxamide, compound 163A;824) 8-FI uoro-N -(4-(2, 2, 2-trifl uoroethy I )cyclohexyl)-5, 6-d i hydrobenzo[f]i mid azo[ 1 ,5-d][1 ,4]oxazepine-10- carboxamide, compound 164A;825) 8-C h loro-N-(4-(2,2, 2-trifl uoroethy l)cyclohexyl)-5, 6-d i hyd robenzo[f]i mid azo[ 1 , 5-d][ 1 ,4]oxazepine-10- carboxamide, compound 165A;826) N-((1 r,4r)-4-(3,3-Difluorocyclobutoxy)cyclohexyl)-8-fluoro-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1,4]oxazepine-10- carboxamide, compound 166A;827) N-((1s,4s)-4-(3,3-Difluorocyclobutoxy)cyclohexyl)-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,5-d][1 ,4]oxazepine- 10-carboxamide, compound 167A;828) 8-Fluoro-N-((1s,4s)-4-(3,3,3-trifluoro-2,2-dimethylpropoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5- d][1 ,4]oxazepine-10-carboxamide, compound 168A;829) 8-Fluoro-N-(3-methyl-1 ,1-dioxidotetrahydrothiophen-3-yl)-5,6-dihydrobenzo[f]imidazo[1,5-d][1 ,4]oxazepine-10- carboxamide, compound 169A;830) 8-Chloro-N-((1 r,4r)-4-(3,3,3-trifluoro-2,2-dimethylpropoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5- d][1,4]oxazepine-10-carboxamide, compound 170A;831) 8-Chloro-N-((1s,4s)-4-(3,3,3-trifluoro-2,2-dimethylpropoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5- d][1,4]oxazepine-10-carboxamide, compound 171 A;832) N-((1 r,4r)-4-(3,3-difluorocyclobutoxy)cyclohexyl)-8-chloro-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1,4]oxazepine-10- carboxamide, compound 172A;833) N-((1 s,4s)-4-(3,3-difluorocyclobutoxy)cyclohexyl)-8-chloro-5,6-dihydrobenzo[f]imidazo[1 ,5- d][1,4]269xazepane-10-carboxamide, compound 173A;834) 8-Fluoro-N-(trans-2-methylcyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10-carboxamide, compound 174A;835) 8-Fluoro-N-(cis-2-methylcyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 , 5-d][ 1 ,4]oxazepine-10-carboxamide, compound 175A;836) N-(trans-2-trans-6-Dimethylcyclohexyl)-8-fluoro-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10- carboxamide, compound 176A;837) N -(trans-2-cis-6-D i methy Icyclohexy l)-8-f I uoro-5,6-d ihyd robenzo[f]im id azo[1 , 5-d][ 1 ,4]oxazepine-10- carboxamide, compound 177 A;838) N-(cis-2-cis-6-Dimethylcyclohexyl)-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,5-d][1 ,4]oxazepine-10-carboxamide, compound 178A;839) N-((1 r,4r)-4-(2-Methoxyethoxy)cyclohexyl)-8,9-dimethyl-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1,4]oxazepine-10- carboxamide, compound 179A;840) N-(4,4-Difluorocyclohexyl)-8,9-dimethyl-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10-carboxamide, compound 180A;841 ) 8-C h loro-N-(3-(trif I uoromethy l)cyclohexy l)-5, 6-d i hyd robenzoffl i m idazo[1 , 5-d][ 1 ,4]oxazepine-10-carboxamide, compound 181 A;842) 8-C h loro-N-(2-methyl-4-(2, 2, 2-trif I uoroethyl) pheny l)-5,6-d i hyd robenzo[f]i mid azo[ 1 , 5-d][ 1 ,4]oxazepine-10- carboxamide, compound 182A;843) 8-Chloro-N-(2-methyl-4-(2,2,2-trifluoroethyl)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1,5-d][1 ,4]oxazepine-10- carboxamide, compound 183A;844) 8-Chloro-N-(cis-2-methyl-cis-4-(2,2,2-trifluoroethyl)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5- d][1,4]oxazepine-10-carboxamide, compound 184A;845) 8-FI uoro-N-(2-methyl-4-(2, 2, 2-trif I uoroethyl)cyclohexyl)-5, 6-di hydrobenzo[f]i m id azo[1 , 5-d][ 1 ,4]oxazepine-10- carboxamide, compound 185A;846) 8-Fluoro-N-(cis-2-methyl-cis-4-(2,2,2-trifluoroethyl)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1,5- d][1,4]oxazepine-10-carboxamide, compound 186A;847) 8,9-Difluoro-N-(( 1 r,4r)-4-(2,2,2-trifl uoroethoxy)cyclohexy l)-5, 6-d i hydrobenzo[f]i m idazo[ 1 ,5-d][1 ,4]oxazepine- 10-carboxamide, compound 187A;848) 8,9-Difluoro-N-((1s,4s)-4-(2,2,2-trifluoroethoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1,5-d][1,4]oxazepine- 10-carboxamide, compound 188A;849) 8, 9-D i methy l-N-(4-(2, 2, 2-trif I uoroethoxy)cyclohexyl)-5, 6-di hydrobenzo[f]i mid azo[ 1 , 5-d][ 1 ,4]oxazepine-10- carboxamide, compound 189A;850) 8-Ch loro-N -(4, 4-d if I uorocyclohexy l)-9-methyl-5, 6-d i hyd robenzo[f]i mid azo[ 1 ,5-d][1 ,4]oxazepine-10- carboxamide, compound 190A; or851) 8-Chloro-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-9-methyl-5,6-dihydrobenzo[f]imidazo[1 ,5- d][1 ,4]oxazepine-10-carboxamide, compound 191 A; or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[0148] In most preferred embodiments, the CD38 inhibitor is :• (R)-N-(Tetrahydro-2H-pyran-3-yl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10-carboxamide, compound 1A,• (R)-N-(1 , 1 -D ioxidotetrahydrothiophen-3-y l)-5,6-di hydrobenzo[f]i m idazo[1 , 5-d][ 1 ,4]oxazepine-10- carboxamide, compound 2A,• N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 , 5-d][ 1 ,4]oxazepine-10- carboxamide, compound 3A,• N-(1-(Methylsulfonyl)piperidin-4-yl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10-carboxamide 4A, compound 4A, or• (R)-N-(1,1-Dioxidotetrahydrothiophen-3-yl)-4-oxo-4,5-dihydroimidazo[1 ,5-a]quinoxaline-8-carboxamide, compound 12A, or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.N-(4-aminocyclohexyl)pyrimidine-4-carboxamide of formula (X), includingExamples 1 , 2, 3, 10, and 21 of WO 2023 / 084206

[0149] In embodiments, the CD38 inhibitor is a N-(4-aminocyclohexyl)pyrimidine-4-carboxamide as described in WO 2023 / 084206, incorporated herein by reference.

[0150] In preferred embodiments, the CD38 inhibitor is of formula (X):wherein:Het is a 5-membered heteroaryl group comprising two heteroatoms independently selected from N and S, wherein the 5-membered heteroaryl group is substituted with one or two substituents independently selected from C1-C3alkyl, C1-C3fluoroalkyl and C1-C3hydroxyalkyl;X1is CH or N, and X2is CH or N, wherein at least one of X1and X2is N;L is a bond, CH2, CHMe, CMe2 or CO;R1is C1-C4 alkyl, C3-C6cycloalkyl, hydroxyl, -O-(C1-C4 alkyl), or -O-( C3-C6cycloalkyl), each of which may optionally be fluoro-substituted;R2is hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, -CHO, -CO-(C1-C3alkyl) or -CO-(C1-C3fluoroalkyl);R3is hydrogen or methyl; orR2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl or piperidin-1-yl group, each of which may optionally be fluoro-substituted, or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[0151] Preferably, Het is a 5-membered heteroaryl group comprising two N heteroatoms, preferably

[0152] Preferably, X1is N.

[0153] Preferably, X2is N.

[0154] Preferably, R1is C1-C4alkyl or C3-C6cycloalkyl, preferably methyl, or cyclopropyl.

[0155] Preferably, L is a bond.

[0156] Preferably, R2is C1-C4 fluoroalkyl, preferably -CH2-CF3, -CH2-CHF2, or -CfCHa -CF3

[0157] Preferably, R3is hydrogen.

[0158] Preferably, R2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin- 1-yl or piperidin-1-yl group, each of which may optionally be fluoro-substituted. More preferably, R2and R3, together with the nitrogen to which they are attached, form

[0159] In embodiments, the CD38 inhibitor is:

[0160] 2-(1H-midazol-1 -yI)-6-methyl-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)pyrimidine-4-carboxamide;852) N-((1 r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-2-(1H-midazol-1 -yI)-6-methyl-pyrimidine-4-carboxamide;853) 6-cyclopropyl-N-((1 r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-2-(1 H-imidazol-1 -yl)pyrimidine-4- carboxamide;854) 6-methyl-2-(1 -methyl-1H-imidazol-5-yl)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)pyrimidine-4- carboxamide;855) 6-methyl-2-(thiazol-5-yl)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)pyrimidine-4-carboxamide;856) 6-ethyl-2-(1 H-imidazol-1-yl)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)pyrimidine-4-carboxamide;857) 2-(1H-midazol-1 -yI)-6-methyl-N-((1 r,4r)-4-(methyl(2, 2, 2-trifluoroethyl)amino)cyclohexyl)pyrimidine-4- carboxamide;858) N-((1r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-6-methyl-2-(thiazol-5-yl)pyrimidine-4-carboxamide;859) N-((1r,4r)-4-((2-fluoroethyl)amino)cyclohexyl)-2-(1 H-imidazol-1-yl)-6-methyl-pyrimidine-4-carboxamide;860) N-((1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-2-(1H-midazol-1 -yI)-6-methyl-pyrimidine-4-carboxamide;861) N-((1s,4s)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-2-(1 H-imidazol-1-yl)-6-methyl-pyrimidine-4-carboxamide;862) N-((1s,4r)-4-((S)-3-fluoropyrrolidin-1 -yl)cyclohexyl)-2-(1H-midazol-1 -yI)-6-methyl-pyrimidine-4-carboxamide;863) N-((1 r,4r)-4-((R)-3-fluoropyrrolidin-1-yl)cyclohexyl)-2-(1H-midazol-1 -yI)-6-methyl-pyrimidine-4-carboxamide;864) 6-methyl-2-(1 H-pyrazol-4-yl)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)pyrimidine-4-carboxamide;865) N-((1 r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-6-methyl-2-(1 H-pyrazol-4-yl)pyrimidine-4-carboxamide;866) 4-cyclopropyl-N-((1 r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-6-(1 H-imidazol-1 -yl)picolinamide;867) N-((1 r,4r)-4-(ethylamino)cyclohexyl)-2-(1H-midazol-1 -yI)-6-methyl-pyrimidine-4-carboxamide;868) 4-cyclopropyl-6-(1H-midazol-1 -yI)-N-((1r,4r)-4-((2, 2, 2-trifluoroethyl)amino)cyclohexyl)picolinamide;869) 2-(1H-midazol-1 -yI)-6-methyl-N-((1 r,4r)-4-((1 ,1 ,1-trifluoro-2-methylpropan-2-yl)amino)cyclohexyl)pyrimidine- 4-carboxamide;870) 2-(1 H-i m idazol- 1 -yl)-6-methy l-N -(( 1 S,4r)-4-(((S)-1 ,1,1 -trifl uoropropan-2-yl) am i no)cyclohexyl) pyri mid i ne-4- carboxamide;871 ) 2-(1 H-i m idazol- 1 -yl)-6-methy l-N -(( 1 R,4r)-4-(((R)-1 ,1 ,1 -trif I uoropropan-2-y I) am i no)cyclohexy I) py ri mid ine-4- carboxamide;872) 6-methyl-2-(5-methyl-1H-imidazol-1 -yl)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)pyrimidine-4- carboxamide;873) 2-(1H-midazol-1 -yI)-6-methyl-N-((1 r,4r)-4-(((2, 2, 2-trifluoroethyl)amino)methyl)cyclohexyl)pyrimidine-4- carboxamide;874) 2-(1H-midazol-1 -yI)-6-methyl-N-((1 r,4r)-4-((2, 2, 2-trifluoroethyl)carbamoyl)cyclohexyl)pyrimidine-4- carboxamide;875) N-((1 r,4r)-4-aminocyclohexyl)-2-(1H-midazol-1 -yI)-6-methyl-pyrimidine-4-carboxamide; or876) 2-(1H-midazol-1 -yI)-6-methyl-N-((1 r,4r)-4-((2, 2, 2-trifluoroethyl-1 ,1-d2)amino)cyclohexyl)pyrimidine-4- carboxamide; or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[0161] In most preferred embodiments, the CD38 inhibitor is:• 2-(1H-midazol-1 -yI)-6-methyl-N-((1 r,4r)-4-((2, 2, 2- trifluoroethyl)amino)cyclohexyl)pyrimidine-4-carboxamide (corresponding to Example 1 of WO 2023 / 084206),• N-((1 r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-2-(1 H- imidazol-1-yl)-6-methyl-pyrimidine-4-carboxamide (corresponding to Example 2 of WO 2023 / 084206),• 6-cyclopropyl-N-((1 r,4r)-4-((2,2- difluoroethyl)amino)cyclohexyl)-2-(1 H-imidazol-1 -yl)pyrimidine-4- carboxamide (corresponding to Example 3 of WO 2023 / 084206),• N-((1 r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-2-(1 H- imidazol-1-yl)-6-methyl-pyrimidine-4-carboxamide (corresponding to Example 10 of WO 2023 / 084206),• 2-(1H-midazol-1 -yI)-6-methy l-N-(( 1 r, 4r)-4-(( 1 , 1 , 1 -trifl uoro-2- methylpropan-2- yl)amino)cyclohexyl)pyrimidine-4-carboxamide (corresponding to Example 21 of WO 2023 / 084206), which are of formula:or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof. 1 ,3-thiazoles and 1 ,2,4-thiadiazoles of formula (XI), including Examples 1 , 2, 4, and 9 of WO 2024 / 236315

[0162] In embodiments, the CD38 inhibitor is a 1 ,3-thiazole or 1 ,2,4-thiadiazole as described in WO 2024 / 236315, incorporated herein by reference.

[0163] In preferred embodiments, the CD38 inhibitor is of formula (XI):whereinHet is a 5-membered heteroaryl group comprising two heteroatoms independently selected from N and S, wherein the 5-membered heteroaryl group is optionally substituted with one or two substituents independently selected from C1-C3alkyl, C1-C3fluoroalkyl, C1-C3hydroxyalkyl, and 3- to 6-membered saturated heterocyclyl; one of X1and X2is S and the other of X1and X2is CR4or N, wherein R4is hydrogen, halo, CH3, CF3, or cyclopropyl;Cy is a C3-C9cycloalkyl, 3- to 9-membered saturated heterocyclyl, phenyl, or 5- or 6-membered heteroaryl group, each of which is optionally substituted with one, two or three substituents independently selected from halo and C1-C3alkyl;L is a bond, CH2, CHMe, CMe2 or CO;R1is -NR2R3, halo or C1-C4 fluoroalkyl;R2is hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, -CHO, -CO-(C1-C3alkyl) or -CO-(C1-C3fluoroalkyl);R3is hydrogen or methyl; orR2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin-1 -yl, piperidin-1-yl or piperazin-1 -yl group, each of which is optionally fluoro-substituted and / or optionally substituted with one or two substituents independently selected from C1-C4 fluoroalkyl. or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[0164] Preferably, Het is a 5-membered heteroaryl group comprising two N heteroatoms (preferably), substituted with C1-C3alkyl (preferably methyl). Preferably, X2is S and X1is CR4, wherein R4is hydrogen.Alternatively, X2is S and X1is N. Alternatively, X2is CR4, wherein R4is hydrogen, and X1is S. Preferably, Cy is a C3- C9cycloalkyl (preferably cyclohexyl). Preferably, L is a bond. Preferably, R1is -NR2R3. Preferably, R2is C1-C4fluoroalkyl (preferably -CH2CF3). Preferably, R3is hydrogen. Alternatively, R2and R3, together with the nitrogen to which they are attached, form a fluoro-substituted pyrrolidin-1 -yl group (preferably

[0165] In embodiments, the CD38 inhibitor is:

[0166] 4-(1 -methyl-1H-imidazol-5-yl)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)thiazole-2-carboxamide, Example 1;878) 3-(1 -methyl-1H-imidazol-5-yl)-N-((1 r,4r)-4-((2, 2, 2-trifluoroethyl)amino)cyclohexyl)-1 , 2, 4-thiadiazole-5- carboxamide, Example 2;879) 4-(1-(2-fluoroethyl)-1 H-imidazol-5-yl)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)thiazole-2- carboxamide, Example 3;880) 2-(1 -methyl-1H-imidazol-5-yl)-N-((1 r,4r)-4-((2, 2, 2-trifluoroethyl)amino)cyclohexyl)thiazole-4-carboxamide Example 4;881) 4-(1-(2,2-difluoroethyl)-1 H-imidazol-5-yl)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)thiazole-2- carboxamide, Example 5;882) 4-(1 -methyl-1H-imidazol-5-yl)-N-(2-(2,2,2-trifluoroethyl)-2-azaspiro[3,5]nonan-7-yl)thiazole-2-carboxamide, Example 6;883) 4-(1 -methyl-1H-imidazol-5-yl)-N-(6-((2, 2, 2-trifluoroethyl)amino)spiro[3,3]heptan-2-yl)thiazole-2-carboxamide, Example 7;884) N-((1S,4r)-4-((S)-3-fluoropyrrolidin-1 -yl)cyclohexyl)-4-(1 -methyl-1H-imidazol-5-yl)thiazole-2-carboxamide, Example 8;885) N-((1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-4-(1 -methyl-1H-imidazol-5-yl)thiazole-2-carboxamide, Example 9;886) N-((1r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-4-(1 -methyl-1H-imidazol-5-yl)thiazole-2-carboxamide, Example 10;887) N-((1r,4r)-4-((2,2-difluoropropyl)amino)cyclohexyl)-4-(1 -methyl-1H-imidazol-5-yl)thiazole-2-carboxamide, Example 11 ;888) 4-(1-(oxetan-3-yl)-1 H-imidazol-5-yl)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)thiazole-2- carboxamide, Example 12;889) N-(4-((3,3-difluoropyrrolidin-1-yl)methyl)phenyl)-4-(1 H-imidazol-1-yl)thiazole-2-carboxamide, Example 13;890) N-(4-((3,3-difluoropyrrolidin-1-yl)methyl)phenyl)-4-(1-methyl-1 H-imidazol-5-yl)thiazole-2-carboxamide, Example 14;891) 4-(1H-midazol-1 -yI)-N-(6-(4-(2,2,2-trifluoroethyl)piperazin-1 -yl)pyridin-3-yl)thiazole-2-carboxamide, Example 15;892) N-(4-chloro-3-fluorophenyl)-2-(1H-midazol-1 -yI)thiazole-4-carboxamide, Example 16;893) 3-(1 -methyl-1H-imidazol-5-yl)-N-((1s,4s)-4-methyl-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)-1 ,2,4- thiadiazole-5-carboxamide, Example 16;894) 3-(1 -methyl-1H-imidazol-5-yl)-N-((1 r,4r)-4-methyl-4-((2, 2, 2-trifluoroethyl)amino)cyclohexyl)-1 , 2, 4-thiadiazole- 5-carboxamide, Example 17;895) 3-(5-methyl-1H-imidazol-1 -yl)-N-((1 r,4r)-4-((2, 2, 2-trifluoroethyl)amino)cyclohexyl)-1 , 2, 4-thiadiazole-5- carboxamide, Example 18;896) 3-(1-methyl-iH-imidazol-5-yl)-N-((1 r,4r)-4-methyl-4-((2, 2, 2-trifluoroethyl)amino)cyclohexyl)-i, 2, 4-thiadiazole- 5-carboxamide 1.1 eq. formate, Example 19;897) 4-(1 -methyl-1H-imidazol-5-yl)-N-((1 r,4r)-4-((1,1 ,1-trifluoro-2-methylpropan-2-yl)amino)cyclohexyl)thiazole-2- carboxamide, Example 20;898) 4-(1 -methyl-1H-imidazol-5-yl)-N-((1s,4s)-4-((1,1 ,1-trifluoro-2-methylpropan-2-yl)amino)cyclohexyl)thiazole-2- carboxamide, Example 211 ;899) N-((1r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-3-(1-methyl-1H-imidazol-5-yl)-1 ,2,4-thiadiazole-5- carboxamide, Example 22;900) N-((1 r,4r)-4-(3,3-difluoropyrrolidin-1 -yl)cyclohexyl)-3-(1 -methyl-1H-imidazol-5-yl)-1 ,2,4-thiadiazole-5- carboxamide, Example 23; or901) N-((1r,4r)-4-(3,3-difluoroazetidin-1-yl)cyclohexyl)-4-(1 -methyl-1H-imidazol-5-yl)thiazole-2-carboxamide Example 24; or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[0167] In embodiments, the CD38 inhibitor is not:(i) N-(2-bromophenyl)-4-(3-(difluoromethyl)-1 -methyl-1H-pyrazol-4-yl)thiazole- 2-carboxamide;(ii) N-(3-bromophenyl)-4-(3-(difluoromethyl)-1 -methyl-1H-pyrazol-4-yl)thiazole- 2-carboxamide;(iii) 4-(3-(difl uoromethyl)-1 -methyl-1H-pyrazol-4-yl)-N-(3- (trifluoromethyl)phenyl)thiazole-2-carboxamide; or(iv) 4-(3-(difl uoromethyl)-1 -methyl-1H-pyrazol-4-yl)-N-(2- (trifluoromethyl)phenyl)thiazole-2-carboxamide.(i) 2-(1 H-imidazol-5-yl)-N-(3-(trifluoromethyl)cyclohexyl)thiazole-4-carboxamide;(ii) 2-(1 H-imidazol-5-yl)-N-(4-(trifluoromethyl)cyclohexyl)thiazole-4-carboxamide;(iii) 2-(1 H-imidazol-5-yl)-N-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide; (iv) 2-(1 H-imidazol-2-yl)-N-(3- (trifluoromethyl)phenyl)thiazole-4-carboxamide;(v) 2-(1 H-imidazol-5-yl)-N-((3S,4S)-3-(trifluoromethyl)tetrahydro-2H-pyran-4- yl)thiazole-4-carboxamide; vi) 2-(1 H-imidazol-2-yl)-N-((3S,4S)-3-(trifluoromethyl)tetrahydro-2H-pyran-4- yl)thiazole-4-carboxamide;(vii) N-(1- (difluoromethyl)cyclohexyl)-2-(1 H-imidazol-5-yl)thiazole-4-carboxamide;(viii) N-(3,3-difluorocyclohexyl)-2-(1 H-imidazol-5-yl)thiazole-4-carboxamide;(ix) 2-(1H-midazol-1 -yI)-N-(2-(piperazin-1 -yl)phenyl)thiazole-4-carboxamide or the hydrochloride salt thereof;(x) 2-(1H-midazol-1 -yI)-N-(4-(piperazin-1 -yl)pyridin-3-yl)thiazole-4-carboxamide; (xi) N-(4-acetamidocyclohexyl)-2- (1 H-imidazol-5-yl)thiazole-4-carboxamide;(xii) N-(4-(dimethylamino)cyclohexyl)-2-(1 H-imidazol-5-yl)thiazole-4-carboxamide;(xiii) 2-(1 H-imidazol-5-yl)-N-(6-(pyrrolidin-1 -yl)pyridin-3-yl)thiazole-4- carboxamide;(xiv) 2-(1 H-imidazol-5-yl)-N-(4-(pyrrolidin-1 -yl)pyrimidin-5-yl)thiazole-4- carboxamide;(xv) 2-(1 H-imidazol-5-yl)-N-(3-(pyrrolidin-1 -yl)tetrahydro-2H-pyran-4-yl)thiazole- 4-carboxamide;(xvi) 2-(1 H-imidazol-5-yl)-N-(5-(pyrrolidin-1 -yl)pyridin-2-yl)thiazole-4- carboxamide;(xvii) N-((1 R,2R)-2-fluorocyclohexyl)-2-(1 H-imidazol-5-yl)thiazole-4-carboxamide;(xviii) N-((1S,2R)-2-fluorocyclohexyl)-2-(1 H-imidazol-5-yl)thiazole-4-carboxamide;(xix) N-(1-(2,2-difluoroethyl)piperidin-4-yl)-2-(1 H-imidazol-5-yl)thiazole-4- carboxamide;(xx) 2-(1 H-imidazol-5-yl)-N-(1-(methylcarbamoyl)cyclohexyl)thiazole-4- carboxamide; or(xxi) N-(3-(dimethylcarbamoyl)cyclohexyl)-2-(1 H-imidazol-5-yl)thiazole-4- carboxamide.(i) 2-(3-(difluoromethyl)-1-methyl-1 H-pyrazol-4-yl)-N-(4- (trifluoromethyl)phenyl)thiazole-4-carboxamide;(ii) 2-(3-(difluoromethyl)-1 -methyl-1H-pyrazol-4-yl)-N-(3- (trifluoromethyl)phenyl)thiazole-4-carboxamide; (iii) 2-(3- (difluoromethyl)-1-methyl-1 H-pyrazol-4-yl)-N-(2- (trifluoromethyl)phenyl)thiazole-4-carboxamide;(iv) 2-(1 H-imidazol-5-yl)-N-(3-(trifluoromethyl)cyclohexyl)thiazole-4-carboxamide;(v) 2-(1 H-imidazol-5-yl)-N-(4-(trifluoromethyl)cyclohexyl)thiazole-4-carboxamide; (vi) 2-(1 H-imidazol-5-yl)-N-(3- (trifluoromethyl)phenyl)thiazole-4-carboxamide;(vii) 2-(1 H-pyrazol-4-yl)-N-(4-(trifluoromethyl)phenyl)thiazole-4-carboxamide;(viii) 2-(1 H-imidazol-2-yl)-N-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide;(ix) 2-(1 H-imidazol-5-yl)-N-((3S,4S)-3-(trifluoromethyl)tetrahydro-2H-pyran-4- yl)thiazole-4-carboxamide;(x) 2-(1 H-pyrazol-4-yl)-N-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide;(xi) 2-(1 H-imidazol-2-yl)-N-((3S,4S)-3-(trifluoromethyl)tetrahydro-2H-pyran-4- yl)thiazole-4-carboxamide;(xii) 2-(1 -methyl-1H-pyrazol-4-yl)-N-(3-(trifluoromethyl)phenyl)thiazole-4- carboxamide;(xiii) 2-(1 -methyl-1H-pyrazol-4-yl)-N-(4-(trifluoromethyl)cyclohexyl)thiazole-4- carboxamide;(xiv) 2-(1 -methyl-1 H -py razol-4-y l)-N -(3-(trif I uoromethy l)cyclohexy I) th i azole-4- carboxamide;(xv) N-(1-(difluoromethyl)cyclohexyl)-2-(1 H-imidazol-5-yl)thiazole-4-carboxamide;(xvi) 2-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)-N-(3- (trifluoromethyl)phenyl)thiazole-4-carboxamide;(xvii) 2-(1 -methyl-1H-pyrazol-4-yl)-N-(2-((2, 2, 2- trifluoroethyl)amino)phenyl)thiazole-4-carboxamide;(xviii) N-(4-chlorophenyl)-2-(3-(d if I uoromethy I)- 1 -methyl-1H-pyrazol-4-y I) th i azole-4- carboxamide;(xix) N-(3-chlorophenyl)-2-(3-(difluoromethyl)-1 -methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide;(xx) N-(2-ch loropheny l)-2-(3-(dif I uoromethy l)-1 -methyl-1 H -py razol-4-yl) thi azole-4- carboxamide;(xxi) 2-(3-(difluoromethyl)-1 -methyl-1H-pyrazol-4-yl)-N-(2-fluorophenyl)thiazole-4- carboxamide;(xxii) N-(( 1 R,2R)-2-fluorocyclohexyl)-2-( 1 H-imidazol-5-yl)thiazole-4-carboxamide;(xxiii) N-((1 S,2R)-2-fluorocyclohexyl)-2-(1 H-imidazol-5-yl)thiazole-4-carboxamide;(xxiv) N-(3-chlorophenyl)-2-(1 H-pyrazol-4-yl)thiazole-4-carboxamide;(xxv) N-(3-fluorocyclohexyl)-2-(1 -methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;(xxvi) N-((1 R,2R)-2-fluorocyclohexyl)-2-( 1 -methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide;(xxvii) N -(4-f I uoropheny l)-2-(3-methyl-5-(trifl uoromethyl)-1H-pyrazol-1 -yl)th i azole-4- carboxamide;(xxviii)N-(3,5-dichlorophenyl)-2-(3-(difluoromethyl)-1 -methyl-1H-pyrazol-4- yl)thiazole-4-carboxamide;(xxix) N -(3 , 4-dichloropheny l)-2-(3-(d if I uoromethy l)-1 -methyl-1H-pyrazol-4- yl)thiazole-4-carboxamide;(xxx) 2-(3-(difluoromethyl)-1 -methyl-1H-pyrazol-4-yl)-N-(3, 4, 5- trifluorophenyl)thiazole-4-carboxamide;(xxxi) N-(3,3-difluorocyclohexyl)-2-(1 H-imidazol-5-yl)thiazole-4-carboxamide;(xxxii) N-(3,3-difluorocyclohexyl)-2-(1 -methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide;(xxxiii)N-(4,4-difluorocyclohexyl)-2-(1 -methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide;(xxxiv)N-(5-chloro-2-fluorophenyl)-2-(1 -methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide;(xxxv) N-(5-bromo-2-chlorophenyl)-2-(1 -methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide;(xxxvi) N-(4-bromo-2-chloro-6-methylphenyl)-2-(1 -methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide;(xxxvii) N-(2-chloro-4-methylphenyl)-2-(1 -methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide;(xxxviii) N-(4-fluoro-4-methylcyclohexyl)-2-(1 -methyl-1H-pyrazol-4-yl)thiazole- 4-carboxamide;(xxxix) N-(2,5-dichlorophenyl)-2-(1 -methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;(xl) N-(6-bromo-2-chloro-pyridin-3-yl)-2-(1 -methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide;(xli) N-(1-(2,2-difluoroethyl)piperidin-4-yl)-2-(1 H-imidazol-5-yl)thiazole-4- carboxamide;(xlii) 2-(1 -methyl-1H-pyrazol-4-yl)-N-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)thiazole- 4-carboxamide; or(xliii) 2-(1 -methyl-1H-pyrazol-4-yl)-N-(1-(2, 2, 2-trifluoroethyl)piperidin-4-yl)thiazole- 4-carboxamide.(i) 2-(1H-midazol-1 -yI)-N-(2-(piperazin-1 -yl)phenyl)thiazole-4-carboxamide or the hydrochloride salt thereof;(ii) 2-(1 H-imidazol-1-yl)-N-(4-(piperazin-1 -yl)pyridin-3-yl)thiazole-4-carboxamide;(iii) N-(3,3-difluorocyclohexyl)-2-(1 H-imidazol-5-yl)thiazole-4-carboxamide;(iv) N-(3,3-dichlorocyclobutyl)-2-(1 H-imidazol-5-yl)thiazole-4-carboxamide;(v) N-(3,3-difluoro-1-methylcyclobutyl)-2-(1 H-imidazol-5-yl)thiazole-4- carboxamide;(vi) N-(6,6-difluorobicyclo[3.i.o]hexan-3-yl)-2-(1 H-imidazol-5-yl)thiazole-4- carboxamide;(vii) N-(i,i-difluorospiro[2.5]octan-6-yl)-2-(1 H-imidazol-5-yl)thiazole-4- carboxamide;(viii) N-(3-(dimethylamino)-2,2-dimethylcyclobutyl)-2-(1 H-imidazol-5-yl)thiazole-4- carboxamide;(ix) 2-(1 H-imid azol-5-yl)-N-(( 1 R,2R)-2-(trifl uoromethyl)cyclopropyl)thi azole-4- carboxamide;(x) 2-(1 H-imidazol-5-yl)-N-(3-(trifluoromethyl)cyclobutyl)thiazole-4-carboxamide;(xi) 2-(1 H-imidazol-5-yl)-N-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide;(xii) 2-(1 H-imidazol-5-yl)-N-(3-(trifluoromethyl)cyclohexyl)thiazole-4-carboxamide;(xiii) 2-(1 H-imidazol-5-yl)-N-(4-(trifluoromethyl)cyclohexyl)thiazole-4-carboxamide;(xiv) N-(1-(2,2-difluoroethyl)pyrrolidin-3-yl)-2-(1 H-imidazol-5-yl)thiazole-4- carboxamide;(xv) N-(1-(2,2-difluoroethyl)piperidin-4-yl)-2-(1 H-imidazol-5-yl)thiazole-4- carboxamide;(xvi) 2-(1 H-imidazol-5-yl)-N-((3S,4S)-3-(trifluoromethyl)tetrahydro-2H-pyran-4- yl)thiazole-4-carboxamide;(xvii) 2-(1 H-imidazol-5-yl)-N-(1-(trifluoromethyl)cyclopropyl)thiazole-4- carboxamide;(xviii) N-(( 1 R,2R)-2-fl uorocyclohexy l)-2-( 1 H-imidazol-5-yl)thiazole-4-carboxamide;(xix) N-((3S,4S)-4-fluorotetrahydrofuran-3-yl)-2-( 1 H-imidazol-5-yl)thiazole-4- carboxamide;(xx) N-((1S,2R)-2-fluorocyclohexyl)-2-(1 H-imidazol-5-yl)thiazole-4-carboxamide;(xxi) 2-(1 H-imidazol-5-yl)-N-(5-(pyrrolidin-1 -yl)pyridin-2-yl)thiazole-4- carboxamide;(xxii) 2-(1 H-imidazol-5-yl)-N-(6-(pyrrolidin-1 -yl)pyridin-3-yl)thiazole-4- carboxamide;(xxiii) N-(1-(difluoromethyl)cyclopentyl)-2-(1 H-imidazol-5-yl)thiazole-4-carboxamide;(xxiv) 2-(1 H-imidazol-5-yl)-N-(4-(pyrrolidin-1 -yl)pyrimidin-5-yl)thiazole-4- carboxamide;(xxv) N-(1-(difluoromethyl)cyclohexyl)-2-(1 H-imidazol-5-yl)thiazole-4-carboxamide;(xxvi) 2-(1 H-imidazol-5-yl)-N-(3-(piperidin-1 -yl)cyclobutyl)thiazole-4-carboxamide;(xxvii) N-(3-(dimethylamino)cyclobutyl)-2-(1 H-imidazol-5-yl)thiazole-4-carboxamide;(xxviii)N-(1-(fluoromethyl)cyclobutyl)-2-(1 H-imidazol-5-yl)thiazole-4-carboxamide;(xxix) N-((1 R, 2 R)-2-(dimethylam i no)cyclopentyl)-2-( 1 H-imidazol-5-yl)thiazole-4- carboxamide;(xxx) N-(4-acetamidocyclohexyl)-2-(1 H-imidazol-5-yl)thiazole-4-carboxamide;(xxxi) N-(4-(dimethylamino)cyclohexyl)-2-(1 H-imidazol-5-yl)thiazole-4-carboxamide;(xxxii) 2-(1 H-imidazol-5-yl)-N-(3-(pyrrolidin-1 -yl)tetrahydro-2H-pyran-4-yl)thiazole- 4-carboxamide;(xxxiii)N-(3-(dimethylamino)spiro[3.3]heptan-1 -yl)-2-(1 H-imidazol-5-yl)thiazole-4- carboxamide;(xxxiv)N-(5-(azetidin-1 -yl)-i,3-dimethyl-1H-pyrazol-4-yl)-2-(1 H-imidazol-5- yl)thiazole-4-carboxamide;(xxxv) 2-(1 H-imidazol-2-yl)-N-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide;(xxxvi) N-((1 R,2R)-2-(fluoromethyl)cyclopropyl)-2-(1 H-imidazol-2-yl)thiazole-4- carboxamide;(xxxvii) N-((3S,4S)-4-fluorotetrahydrofuran-3-yl)-2-(1 H-imidazol-2-yl)thiazole- 4-carboxamide;(xxxviii) 2-(1 H-imidazol-2-yl)-N-((3S,4S)-3-(trifluoromethyl)tetrahydro-2H- pyran-4-yl)thiazole-4-carboxamide;(xxxix) N-(3,3-dichlorocyclobutyl)-2-( 1 H-imidazol-2-yl)thiazole-4-carboxamide; or(i) N-(3,3-difluorocyclohexyl)-2-(1 H-imidazol-5-yl)thiazole-4-carboxamide;(ii) 2-(1 H-imidazol-5-yl)-N-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide;(iii) 2-(1 H-imidazol-5-yl)-N-(3-(trifluoromethyl)cyclohexyl)thiazole-4-carboxamide;(iv) 2-(1 H-imidazol-5-yl)-N-(4-(trifluoromethyl)cyclohexyl)thiazole-4-carboxamide; (v) N-(1-(2,2-difluoroethyl)piperidin- 4-yl)-2-(1 H-imid azol-5-y l)thiazole-4- carboxamide;(vi) 2-(1 H-imidazol-5-yl)-N-((3S,4S)-3-(trifluoromethyl)tetrahydro-2H-pyran-4- yl)thiazole-4-carboxamide;(vii) N-((1 R,2R)-2-fluorocyclohexyl)-2-(1 H-imidazol-5-yl)thiazole-4-carboxamide; (viii) N-((1S,2R)-2-fluorocyclohexyl)- 2-(1 H-imidazol-5-yl)thiazole-4-carboxamide;(ix) N-(1-(difluoromethyl)cyclohexyl)-2-(1 H-imidazol-5-yl)thiazole-4-carboxamide;(x) 2-(1 H-imidazol-2-yl)-N-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide; or(xi) 2-(1 H-imidazol-2-yl)-N-((3S,4S)-3-(trifluoromethyl)tetrahydro-2H-pyran-4- yl)thiazole-4-carboxamide.(i) N-(3-(d i methyl amino)-2, 2-di methylcyclobuty l)-2-( 1 H-imid azol-5-yl)th i azole-4- carboxamide;(ii) N-(3,3-difluoro-1-methylcyclobutyl)-2-(1 H-imidazol-5-yl)thiazole-4- carboxamide;(iii) N-(3-(dimethylamino)cyclobutyl)-2-(1 H-imidazol-5-yl)thiazole-4-carboxamide;(iv) N-((1 R,2R)-2-(dimethylamino)cyclopentyl)-2-( 1 H-imidazol-5-yl)thiazole-4- carboxamide;(v) N-(4-(dimethylamino)cyclohexyl)-2-(1 H-imidazol-5-yl)thiazole-4-carboxamide;(vi) 2-(1 H-imidazol-5-yl)-N-(3-(piperidin-1 -yl)cyclobutyl)thiazole-4-carboxamide; (vii) 2-(1 H-imidazol-5-yl)-N-(3- (trifluoromethyl)cyclobutyl)thiazole-4-carboxamide;(viii) 2-(1 H-imidazol-5-yl)-N-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide;(ix) N-(1-(fluoromethyl)cyclobutyl)-2-(1 H-imidazol-5-yl)thiazole-4-carboxamide;(x) 2-(1 H-imidazol-5-yl)-N-(5-(pyrrolidin-1 -yl)pyridin-2-yl)thiazole-4- carboxamide;(xi) 2-(1 H-imidazol-5-yl)-N-(6-(pyrrolidin-1 -yl)pyridin-3-yl)thiazole-4- carboxamide;(xii) N-(3-(dimethylamino)spiro[3.3]heptan-1-yl)-2-(1 H-imidazol-5-yl)thiazole-4- carboxamide;(xiii) 2-(1 H-imidazol-5-yl)-N-(3-(pyrrolidin-1 -yl)tetrahydro-2H-pyran-4-yl)thiazole- 4-carboxamide;(xiv) N-(1-(2,2-difluoroethyl)piperidin-4-yl)-2-(1 H-imidazol-5-yl)thiazole-4- carboxamide;(xv) 2-(1 H-imidazol-5-yl)-N-(3-(trifluoromethyl)cyclohexyl)thiazole-4-carboxamide;(xvi) 2-(1 H-imidazol-5-y l)-N-(4-(trifluoromethy l)cyclohexyl)th i azole-4-carboxamide; (xvii) 2-( 1 H-imidazol-5-yl)-N-(4- (pyrrolidin-1-yl)pyrimidin-5-yl)thiazole-4- carboxamide;(xviii) N-(1-(difluoromethyl)cyclopentyl)-2-(1 H-imidazol-5-yl)thiazole-4-carboxamide;(xix) 2-(1 H-imidazol-5-yl)-N-((3S,4S)-3-(trifluoromethyl)tetrahydro-2H-pyran-4- yl)thiazole-4-carboxamide;(xx) N-(1-(difluoromethyl)cyclohexyl)-2-(1 H-imidazol-5-yl)thiazole-4-carboxamide;(xxi) 2-(1H-midazol-1 -yI)-N-(2-(piperazin-1 -yl)phenyl)thiazole-4-carboxamide or the hydrochloride salt thereof;(xxii) 2-(1 H-imidazol-1-yl)-N-(4-(piperazin-1 -yl)pyridin-3-yl)thiazole-4-carboxamide;(xxiii) N-((1 R,2R)-2-fluorocyclohexyl)-2-(1 H-imidazol-5-yl)thiazole-4-carboxamide; (xxiv) 2-(1 H-imidazol-2-yl)-N-((3S,4S)-3-(trifluoromethyl)tetrahydro-2H-pyran-4- yl)thiazole-4-carboxamide;(xxv) N-(3,3-difluorocyclohexyl)-2-(1 H-imidazol-5-yl)thiazole-4-carboxamide;(xxvi) N-((1S,2R)-2-fluorocyclohexyl)-2-(1 H-imidazol-5-yl)thiazole-4-carboxamide;(xxvii) 2-(1 H-imidazol-2-yl)-N-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide; (xxviii)N-(3,3-dichlorocyclobutyl)-2- (1 H-imidazol-5-yl)thiazole-4-carboxamide;(xxix) N-(3,3-dichlorocyclobutyl)-2-(1 H-imidazol-2-yl)thiazole-4-carboxamide; or (xxx) N-((1 R,2R)-2-(dimethylamino)cyclopentyl)-2-(1 H-imidazol-2-yl)thiazole-4- carboxamide.(i) N-(3,3-difluorocyclohexyl)-2-(1 H-imidazol-5-yl)thiazole-4-carboxamide;(ii) 2-(1 H-imidazol-5-yl)-N-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide;(iii) 2-(1 H-imidazol-5-yl)-N-(3-(trifluoromethyl)cyclohexyl)thiazole-4-carboxamide; (iv) 2-(1 H-imidazol-5-yl)-N-(4- (trifluoromethyl)cyclohexyl)thiazole-4-carboxamide;(v) N-(1-(2,2-difluoroethyl)piperidin-4-yl)-2-(1 H-imidazol-5-yl)thiazole-4- carboxamide;(vi) 2-(1 H-imidazol-5-yl)-N-((3S,4S)-3-(trifluoromethyl)tetrahydro-2H-pyran-4- yl)thiazole-4-carboxamide;(vii) N-((1 R,2R)-2-fluorocyclohexyl)-2-(1 H-imidazol-5-yl)thiazole-4-carboxamide;(viii) N-((1S,2R)-2-fluorocyclohexyl)-2-(1 H-imidazol-5-yl)thiazole-4-carboxamide;(ix) N-(1-(difluoromethyl)cyclohexyl)-2-(1 H-imidazol-5-yl)thiazole-4-carboxamide;(x) 2-(1 H-imidazol-2-yl)-N-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide; or(xi) 2-(1 H-imidazol-2-yl)-N-((3S,4S)-3-(trifluoromethyl)tetrahydro-2H-pyran-4- yl)thiazole-4-carboxamide.

[0168] In most preferred embodiments, the CD38 inhibitor is:• 4-(1-methyl-1H-imidazol-5-yl)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)thiazole-2-carboxamide, Example 1 ;• 3-(1-methyl-1H-imidazol-5-yl)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)-1 ,2,4-thiadiazole-5- carboxamide, Example 2;2-(1-methyl-1H-imidazol-5-yl)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)thiazole-4-carboxamideExample 4; or• N-((1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-4-(1-methyl-1 H-imidazol-5-yl)thiazole-2-carboxamide, Example 9; or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.3-Carbonyl imidazo[1 ,5-a]pyridines of formula (XII), including Examples 1 and 2 of WO 2024 / 236316

[0169] In embodiments, the CD38 inhibitor is a 3-carbonyl imidazo[1 ,5-a]pyridine as described in WO 2024 / 236316, incorporated herein by reference.

[0170] In preferred embodiments, the CD38 inhibitor is of formula (XII):wherein:Het is a 5- or 6-membered heteroaryl group comprising one, two or three heteroatoms independently selected from N and S, wherein the heteroaryl group is optionally substituted with one or more substituents independently selected from halo, C1-C3alkyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, and 3- to 6-membered saturated heterocyclyl;Cy is a C3-C9cycloalkyl, 3- to 9-membered saturated heterocyclyl, phenyl, or 5- or 6-membered heteroaryl group, each of which is optionally substituted with one or more substituents independently selected from halo, C1-C3alkyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, -O(C1-C3alkyl), and -O(C1-C3haloalkyl);L is a bond, CH2, CHMe, CMe2 or CO;R1is hydrogen, halo, -NR2R3, C1-C3alkyl, C1-C3haloalkyl, -O(C1-C3alkyl), or -O(C1-C3haloalkyl);R2is hydrogen or C1-C3alkyl;R3is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 hydroxyalkyl; orR2and R3together with the nitrogen atom to which they are attached form a 3- to 6-membered saturated heterocyclic group, wherein the 3- to 6-membered saturated heterocyclic group is optionally substituted with one or more substituents independently selected from halo, hydroxyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, -O(C1-C3alkyl), -O(C1-C3haloalkyl), and oxo (=O); each of A1, A2, A3and A4is independently selected from N and CR4, provided that at least two of A1, A2, A3and A4are CR4, wherein R4is hydrogen, halo, C1-C3alkyl, or C1-C3haloalkyl; provided that the compound is not: (i) 1-(pyridin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyridine-3- carboxamide or the 2,2,2-trifluoroacetate salt thereof; (ii) N-(4,4-difluorocyclohexyl)-1 -(pyridin-4- yl)imid azo[1 , 5-a]pyridi ne-3- carboxamide or the 2,2,2-trifluoroacetate salt thereof; (iii) N-(2,2- dimethyltetrahydro-2H-pyran-4-yl)-1-(pyridin-4-yl)imidazo[1 ,5- a]pyridine-3-carboxamide or the 2,2,2- trifluoroacetate salt thereof; (iv) 1 -(pyridin-4-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1 ,5-a]pyridine-3- carboxamide or the 2,2,2-trifluoroacetate salt thereof; (v) 1 -(py rid in-4-y l)-N-(( 1 R,2S,4R)-1 ,7,7- trimethylbicyclo[2.2.1 ]heptan-2- yl)imidazo[1 ,5-a]pyridine-3-carboxamide or the 2,2,2-trifluoroacetate salt thereof; or (vi) 1-(pyridin-4-yl)-N-((1S,2R,4R)-1 ,3,3-trimethylbicyclo[2.2.1 ]heptan-2- yl)imidazo[1 ,5- a]pyridine-3-carboxamide or the 2,2,2-trifluoroacetate salt thereof. or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[0171] Preferably, Het is a 5-membered heteroaryl group comprising two N heteroatoms (preferablyPreferably, Cy is a C3-C9 cycloalkyl, preferably cyclohexyl. Preferably, L is a bond. Preferably, R1is -NR2R3.

[0172] Preferably, R2is hydrogen. Preferably, R3is C1-C4 haloalkyl (preferably -CH2CF3). Alternatively, R2and R3together with the nitrogen atom to which they are attached form a 3- to 6-membered saturated heterocyclic group (preferably pyrrolidinyl). Preferably, each of A1, A2, A3and A4is CR4. Preferably, each R4is hydrogen.

[0173] In embodiments, the CD38 inhibitor is:

[0174] 1-(1H-midazol-1 -yI)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)imidazo[1 ,5-a]pyridine-3- carboxamide (Example 1);902) N-((1 r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-1-(1H-midazol-1 -yI)imidazo[1 ,5-a]pyridine-3-carboxamide (Example 2);903) 1 -(1 H-imidazol-1 -y l)-N-(5-methoxy py ridi n-3-y l)i m id azo[ 1 ,5-a]pyridine-3-carboxamide (Example 3);904) N-(4-((3,3-difluoropyrrolidin-1-yl)methyl)phenyl)-1-(1H-midazol-1 -yI)imidazo[1 ,5-a]pyridine-3-carboxamide (Example 4);905) 1-(1H-midazol-1 -yI)-N-(2-(2, 2, 2-trifluoroethyl)-2-azaspiro[3.5]nonan-7-yl)imidazo[1 ,5-a]pyridine-3- carboxamide (Example 5);906) 1 -(thiazol-5-yl)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)imidazo[1 ,5-a]pyridine-3-carboxamide (Example 6);907) 1-(1H-midazol-1 -yI)-N-(6-((2, 2, 2-trifluoroethyl)amino)spiro[3.3]heptan-2-yl)imidazo[1,5-a]pyridine-3- carboxamide (Example 7);908) N-((1r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-1-(1H-midazol-1 -yI)imidazo[1 ,5-a]pyridine-3-carboxamide (Example 10);909) 1 -(1H-midazol-1 -yI)-N-(6-(4-(2,2,2-trifluoroethyl)piperazin-1 -yl)pyridin-3-yl)imidazo[1 ,5-a]pyridine-3- carboxamide (Example 11 );910) 1 -(1H-midazol-1 -yI)-N-((1 r,4r)-4-((2, 2, 2-trifluoroethyl)amino)cyclohexyl)imidazo[1 ,5-a]pyrazine-3- carboxamide (Example 12);911 ) N-((1 r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-1 -(1H-midazol-1 -yI)imidazo[1 ,5-a]pyrazine-3-carboxamide (Example 13);912) 1 -(pyridazin-4-yl)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)imidazo[1 ,5-a]pyridine-3-carboxamide (Example 14);913) 1 -(pyridin-3-yl)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)imidazo[1 ,5-a]pyridine-3-carboxamide (Example 15);914) N-((1 r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-1 -(1H-midazol-1 -yI)imidazo[1 ,5-a]pyrazine-3- carboxamide (Example 16);915) 1 -(1H-midazol-1 -yI)-N-(6-((2, 2, 2-trifluoroethyl)amino)spiro[3.3]heptan-2-yl)imidazo[1 ,5-a]pyrazine-3- carboxamide (Example 17);916) 1 -(1H-midazol-1 -yI)-N-(5-(trifluoromethyl)pyridin-3-yl)imidazo[1 ,5-a]pyridine-3-carboxamide (Example 18);917) N-(5-fluoropyridin-3-yl)-1 -(1H-midazol-1 -yI)imidazo[1 ,5-a]pyridine-3-carboxamide (Example 19);918) 1 -(1H-midazol-1 -yI)-N-(6-(trifluoromethyl)pyridin-3-yl)imidazo[1 ,5-a]pyridine-3-carboxamide (Example 20); or919) 1-(1H-midazol-1 -yI)-N-(pyrimidin-5-yl)imidazo[1 ,5-a]pyridine-3-carboxamide (Example 21 ); or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[0175] In embodiments, the CD38 inhibitor is not:(i) 1 -(pyridin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)imidazo[1 ,5-a]pyridine-3- carboxamide or the 2,2,2- trifluoroacetate salt thereof;(ii) N-(4,4-difluorocyclohexyl)-1-(pyridin-4-yl)imidazo[1 ,5-a]pyridine-3- carboxamide or the 2,2,2- trifluoroacetate salt thereof;(iii) N-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1 -(pyridin-4-yl)imidazo[1 ,5- a]pyridine-3-carboxamide or the 2,2,2-trifluoroacetate salt thereof;(iv) 1 -(pyridin-4-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1 ,5-a]pyridine-3- carboxamide or the 2,2,2- trifluoroacetate salt thereof;(v) 1 -(pyrid i n-4-yl)-N-(( 1 R,2S,4R)-1 , 7, 7-tri methy lbicyclo[2.2.1 ]heptan-2- y l)i mi dazo[ 1 ,5-a]py ridi ne-3- carboxamide or the 2,2,2-trifluoroacetate salt thereof;(vi) 1 -(pyrid i n-4-yl)-N-(( 1 S,2R,4R)-1 , 3,3-tri methyl bicyclo[2.2.1 ]heptan-2- y l)i m idazo[1 , 5-a]py rid i ne-3- carboxamide or the 2,2,2-trifluoroacetate salt thereof;(vii) 1 -(6-f I uoropy rid i n-3-yl)-N-(4-(hydroxy methy l)tetrahyd ro-2H -py ran-4- y I) i midazo[ 1 , 5-a]py rid i ne-3- carboxamide or the 2,2,2-trifluoroacetate salt thereof;(viii) N-(4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)-1-(pyridin-4-yl)imidazo[1 ,5- a]pyridine-3-carboxamide or the 2,2,2-trifluoroacetate salt thereof;(ix) N-(4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)-1-(1 ,3,5-trimethyl-1H-pyrazol- 4-yl)imidazo[1 ,5- a]pyridine-3-carboxamide or the 2,2,2-trifluoroacetate salt thereof;(x) N-(4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)-1 -(6-morphol i nopy rid i n-3- y I) im id azo[ 1 , 5-a]py ridi ne-3- carboxamide or the 2,2,2-trifluoroacetate salt thereof;(xi) N-(4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)-1-(6-(piperazin-1 -yl)pyridin- 3-yl)imidazo[1 ,5-a]pyridine- 3-carboxamide or the 2,2,2-trifluoroacetate salt thereof; or(xii) N-(4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)-1-(pyridin-3-yl)imidazo[1 ,5- a]pyridine-3-carboxamide or the 2,2,2-trifluoroacetate salt thereof; or (xiii) N-phenyl-1 -(pyridin-2-yl)imidazo[1 ,5-a]pyridine-3-carboxamide.

[0176] In most preferred embodiments, the CD38 inhibitor is:• 1-(1H-midazol-1 -yI)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)imidazo[1 ,5-a]pyridine-3- carboxamide (Example 1)• N-((1 r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-1-(1H-midazol-1 -yI)imidazo[1,5-a]pyridine-3-carboxamide (Example 2) or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.Pyrazoles of formula (Xl lla), (Xl llb), or (Xlllc), including compounds 1 1 to 14 of Doyle 2023

[0177] In embodiments, the CD38 inhibitor is a pyrazole as described in Doyle et al., A Covalent Binding Mode of a Pyrazole-Based CD38 Inhibitor, Publication Helv. Chim. Acta 2023, 106, e202300080, incorporated herein by reference.

[0178] In preferred embodiments, the CD38 inhibitor is of formula (Xllla), (Xlllb), or (Xlllc):(Xlllc).

[0179] In embodiments, the CD38 inhibitor is: • 4-{[(1 r,4r)-4-(2-Methoxyethoxy)cyclohexyl]amino}-1-methyl-6-[1-(oxan-2-yl)-1 H-pyrazol-4-yl]quinolin-2(1 H)- one, corresponding to Compound 11 of Doyle 2023;• 4-{[(1 r,4r)-4-(2-Methoxyethoxy)cyclohexyl]amino}-1-methyl-6-(1 H-pyrazol-4yl)quinolin-2(1 H)-one, Compound corresponding to Compound 12 of Doyle 2023;• 8-{[(1 r,4r)-4-Hydroxy-4-methylcyclohexyl]amino}2-(1H-midazol-1 -yI)-5-methylpyrido[3,2-d]pyrimidin-6(5H)- one, corresponding to Compound 13 of Doyle 2023;• 2-(1 H-lmidazol-1 -yl)-5-methyl-8-[(oxan-4-yl)amino]pyrido[3,2-d]pyrimidin-6(5H)-one corresponding toCompound 14 of Doyle 2023; or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.Heterobicyclic amides of formula (XIV), including Examples 4, 12, 13, 14, 19,20, 21 , 29, 41 , 45, and 48 of WO 2023 / 227867

[0180] In embodiments, the CD38 inhibitor is a heterobicyclic amide as described in WO 2023 / 227867, incorporated herein by reference.

[0181] In preferred embodiments, the CD38 inhibitor is of formula (XIV):wherein: one of R1and R2is -C(O)NHR3and the other one of R1and R2is a 5-membered heteroaryl group containing one, two or three heteroatoms independently selected from N and S, wherein the heteroaryl group is optionally substituted with one or more substituents independently selected from C1-C3alkyl, wherein the C1-C3alkyl is optionally substituted with one or more substituents independently selected from halo, hydroxyl and C1-C3alkoxy;R3is a saturated 3- to 9-membered carbocyclic or heterocyclic group optionally substituted with one or more substituents independently selected from -NR4R5and C1-C3alkyl, wherein the C1-C3alkyl is optionally substituted with one or more substituents independently selected from halo, hydroxyl and C1-C3alkoxy;R4is hydrogen or C1-C3alkyl;R5is C1-C4 alkyl (preferably C1-C3alkyl) optionally substituted with one or more substituents independently selected from halo, hydroxyl and C1-C3alkoxy; orR4and R5together with the nitrogen atom to which they are attached form a saturated 3- to 6-membered heterocyclic group, wherein the saturated 3- to 6-membered heterocyclic group is optionally substituted with one or more substituents independently selected from halo, hydroxyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy and oxo ( =O) [preferably independently selected from halo, hydroxyl, C1-C3alkoxy and oxo (=O)]; each of A1, A2, A3and A4is independently selected from N and CH; each X and Y is independently selected from N and C; and n is 1 or 2;provided that: when n is 1 , one of X and Y is N and the other one of X and Y is C; and when n is 2, X and Y are C and at least one of A2, A3 and A4 is N. or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[0182] Preferably, R1 is a 5-membered heteroaryl group containing two N heteroatoms (preferablyor) unsubstituted or substituted with C1-C3alkyl (preferably ethyl) substituted with hydroxyl; and R2is - C(O)NHR3. Alternatively, R1is -C(O)NHR3and R2is a 5-membered heteroaryl group containing two N heteroatoms independently (preferably

[0183] Preferably, R3is a saturated 3- to 9-membered carbocyclic (preferably cyclohexyl), substituted with -NR4R5. Preferably, R4is hydrogen. Preferably, R5is C1-C4 alkyl (preferably ethyl) substituted with halo. Alternatively, R4and R5together with the nitrogen atom to which they are attached form a saturated 3- to 6-membered heterocyclic group (preferably pyrrolidinyl or azetidinyl) substituted with one or more halo.

[0184] Preferably, A1and A2are N, A3and A4are CH; and X and Y are C. Alternatively, A1is N, and A2, A3and A4are CH, X is N, and Y is C. Alternatively, A1, A2, and A3are CH, A4is N, X is N, and Y is C. Alternatively, A1and A3are CH, A2and A4are N, X is N, and Y is C. Alternatively, A1, A3, and A4are CH, A2is N, X is N, and Y is C.Alternatively, A1is N, A2, A3, A4are CH, X is N, and Y is C.

[0185] Preferably, n is 1.

[0186] In embodiments, the CD38 inhibitor is:920) 7-(1H-midazol-1 -yI)-N-(tetrahydro-2H-pyran-4-yl)imidazo[1 ,2-c]pyrimidine-5-carboxamide, Example 1 ;921) 7-(1H-midazol-1 -yI)-N-((1 r,4r)-4-((2, 2, 2-trifluoroethyl)amino)cyclohexyl)imidazo[1 ,2-c]pyrimidine-5- carboxamide, Example 2;922) 2-(1H-midazol-1 -yI)-N-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidine-4-carboxamide, Example 3;923) 2-(1H-midazol-1 -yI)-N-((1r,4r)-4-((2, 2, 2-trifluoroethyl)amino)cyclohexyl)pyrido[2,3-d]pyrimidine-4- carboxamide, Example 4;924) 3-(thiazol-5-yl)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)pyrrolo[1 ,2-a]pyrazine-i-carboxamide, Example 5;925) 8-(1H-midazol-1 -yI)-N-((1 r, 4r)-4-((2, 2, 2-trifl uoroethy l)am i no)cyclohexy I)- 1 ,7-naphthyridine-6-carboxamide, Example 6;926) 8-(thiazol-5-yl)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)-1,7-naphthyridine-6-carboxamide, Example 7;927) 2-(1H-midazol-1 -yI)-N-(2-(2,2,2-trifluoroethyl)-2-azaspiro[3.5]nonan-7-yl)pyrrolo[2,1 -f][1 ,2,4]triazine-4- carboxamide, Example 8;928) 2-(1 H-imidazol-1 -y l)-N-(6-((2, 2,2-trifl uoroethy I) ami no)spi ro[3 ,3]heptan-2-y I) py rrolo[2, 1 -f][1 ,2, 4]tri azi ne-4- carboxamide, Example 9;929) 2-(1H-midazol-1 -yI)-N-(6-((2, 2,2-trifl uoroethy I) ami no)spi ro[3 ,3]heptan-2-y I) pyrrolo[2, 1 -f][1 , 2, 4]tri azi ne-4- carboxamide, Example 10;930) 2-(1H-midazol-1 -yI)-N-((1 r, 3r)-3-((2, 2, 2-trifl uoroethy l)am i no)cyclobuty l)py rrolo[2, 1 -f][1 , 2, 4]triazi ne-4- carboxamide, Example 11;931 ) N-(( 1 r, 4r)-4-(3, 3-dif I uoropy rrol id i n- 1 -yl)cyclohexy l)-2-( 1 H-imidazol-1 -y I) py rrolo[2, 1 -f][1 , 2, 4]tri azi ne-4- carboxamide, Example 12;932) N-((1s,4r)-4-((S)-3-fluoropyrrolidin-1-yl)cyclohexyl)-2-(1H-midazol-1 -yI)pyrrolo[2,1-f][1, 2, 4]triazine-4- carboxamide, Example 13;933) N-((1 r,4r)-4-((R)-3-fluoropyrrolidin-1-yl)cyclohexyl)-2-(1H-midazol-1 -yI)pyrrolo[2,1-f][1 ,2,4]triazine-4- carboxamide, Example 14;934) 1 -(1H-midazol-1 -yI)-N-((1 r, 4r)-4-((2, 2, 2-trifl uoroethy l)am i no)cyclohexy l)py rrolo[1 ,2-a]pyrazine-3- carboxamide, Example 15;935) 4-(1H-midazol-1 -yI)-N-((1r,4r)-4-((2, 2, 2-trifluoroethyl)amino)cyclohexyl)pyrrolo[2,1-f][1 , 2, 4]triazine-2- carboxamide, Example 16;936) 2-(1-methyl-1 H-imidazol-5-yl)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)pyrrolo[2,1-f][1,2,4]triazine- 4-carboxamide, Example 17;937) 2-(1-(2-hydroxyethyl)-1 H-imidazol-5-yl)-N-((1r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)pyrrolo[2,1- f][1,2,4]triazine-4-carboxamide, Example 18;938) 8-(1H-midazol-1 -yI)-N-((1 r, 4r)-4-((2, 2, 2-trifl uoroethy l)am i no)cyclohexy l)i m idazo[ 1 ,2-a]pyrazine-6- carboxamide, Example 19;939) 8-(1H-midazol-1 -yI)-N-((1r,4r)-4-((2, 2, 2-trifluoroethyl)amino)cyclohexyl)-[1 , 2, 4]triazolo[1 ,5-a]pyrazine-6- carboxamide, Example 20;940) 4-(1H-midazol-1 -yI)-N-((1r,4r)-4-((2, 2, 2-trifluoroethyl)amino)cyclohexyl)pyrazolo[1 ,5-a]pyrazine-6- carboxamide, Example 21 ;941) N-((1s,4r)-4-((S)-3-fluoropyrrolidin-1-yl)cyclohexyl)-1-(iH-imidazol-1-yl)pyrrolo[1,2-a]pyrazine-3-carboxamide, Example 22;942) N-((1s,4r)-4-((S)-3-hydroxypyrrolidin-1-yl)cyclohexyl)-2-(1H-midazol-1 -yI)pyrrolo[2,1-f][1 , 2, 4]triazine-4- carboxamide, Example 23;943) N-((1r,4r)-4-((R)-3-fluoropyrrolidin-1-yl)cyclohexyl)-1-(1 H-imidazol-1-yl)pyrrolo[1 ,2-a]pyrazine-3- carboxamide, Example 24;944) N-((1s,4r)-4-((S)-3-fluoropyrrolidin-1-yl)cyclohexyl)-8-(1H-midazol-1 -yI)-[1 ,2,4]triazolo[1 ,5-a]pyrazine-6- carboxamide, Example 25;945) N-((1r,4r)-4-((R)-3-fluoropyrrolidin-1-yl)cyclohexyl)-8-(1H-midazol-1 -yI)-[1 ,2,4]triazolo[1 ,5-a]pyrazine-6- carboxamide, Example 26;946) N-((1r,4r)-4-((R)-3-hydroxypyrrolidin-1-yl)cyclohexyl)-2-(1 H-imidazol-1-yl)pyrrolo[2,1-f][1 ,2,4]triazine-4- carboxamide, Example 27;947) N-((1r,4r)-4-((R)-3-fluoropyrrolidin-1-yl)cyclohexyl)-4-(1 H-imidazol-1-yl)pyrrolo[2,1-f][1,2,4]triazine-2- carboxamide, Example 28;948) 2-(1 H-imidazol-1-yl)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)pyrrolo[2,1-f][1,2,4]triazine-4- carboxamide, Example 29;949) 2-(thiazol-5-yl)-N-((1r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)pyrrolo[2,1-f][1 ,2,4]triazine-4- carboxamide, Example 30;950) N-((1 r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-2-(1H-midazol-1 -yI)pyrrolo[2,1-f][1 ,2,4]triazine-4- carboxamide, Example 31;951) N-((1 s,4r)-4-((S)-3-fluoropyrrolidin-1-yl)cyclohexyl)-2-(1 H-imidazol-1-yl)pyrido[2,3-d]pyrimidine-4- carboxamide, Example 32;952) N-((1 r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-2-(1 H-imidazol-i-yl)pyrido[2,3-d]pyrimidine-4-carboxamide, Example 33;953) N-((1 r,4r)-4-(3,3-difluoropyrrolidin-i-yl)cyclohexyl)-4-(1 H-imidazol-i-yl)pyrazolo[i,5-a]pyrazine-6-carboxamide, Example 34;954) N-((1 r,4r)-4-((R)-3-fluoropyrrolidin-i-yl)cyclohexyl)-4-(1H-midazol-1 -yI)pyrazolo[1 ,5-a]pyrazine-6- carboxamide, Example 35;955) N-((1s,4r)-4-((S)-3-fluoropyrrolidin-1-yl)cyclohexyl)-4-(1 H-imidazol-i-yl)pyrazolo[1 ,5-a]pyrazine-6- carboxamide, Example 36;956) N-((1 r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-4-(1 H-imidazol-i-yl)pyrazolo[1,5-a]pyrazine-6-carboxamide, Example 37;957) N-((1 r,4r)-4-((2,2-difluoroethy I) amino)cyclohexyl)-8-( 1 H-imid azol-i-yl)imid azo[1 ,2-a]pyrazine-6-carboxamide, Example 38;958) N-((1 r,4r)-4-((R)-3-fluoropyrrolidin-i-yl)cyclohexyl)-8-(1H-midazol-1 -yI)imidazo[1 ,2-a]pyrazine-6- carboxamide, Example 39;959) N-((1s,4r)-4-((S)-3-fluoropyrrolidin-1-yl)cyclohexyl)-8-(1H-midazol-1 -yI)imidazo[1 ,2-a]pyrazine-6- carboxamide, Example 40;960) N-((1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-8-(1H-midazol-1 -yI)imidazo[1 ,2-a]pyrazine-6- carboxamide, Example 41 ;961) 2-(5-methyl-1H-imidazol-1 -yl)-N-((1 r,4r)-4-((2, 2, 2-trifluoroethyl)amino)cyclohexyl)pyrrolo[2,1-f][1 , 2, 4]triazine- 4-carboxamide, Example 42;962) 2-(1H-midazol-1 -yI)-N-((1 r, 4r)-4-(py rrol id i n-1 -y I Jcyclohexy I) py rrolo[2 , 1 -f][1 ,2,4]triazine-4-carboxamide, Example 43;963) 2-(1H-midazol-1 -yI)-N-((1 s,4s)-4-(py rrol id i n- 1 -y I Jcyclohexy I) py rrolo[2, 1 -f][1 ,2,4]triazine-4-carboxamide, Example 44;964) N-((1 r,4r)-4-(3,3-difluoroazetidin-1-yl)cyclohexyl)-8-(1H-midazol-1 -yI)-[1 , 2, 4]triazolo[1 ,5-a]pyrazine-6- carboxamide, Example 45;965) N-((1 r,4r)-4-(3-fluoro-3-methylazetidin-1-yl)cyclohexyl)-8-(1H-midazol-1 -yI)-[1 ,2,4]triazolo[1,5-a]pyrazine-6- carboxamide, Example 46;966) 8-(1H-midazol-1 -yI)-N-((1r,4r)-4-(methyl(2, 2, 2-trifluoroethyl)amino)cyclohexyl)-[1, 2, 4]triazolo[1 ,5-a]pyrazine- 6-carboxamide, Example 47;967) N-((1 r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-8-(1H-midazol-1 -yI)-[1 , 2, 4]triazolo[i,5-a]pyrazine-6- carboxamide, Example 48;968) 8-(1H-midazol-1 -yI)-N-((1 r,4r)-4-morpholinocyclohexyl)-[1 , 2, 4]triazolo[1 ,5-a]pyrazine-6-carboxamide, Example 49;969) 8-(1H-midazol-1 -yI)-N-(1-(2, 2, 2-trifluoroethyl)piperidin-4-yl)-[1 , 2, 4]triazolo[1 ,5-a]pyrazine-6-carboxamide, Example 50;970) N-((1r,4r)-4-(1 , 1 -dioxidothiomorpholino)cyclohexyl)-8-(1H-midazol-1 -yI)-[1 ,2,4]triazolo[1 ,5-a]pyrazine-6- carboxamide, Example 51;971) N-((1 r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-8-(1H-midazol-1 -yI)-[1 , 2, 4]triazolo[1,5-a]pyrazine-6- carboxamide, Example 52;972) 8-(1H-midazol-1 -yI)-N-(( 1 r, 4r)-4-(( 1 ,1 ,1 -trifl uoro-2-methyl propan-2-yl)ami no)cyclohexy l)-[ 1 , 2,4]tri azolo[ 1 ,5- a]pyrazine-6-carboxamide, Example 53;973) 8-(1H-midazol-1 -yI)-N-((1s,4s)-4-((R)-3-methoxypyrrolidin-1-yl)cyclohexyl)- [1 ,2,4]triazolo[1,5-a]pyrazine-6- carboxamide, Example 54;974) 8-(1H-midazol-1 -yI)-N-((1s,4s)-4-thiomorpholinocyclohexyl)-[1 , 2, 4]triazolo[1,5-a]pyrazine-6-carboxamide, Example 55;975) 8-(1 H-imidazol-1-yl)-N-((1 r,4r)-4-(3-(trifluoromethyl)azetidin-1-yl)cyclohexyl)- [1,2,4]triazolo[i,5-a]pyrazine-6- carboxamide, Example 56;976) N-((1 r,4r)-4-((2,2-difluoropropyl)amino)cyclohexyl)-8-(1H-midazol-1 -yI)-[1 ,2,4]triazolo[1 ,5-a]pyrazine-6- carboxamide, Example 57;977) N-((1 R,4r)-4-((R)-3-fluoropyrrolidin-1-yl)cyclohexyl)-2-(1H-midazol-1 -yI)pyrido[2,3-d]pyrimidine-4- carboxamide, Example 58;978) 6-(1H-midazol-1 -yI)-N-((1 r, 4r)-4-((2, 2, 2-trifl uoroethy l)am i no)cyclohexy l)-[ 1 ,2,4]triazolo[1 ,5-a]pyrazine-8- carboxamide, Example 59;979) 5-(1H-midazol-1 -yI)-N-((1r,4r)-4-((2, 2, 2-trifluoroethyl)amino)cyclohexyl)-[1 , 2, 4]triazolo[1 ,5-c]pyrimidine-7- carboxamide, Example 60; or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[0187] In most preferred embodiments, the CD38 inhibitor is:• 2-(1 H-imidazol-1-yl)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)pyrido[2,3-d]pyrimidine-4- carboxamide, Example 4;• N-((1 r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-2-(1H-midazol-1 -yI)pyrrolo[2,1-f][1 , 2, 4]triazine-4- carboxamide, Example 12;• N-(( 1 s, 4r)-4-((S)-3-f I uoropy rrol idi n- 1 -yl)cyclohexy l)-2-( 1 H-imidazol-1 -y I) py rrolo[2, 1 -f][1 , 2, 4]triazi ne-4- carboxamide, Example 13;• N-(( 1 r, 4r)-4-(( R)-3-f I uoropy rrol id i n- 1 -yl)cyclohexyl)-2-( 1 H-imidazol-1 -y I) py rrolo[2, 1 -f][1 , 2, 4]tri azi ne-4- carboxamide, Example 14;• 8-(1H-midazol-1 -yI)-N-((1 r,4r)-4-((2, 2, 2-trifluoroethyl)amino)cyclohexyl)imidazo[1 ,2-a]pyrazine-6- carboxamide, Example 19;• 8-(1H-midazol-1 -yI)-N-((1 r, 4r)-4-((2, 2, 2-trifl uoroethy l)am i no)cyclohexy l)-[ 1 , 2, 4]tri azolo[1 ,5-a]pyrazine-6- carboxamide, Example 20;• 4-(1H-midazol-1 -yI)-N-((1r,4r)-4-((2, 2, 2-trifluoroethyl)amino)cyclohexyl)pyrazolo[1 ,5-a]pyrazine-6- carboxamide, Example 21;• 2-(1 H-imidazol-1-yl)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)pyrrolo[2, 1-f][1 ,2,4]triazine-4- carboxamide, Example 29;• N-((1 r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-8-(1H-midazol-1 -yI)imidazo[1 ,2-a]pyrazine-6- carboxamide, Example 41 ;N-((1 r,4r)-4-(3,3-difluoroazetidin-1-yl)cyclohexyl)-8-(1H-midazol-1 -yI)-[1, 2, 4]triazolo[1 ,5-a]pyrazine-6- carboxamide, Example 45; or• N-((1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-8-(1 H-imidazol-1-yl)-[1 ,2,4]triazolo[i,5-a]pyrazine-6- carboxamide, Example 48;

[0188] or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.Heteroaryl amides of formula (XV) and (XV*), including compounds 32, 25, and 29 of WO 2022 / 077034

[0189] In embodiments, the CD38 inhibitor is a heteroaryl amides as described in WO 2022 / 077034, incorporated herein by reference.

[0190] In preferred embodiments, the CD38 inhibitor is of formula (XV) or (XV*):

[0191] wherein-X-Y-Z- is =CR1— CR2=CR3— , =N-CR2=CR3-, =CRI-N=CR3- or =CR1-CR2=N- if the CD38 inhibitor is of Formula (XV);X-Y-Z- is CR1— CR2=C, N— CR2=C, or CR1-N=C if the CD38 inhibitor is of Formula (XV*);R1is selected from the group consisting of H, halo, -CN, (C1-C6)alkyl, (C1-C6)alkoxy, and perfluoro(C1- C6)alkoxy-; wherein (C1-C6)alkyl is optionally substituted with 1-3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3)alkyl, -NH2, (C1-C3)alkyl-(NH)-, ((C1-C3)alkyl)2N-, -CF3, -OCH3and -OCF3;R2is H, halo, -CN, (C1-C6)alkyl, (C1-C6)alkoxy, perfluoro(C1-C6)alkyl, perfluoro(C1-C6)alkoxy-, cycloalkyl, cycloalkyl-O-, heterocycloalkyl, heterocycloalkyl-O-, aryl, aryl-O-, R5-(C(R4)2)n-O- or (R6)2N-; wherein (C1- C6)alkyl, cycloalkyl, heterocycloalkyl, and aryl are each optionally substituted with 1-3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3)alkyl, -NH2, (C1-C3)alkyl-(NH)-,((C1-C3)alkyl)2N- -CF3, -OCH3and -OCF3;R3is H, halo, (C1-C3)alkyl, -CF3, (C1-C3)alkoxy, -OCF3or (R7)2N-; wherein R7is H or (C1-C3)alkyl; each R4is independently H or (C1-C3)alkyl; wherein (C1-C3)alkyl is optionally substituted with 1-3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3)alkyl, -NH2, (C1- C3)alkyl-(NH)-, ((C1-C3)alkyl)2N-, -CF3, -OCH3and -OCF3;R5is selected from the group consisting of (C1-C3)alkyl, perfluoro(C1-C3)alkyl, HO-(C2-C4)alkyl-, cycloalkyl, heterocycloalkyl, and aryl; wherein (C1-C3)alkyl, cycloalkyl, heterocycloalkyl, and aryl are each optionally substituted with 1-3 substituents independently selected from the group consisting of H, halo, -CN, (C1- C3)alkyl, -NH2, (C1-C3)alkyl-(NH)-, ((C1-C3)alkyl)2N-, -CF3, -OCH3and -OCF3; R6 is independently H or (C1-C3)alkyl; wherein (C1-C3)alkyl is optionally substituted with 1-3 substituents independently selected from the group consisting of H, halo, -CN, (C1-C3)alkyl, -NH2, (C1-C3)alkyl-(NH)-, ((C1-C3)alkyl)2N-, -CF3, -OCH3and -OCF3; n is an integer from one to three;R8is H, -CH3or-CF3;Het is a heterocycle of the formula:each R9is independently selected from H, halo, (C1-C6)alkyl, -CF3, (C1-C6)alkoxy, -OCF3, -CN, (R11)2N-, RI2(O)(C=0)-, R12O((C1-C3)alkyl)-(NR11)-, R13-(C=O)-(NR11)- and (R11)2N-(C=O)-; each R10is independently selected from H, (C1-C3)alkyl, -CF3, -OCH3, -OCF3, -CN, (R11)2N-, Ri2(O)(C=0)-,RI2O-(( C1-C3)alkyl)-(NR11)-, R13-(C=O)-(NR11)-, and (R11)2N-(C=O);R11is independently H or (C1-C3)alkyl;R12is H or (C1-C3)alkyl; andR13is (C1-C3)alkyl, or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[0192] Preferably, the CD38 inhibitor is of formula (XV). Preferably, — X— Y— Z— is =CR1— CR2=CR3— or =N— CR2=CR3— . Preferably, R1is H. Preferably, R2 is (C1-C6)alkoxy or cycloalkyl-O-, optionally substituted with -OCH3, preferably -O-cyclopropyl, -OCH3, or -O-CH2-CH2-O-CH3. Preferably, R3is H.. Preferably, each R9is independently H or -CF3, preferably one R9is H and the other is-CF3. Preferably, each R10is H.

[0194] In embodiments, the CD38 inhibitor is:980) Methyl 5-[6-(1H-midazol-1 -yI)pyridine-2-amido]pyridine-2-carboxylate, Compound 1 ;981) Methyl 5-[6-(1H-midazol-1 -yI)pyridine-2-amido]pyridine-2-amide, Compound 2;982) 5-[6-(1H-midazol-1 -yI)pyridine-2-amido]pyridine-2-amide, Compound 3;983) 4-[6-(1H-midazol-1 -yI)pyridine-2-amido]6-cyano-2-methyl-pyridine, Compound 4;984) 4-[6-(1H-midazol-1 -yI)pyridine-2-amido]6-fluoro-2-fluoro-pyridine, Compound 5;985) Ethyl 4-[6-( 1 H-imidazol-1 -y l)pyrid i ne-2-amido]py rid i ne-6-carboxy I ate, Compound 6;986) 4-[6-(1H-midazol-1 -yI)pyridine-2-amido]6-methyl-2-methyl-pyridine, Compound 7;987) 4-[6-( 1 H-imidazol-1 -y I) py ridi ne-2-am ido]6-f I uoro-py rid i ne, Compound 8;988) 3-[6-( 1 H-imidazol-1 -y I) py ridi ne-2-am ido]6-trif luoromethyl-py rid i ne, Compound 9;989) 4-[6-( 1 H-imidazol-1 -yl)pyridine-2-amido]6-methoxyethoxyamino-pyridine, Compound 10;990) 4-[6-( 1 H-imidazol-1 -yl)py ridi ne-2-am ido]6-methy l-py rid i ne, Compound 11 ;991) 4-[6-(1H-midazol-1 -yI)pyridine-2-amido]6-methoxy-pyridine, Compound 12;992) 4-[6-(1H-midazol-1 -yI)pyridine-2-amido]pyridine, Compound 13;993) 3-[6-(1 H-imidazol-1-yl)pyridine-2-amido]6-methyl-pyridine, Compound 14;994) 5-[6-(1H-midazol-1 -yI)pyridine-2-amido]-2-(methylcarbonyl(methyl)amino)-pyridine, Compound 15;995) 5-[6-(1H-midazol-1 -yI)pyridine-2-amido]-2-(methylcarbonylamino)-pyridine, Compound 16;996) 4-[6-(1H-midazol-1 -yI)pyridine-2-amido]-pyridine-2-carboxamide, Compound 17;997) 5-[6-(1H-midazol-1 -yI)pyridine-2-amido]-2-5-[6-(1 H-imidazol-1-yl)pyridine-2-amido]-2-methoxy-pyridine,Compound 18;998) 5-[6-( 1 H-imidazol-1 -y I) py ridi ne-2-am ido]-2-(methy Icarbony I (ethy I) am i no)-py ridi ne, Compound 19;999) 5-[6-( 1 H-imidazol-1 -yl)py ridi ne-2-am ido]-py rid i ne, Compound 20;1000) 5-[6-(1H-midazol-1 -yI)pyridine-2-amido]-pyridine-2-carboxylic acid, Compound 21 ;1001) 5-[6-(1H-midazol-1 -yI)pyridine-2-amido]-2-fluoro-pyridine, Compound 22;1002) 5-[6-(1H-midazol-1 -yI)pyridine-2-amido]-pyridine-2-carbonyl-methylamine, Compound 23;1003) 4-[6-(1H-midazol-1 -yI)pyridine-2-amido]-pyrimidine, Compound 24;1004) 2-[6-(1H-midazol-1 -yI)pyridine-2-amido]-pyridine, Compound 25;1005) 3-[6-(1H-midazol-1 -yI)pyridine-2-amido]-pyridine, Compound 26;1006) 5-[6-(1H-midazol-1 -yI)pyridine-2-amido]-2-methoxycarbonyl-pyridine, Compound 27;1007) 4-[6-(1H-midazol-1 -yI)pyridine-2-amido]-2-trifluoromethyl-pyridine, Compound 28;1008) 4-(benzyloxy)-6-(1 H-imidazol-1-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)picolinamide, Compound 29;1009) 4-((tetrahydro-2H-pyran-4-yl)oxy)-6-(1 H-imidazol-1-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)picolinamide, Compound 30;1010) 4-(methoxyethoxy)-6-(1H-midazol-1 -yI)-N-(2-(trifluoromethyl)pyridin-4-yl)picolinamide, Compound 31 ;101 1 ) 4-((cyclopropyl)oxy)-6-(1H-midazol-1 -yI)-N-(2-(trifluoromethyl)pyridin-4-yl)picolinamide, Compound 32;1012) 4-((dimethylamino)ethoxy)-6-(1 H-imidazol-1-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)picolinamide, Compound 33;1013) 4-((3-methyloxetan-3-yl)oxy)-6-(1H-midazol-1 -yI)-N-(2-(trifluoromethyl)pyridin-4-yl)picolinamide, Compound 34;1014) 6-(1H-midazol-1 -yI)-4-methoxy-N-(2-(trifluoromethyl)pyridin-4-yl)picolinamide, Compound 35;1015) 6-(1H-midazol-1 -yI)-4-methoxy-N-(pyridin-3-yl)picolinamide, Compound 36;1016) 2-(1H-midazol-1 -yI)-6-methoxy-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide, Compound 37;1017) 2-(1 H-imidazol-1 -y l)-6-ethoxy-N -(2-(trif I uoromethyl) pyridi n-4-y I) py ri midi ne-4-carboxamide, Compound 38;1018) 2-(1H-midazol-1 -yI)-6-methoxyethoxy-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide, Compound 39;1019) 2-(1H-midazol-1 -yI)-6-(cyclopropyl)oxy-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide, Compound 40;1020) 2-(1 H-imidazol-1 -y l)-6-(3-methy loxetan-3-yl )oxy-N-(2-(trif luoromethyl) py rid i n-4-y I) py ri mid i ne-4-carboxam ide, Compound 41 ;1021 ) 6-(1-methyl-1H-imidazol-5-yl)-N-(pyridin-3-yl)pyridine-2-carboxamide, Compound 42;1022) 6-(1 -methyl-1H-imidazol-5-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)pyridine-2-carboxamide, Compound 43;1023) 6-(1 -methyl-1H-imidazol-5-yl)-4-methyl-N-(pyridin-4-yl)pyridine-2-carboxamide, Compound 44;1024) 6-(1 -methyl-1H-imidazol-2-yl)-4-methyl-N-(pyridin-4-yl)pyridine-2-carboxamide, Compound 45;1025) 6-(thiazol-5-yl)-N-(2-(trifluoromethyl)pyridin-5-yl)pyridine-2-carboxamide, Compound 46;1026) 6-(1 -methyl-1H-imidazol-2-yl)-N-(2-(trifluoromethyl)pyridin-5-yl)pyridine-2-carboxamide, Compound 47;1027) 6-(1-methyl-1H-imidazol-5-yl)-4-methyl-N-(6-(trifluoromethyl)pyridin-3-yl)pyridine-2-carboxamide, Compound 47b;1028) 6-(1 -methyl-1H-i mid azol-2-y l)-N -(py ridi n-5-y I) py ridi ne-2-carboxam ide, Compound 48;1029) 2-(1 H-i m id azol- 1 -y l)-6-methy l-N -(py ridi n-3-y I) py ri midi ne-4-carboxamide, Compound 49;1030) 2-(1 H-i m id azol-1 -y l)-6-methy l-N -(py ridi n-4-y I) py ri midi ne-4-carboxamide, Compound 50;1031) 2-(1 H -i m id azol-1 -y l)-6-cyclopropy l-N-(6-(trifl uoromethyl) pyridi n-4-y l)py rim idi ne-4-carboxam ide, Compound 51 ;1032) 6-(1 H -i m id azol-1 -y l)-4-methy l-N-(py rid i n-4-y I) picoli n am ide, Compound 52;1033) 6-(1 H -i m id azol-1 -y l)-4-methy l-N-(py rid i n-3-y I) picoli n am ide, Compound 53;1034) 6-(1 H -i m id azol-1 -y l)-4-methy l-N-(2-(carbamoy I) py rid in-5-y l)picol i n am ide, Compound 54;1035) 6-(1 H -i m id azol-1 -y l)-4-methy l-N-(6-(carbamoy I) py rid in-4-y l)picol i n am ide, Compound 55;1036) 6-(1 H -i m id azol-1 -yl)-4-methy l-N-(6-(methy Icarbamoyl) py rid i n-4-y I) picoli n amide, Compound 56;1037) 6-(1H-midazol-1 -yI)-4-methyl-N-(2-(methylcarbamoyl)pyridin-5-yl)picolinamide, Compound 57;1038) 6-(1 H-imidazol-1 -y l)-5-methy l-N -(py rid i n-3-y I) picoli n am ide, Compound 58;1039) 6-(1 H-imidazol-1 -y l)-3-methy l-N -(py rid i n-3-y I) picoli n am ide, Compound 59;1040) 6-(1 H-imidazol-1 -y l)-5-methoxy-N -(py rid i n-3-y l)picol i namide, Compound 60;1041) 6-(1H-midazol-1 -yI)-5-fluoro-N-(pyridin-3-yl)picolinamide, Compound 611042) 6-(1 H-imidazol-1 -y l)-3-f I uoro-N-(pyrid in-3-y I) picol i namide, Compound 621043) 6-(1H-midazol-1 -yI)-3-methoxy-N-(py rid i n-3-yl) picol i namide, Compound 63;1044) 6-(1 H-imidazol-1 -y l)-3-ami no-N -(py rid i n-4-y I) picoli n am ide, Compound 64;1045) 6-(1 H-imidazol-1 -y l)-3-ami no-N -(2-(f I uoro)py rid i n-4-y I) picol i namide, Compound 65;1046) 6-(1 H-imidazol-1 -y l)-3-ami no-N -(2-(trif I uoromethyl) pyrid i n-4-y I) picol in amide, Compound 66;1047) 6-(1H-midazol-1 -yI)-4-amino-N-(pyridin-3-yl)picolinamide, Compound 67;1048) 6-(1H-midazol-1 -yI)-4-methy I am i no-N -(pyrid i n-3-y I) picol i namide, Compound 68;1049) 2-(1 H-imidazol-1 -y l)-N-(py ridi n-3-y I) py ri m idi ne-4-carboxamide, Compound 69;1050) 6-(1 H-imidazol-1 -y l)-N-(py ridi n-3-y I) py razi ne-2-carboxam ide, Compound 70;1051) 6-(1H-midazol-1 -yI)-2-(3-methyloxetan-3-yl)oxy-N-(6-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide, Compound 71 ;1052) 2-(1H-midazol-1 -yI)-6-((tetrahydro-2H-pyran-4-yl)methoxy)-N-(6-(trifluoromethyl)pyridin-4-yl)pyrimidine-4- carboxamide, Compound 72;1053) 2-(1-methyl-1H-imidazol-5-yl)-6-((tetrahydro-2H-pyran-4-yl)methoxy)-N-(6-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide, Compound 73;1054) 2-(1 -methyl-1H-i mid azol-5-y l)-6-((tetrahyd ro-2H -py ran-4-y l)methoxy)-N-(6-(trif I uoromethy I) py ridi n-4- yl)pyrimidine-4-carboxamide, Compound 74;1055) 2-(1 -methyl-1H-i mid azol-5-yl)-6-(methoxyethoxy)-N-(6-(trif I uoromethy I) py ridi n-4-y l)py ri mid i ne-4- carboxamide, Compound 75;1056) 2-(1 -methyl-1H-i mid azol-2-yl)-6-(methoxyethoxy)-N-(6-(trif I uoromethy I) py ridi n-4-y l)py ri mid i ne-4- carboxamide, Compound 76;1057) 2-(1 -methyl-1H-py razol-5-y l)-6-(methoxyethoxy)-N -(6-(trifl uoromethyl) py rid i n-4-y I) py ri mid i ne-4-carboxamide, Compound 77;1058) 2-(1 H -i m id azol-1 -y l)-6-(2-hydroxy-2-methyl propoxy)-N-(6-(trif I uoromethyl) py rid i n-4-y I) pyri mid i ne-4- carboxamide, Compound 78;1059) 6-(1 H -i m id azol-1 -y l)-N-(pyridi n-4-y I) py ri mido[5, 4-d]py rim idi n-4-am i ne, Compound 79;1060) 2-(1-methyl-1H-imidazol-5-yl)-6-(3-methyloxetan-3-yl)oxy-N-(6-(trifluoromethyl)pyridin-4-yl)pyrimidine-4- carboxamide, Compound 80;1061 ) 2-(1-methyl-1H-imidazol-2-yl)-6-(3-methyloxetan-3-yl)oxy-N-(6-(trifluoromethyl)pyridin-4-yl)pyrimidine-4- carboxamide, Compound 81 ; or1062) 2-(1-methyl-1H-pyrazol-5-yl)-6-(3-methyloxetan-3-yl)oxy-N-(6-(trifluoromethyl)pyridin-4-yl)pyrimidine-4- carboxamide, Compound 82; or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[0195] In most preferred embodiments, the CD38 inhibitor is:• 4-((cyclopropyl)oxy)-6-(1H-midazol-1 -yI)-N-(2-(trifluoromethyl)pyridin-4-yl)picolinamide (Compound 32),• 6-(1H-midazol-1 -yI)-4-methoxy-N -(2-(trif I uoromethy I) py rid i n-4-y I) picoli n amide (Compound 35), or• 2-(1H-midazol-1 -yI)-6-methoxyethoxy-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide (Compound 39). or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.Picolinamide and pyrimidine carboxamides of formula (XVI)

[0196] In embodiments, the CD38 inhibitor is a picolinamide and pyrimidine carboxamides as described in WO 2023 / 235880, incorporated herein by reference.

[0197] In preferred embodiments, the CD38 inhibitor is of formula (XVI):R3R1 <^R2R5(XVI), wherein:R1is selected from N and CR11;R2is selected from N and CR12;R3is selected from hydrogen, halogen, -CN, -OR16, -SO2R16, C1-C6alkyl, C3-12carbocycle, and 3- to 12- membered heterocycle, wherein the C1-C6alkyl, C3-12carbocycle, and 3- to 12- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, - NO2, -NH2, -NH-C1-C6alkyl, -N(C1-C6alkyl)2, -C1-C6haloalkyl, -O-C1-C6alkyl, C1-C6alkyl, C2-10alkenyl, C2- 10 alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle;R4is selected from a 5- to 6- membered heteroaryl, wherein the 5- to 6- membered heteroaryl is selected from imidazole, thiazole, oxazole, pyrimidine, pyrazine, pyridazine, oxadiazole, and thiadiazole, each of which is optionally substituted with one or more R9;R5is selected from hydrogen and C1-C6alkyl;R7is selected from an optionally substituted saturated 4- to 8-membered heterocycle, optionally substituted C3-5cycloalkyl, optionally substituted C7-10cycloalkyl, and substituted C6cycloalkyl, wherein the 4- to 8- membered heterocycle, C3-5cycloalkyl, and C7-10cycloalkyl are each optionally substituted with one or more Rs, and the Ce cycloalkyl is substituted with one or more R8A, and the Ce cycloalkyl is further optionally substituted with one or more R8B;R8is independently selected at each occurrence from halogen, -OR20, -S R20, -N(R21)2, -NO2, =O, =S, =N(R20), -CN, C1-6aminoalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkoxyalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C(O)R20, -C(O)OR20, -C(O)N(R21)2, - N(R21)C(O)R20, -N(R21)C(O)N(R21)2, - S(O)2(R20), -S(O)(R2°), -S(O)2(NR2°2), - S(O)(N R21)R20, -S(O)(NR21)N(R21)2, and 4- to 8-membered heterocycle; wherein when R4is imidazole, R3is hydrogen, R7is pyrrolidine substituted with oxo and haloalkyl, the haloalkyl is selected from C1haloalkyl and C3-6haloalkyl; and wherein when R1is N, R3is imidazole, R7is C4 cycloalkyl, and R8is -OR20, the C1-6alkyl of R20is selected from C1alkyl and C3-6alkyl;R8Ais independently selected at each occurrence from halogen, C1-6haloalkyl, -C(O)R20, - C(O)OR20, - C(O)N(R21)2, -N(R21)C(O)R20, -N(R21)C(O)N(R21)2, -S(O)2(R20), -S(O)(R20), - S(O)2(NR202), -S(O)(NR21)R20, and -S(O)(NR21)N(R21)2;R8Bis independently selected each occurrence from -OR20, -SR20, -N(R21)2, -NO2, =O, =S, =N(R20), -CN, C1-6aminoalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl;each R9is independently selected from halogen, -OH, -CN, -NO2, -NH2, -NHC1-10alkyl, -N(C1-10alkyl)2, C1-10alkyl, - C1-10haloalkyl, -0- C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle;R11is selected from hydrogen, halogen, -OH, -CN, -NO2, -NH2, -NHC1-10alkyl, -N(C1-10alkyl)2, -O-C1-10alkyl, C1-C6alkyl, and C1-C6haloalkyl;R12is selected from hydrogen, halogen, -OH, -CN, -NO2, -NH2, -NHC1-10alkyl, -N(C1-10alkyl)2, -O-C1-10alkyl, C1-C6alkyl, and C1-C6haloalkyl;R16is selected from hydrogen; C1-6alkyl, and C3-12carbocycle, wherein the C1-6alkyl, and C3-12carbocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, - CN, -NO2, -NH2, -NHC1-10alkyl, -N( C1-10alkyl)2, -O-C1-10alkyl, C2-10alkenyl, C1-C6alkyl, C1-C6haloalkyl, C2-10alkynyl, C3-12carbocycle, and 3- to 12- membered heterocycle;R20is independently selected at each occurrence from hydrogen; C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, - NO2, -NH2, C1-10alkyl, -C1-10haloalkyl, -O-C1- 10 alkyl, C2-10alkenyl, C2-10alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle; andR21is independently selected at each occurrence from hydrogen; C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, - NO2, -NH2, C1-10alkyl, -C1-10haloalkyl, -O-C1- 10 alkyl, C2-10alkenyl, C2-10alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle. or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[0198] In embodiments, the CD38 inhibitor is:1063) 6-(1 H-lmidazol-1 -yl)-4-methyl-N-(1 -(methylsulfonyl)piperidin-4-yl)picolinamide (1A);1064) N-(1 -(Ethylsulfonyl)piperidin-4-yl)-6-(1H-midazol-1 -yI)-4-methylpicolinamide (2A);1065) N-(1 -(cyclopropylsulfonyl)piperidin-4-yl)-6-(1 H-imidazol-1-yl)-4-methylpicolinamide (3A);1066) 6-(1 H-lmidazol-1 -yl)-N-(1-((2-methoxyethyl)sulfonyl)piperidin-4-yl)-4-methylpicolinamide (4A);1067) N-(1 -(Cyclohexylsulfonyl)piperidin-4-yl)-6-(1 H-imidazol-1-yl)-4-methylpicolinamide (5A);1068) 6-(1 H-lmidazol-1 -yl)-4-methyl-N-(1 -(propylsulfonyl)piperidin-4-yl)picolinamide (6A);1069) 6-(1 H-lmidazol-1 -yl)-4-methyl-N-(1 -(methylsulfonyl)azetidin-3-yl)picolinamide (7A);1070) N-(4,4-Difluorocyclohexyl)-6-(1H-midazol-1 -yI)-4-methylpicolinamide (8A);1071 ) 6-(1 H-lmidazol-1 -yl)-4-methyl-N-(tetrahydro-2H-pyran-3-yl)picolinamide (9A);1072) N-(1 -Acetylpiperidin-4-yl)-6-(1H-midazol-1 -yI)-4-methylpicolinamide (10A);1073) 6-(1 H-lmidazol-1 -yl)-4-methyl-N-(piperidin-4-yl)picolinamide (11 A);1074) N-Cyclobu tyl-6-( 1 H-im id azol-1 -y l)-4-methy Ipicol i n am ide (12A);1075) N-(1-Butyrylpiperidin-4-yl)-6-(1 H-imidazol-1-yl)-4-methylpicolinamide (13A);1076) 6-(1 H-lmidazol-1 -yl)-4-methyl-N-(1-(N-methylsulfamoyl)piperidin-4-yl)picolinamide (14A);1077) 6-(1 H-lmidazol-1 -yl)-4-methoxy-N-(1-(methylsulfonyl)piperidin-4-yl)picolinamide (15A);1078) 6-(1 H-lmidazol-1 -yl)-N-(1-(methylsulfonyl)piperidin-4-yl)picolinamide (16A);1079) tert-Butyl (R)-3-(6-(1H-midazol-1 -yI)-4-methylpicolinamido)piperidine-1 -carboxylate;1080) N-(1-(N,N-Dimethylsulfamoyl)piperidin-4-yl)-6-(1H-midazol-1 -yI)-4-methylpicolinamide (18A);1081) 6-(1 H-lmidazol-1 -yl)-4-methyl-N-(1-(2-morpholinoacetyl)piperidin-4-yl)picolinamide (19A);1082) 6-(1 H-lmidazol-1 -yl)-N-(1-(3-methoxypropanoyl)piperidin-4-yl)-4-methylpicolinamide (20A);1083) N-(1-(Dimethylcarbamoyl)piperidin-4-yl)-6-(1 H-imidazol-1-yl)-4-methylpicolinamide (21 A);1084) 6-(1 H-lmidazol-1 -yl)-4-methyl-N-(1 -(methylcarbamoyl)piperidin-4-yl)picolinamide (22A);1085) N-(1 ,1-Dioxidotetrahydrothiophen-3-yl)-6-(1H-midazol-1 -yI)-4-methylpicolinamide (23A);1086) N-(2,2-Dimethyltetrahydro-2H-pyran-4-yl)-6-(1H-midazol-1 -yI)-4-methylpicolinamide (24A);1087) N-(4,4-Difluorotetrahydro-2H-pyran-3-yl)-6-(1H-midazol-1 -yI)-4-methylpicolinamide (25A);1088) N-(5,5-Difluorotetrahydro-2H-pyran-3-yl)-6-(1H-midazol-1 -yI)-4-methylpicolinamide (26A);1089) N-(3,3-Dimethyltetrahydro-2H-pyran-4-yl)-6-(1H-midazol-1 -yI)-4-methylpicolinamide (27A);1090) N-(8-Oxabicyclo[3.2.1 ]octan-3-yl)-6-(1H-midazol-1 -yI)-4-methylpicolinamide (28A);1091) N-(6,6-Dimethyltetrahydro-2H-pyran-3-yl)-6-(1 H-imidazol-1-yl)-4-methylpicolinamide (29A);1092) 6-(1 H-lmidazol-1 -yl)-4-methyl-N-(2-methyltetrahydro-2H-pyran-4-yl)picolinamide (30A);1093) N-(3-Oxabicyclo[3.1.0]hexan-...

Claims

CLAIMS:1 . A method for reducing TH2 inflammation in a subject, the method comprising administering to the subject a therapeutically effective amount of CD38 inhibitor to said subject.

2. A method for treating or preventing a TH2 inflammation-associated condition in a subject, the method comprising administering to the subject a therapeutically effective amount of CD38 inhibitor to said subject.

3. Use of a CD38 inhibitor for reducing TH2 inflammation in a subject.

4. Use of a CD38 inhibitor for treating or preventing a TH2 inflammation-associated condition in a subject.

5. Use of a CD38 inhibitor for the manufacture of a medicament for reducing TH2 inflammation in a subject.

6. Use of a CD38 inhibitor for the manufacture of a medicament for treating or preventing a TH2 inflammation-associated condition in a subject.

7. A CD38 inhibitor for use in reducing TH2 inflammation in a subject.

8. A CD38 inhibitor for use in treating or preventing a TH2 inflammation-associated condition in a subject.

9. A pharmaceutical composition for reducing TH2 inflammation in a subject, the pharmaceutical composition comprising a CD38 inhibitor and a pharmaceutically acceptable carrier.

10. A pharmaceutical composition for treating or preventing a TH2 inflammation-associated condition in a subject, the pharmaceutical composition comprising a CD38 inhibitor and a pharmaceutically acceptable carrier.11 . The method / use / inhibitor for use / composition for use of any one of claims 1 to 10, wherein the subject is a human subject.

12. The method / use / inhibitor for use / composition for use of any one of claims 1 to 11 , wherein said 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.

13. The method / use / inhibitor for use / composition for use of claim 12, wherein the one or more TH2 inflammatory mediator is an interleukin, a cytokine, a leukotriene, a transcription factor, a prostaglandin, a chemokine, a hormone, and / or histamine.

14. The method / use / inhibitor for use / composition for use of claim 12, wherein the one or more 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.

15. The method / use / inhibitor for use / composition for use of any one of claims 1 to 14, wherein said reducingTH2 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.

16. The method / use / inhibitor for use / composition for use of any one of claims 1 to 15, wherein the TH2 inflammation-associated condition is chronic or acute (present acute manifestations), preferably chronic.

17. The method / use / inhibitor for use / composition for use of any one of claims 1 to 15, wherein the CD38 inhibitor is used to prevent the TH2 inflammation from becoming a chronic TH2 inflammation-associated condition.

18. The method / use / inhibitor for use / composition for use of any one of claims 1 to 17, wherein the 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 (ABPA) and allergic conjunctivitis; eosinophilia; eosinophilic esophagitis; eosinophilic granulomatosis with polyangiitis (eGPA); hypereosinophilic syndrome (HES) including chronic eosinophilic leukemia, idiopathic HES, parasitic infestations, allergic reactions, or a HES secondary to an underlying condition such as helminth infections or eGPA; Chronic Obstructive Pulmonary Disease (COPD), preferably in subjects with elevated eosinophil counts and altered gene and protein expression of several TH2 markers; aspirin-exacerbated respiratory disease; Crohn’s disease; ulcerative colitis (UC); rheumatoid arthritis; lupus erythematosus; or urticaria.

19. The method / use / inhibitor for use / composition for use of any one of claims 1 to 18, wherein the TH2 inflammation-associated condition is chronic rhinosinusitis (CRS), asthma, atopic dermatitis or eosinophilic esophagitis.

20. The method / use / inhibitor for use / composition for use of any one of claims 1 to 18, wherein the TH2 inflammation-associated condition is an allergy.21 . The method / use / inhibitor for use / composition for use of any one of claims 1 to 18, wherein the TH2 inflammation-associated condition is chronic rhinosinusitis (CRS), including CRSsNP and CRSwNP, preferably CRSwNP.

22. The method / use / inhibitor for use / composition for use of claim 21 , wherein the CD38 inhibitor is used to prevent the occurrence or reoccurrence of nasal polyps with CRSwNP.

23. The method / use / inhibitor for use / composition for use of any one of claims 1 to 18, wherein the TH2 inflammation-associated condition is COPD.

24. The method / use / inhibitor for use / composition for use of any one of claims 1 to 18, wherein the TH2 inflammation-associated condition is rheumatoid arthritis.

25. The method / use / inhibitor for use / composition for use of any one of claims 1 to 18, wherein the TH2 inflammation-associated condition is Systemic Lupus Erythematosus (SLE).

26. The method / use / inhibitor for use / composition for use of any one of claims 1 to 18, wherein the TH2 inflammation-associated condition is ulcerative colitis.

27. The method / use / inhibitor for use / composition for use of any one of claims 1 to 17, wherein the CD38 inhibitor is used 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, to prevent a TH2 inflammation-associated condition, such as asthma, CRS, or another TH2 inflammation-associated condition.

28. The method / use / inhibitor for use / composition for use of any one of claims 1 to 17, wherein the TH2 inflammation-associated condition is TH2 inflammation-associated fibrogenesis or TH2 inflammation- associated fibrosis.

29. The method / use / inhibitor for use / composition for use of any one of claims 1 to 17, wherein the TH2 inflammation-associated condition is TH2 inflammation-associated tissue remodeling.

30. The method / use / inhibitor for use / composition for use of claim 29, wherein the TH2 inflammation- associated tissue remodeling is reduced by reducing fibrosis, preferably the deposition of collagen; and / or by reducing tissue hyperresponsiveness.31 . The method / use / inhibitor for use / composition for use of any one of claims 1 to 17, wherein said wherein the TH2 inflammation-associated condition is TH2 inflammation-associated epithelial dysfunction.

32. The method / use / inhibitor for use / composition for use of claim 31, wherein said 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.

33. The method / use / inhibitor for use / composition for use of any one of claims 1 to 32, wherein the CD38 inhibitor is a small molecule, preferably with a molecular weight up to 5000 Da, preferably up to 2000 Da, and most preferably up to about 1000 Da.

34. The method / use / inhibitor for use / composition for use of any one of claims 1 to 33, wherein the CD38 inhibitor comprises a thiazole, imidazole, pyrazole, or pyridazole group, preferably a thiazole or imidazole group, and more preferably a thiazole group.

35. The method / use / inhibitor for use / composition for use of any one of claims 1 to 34, wherein the CD38 inhibitor comprises a 4-(2-methoxyethoxy)cyclohexyl)amino) group, preferably a trans-4-(2- methoxyethoxy)cyclohexyl)amino) group.

36. The method / use / inhibitor for use / composition for use of any one of claims 1 to 35, wherein the CD38 inhibitor comprises a trans-4-(2-methoxyethoxy)cyclohexyl)amino) group and an imidazole group or a thiazole group, preferably a thiazole group.

37. The method / use / inhibitor for use / composition for use of any one of claims 1 to 36, wherein the CD38 inhibitor is: a 6- thiazoloquinolin-2-one of formula (I), including those of formula (II);a cyclohexyl-5-(thiazol-5-yl)-1h-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);Oa 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 formula (XII),a pyrazole of formula (XI I la), (XI I lb), or (XI lie),a heterobicyclic amide of formula (XIV),a heteroaryl amide of formula (XV) or (XV*), ora picolinamide and pyrimidine carboxamide of formula (XVI),wherein the substituents are as described above, or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

38. The method / use / inhibitor for use / composition for use of any one of claims 1 to 37, wherein the CD38inhibitor is:• 4-((-4-(2-Methoxyethoxy)cyclohexyl)amino)-1 -methy l-6-(th i azol-5-y l)q u i nol i n-2( 1 H)one, corresponding to compound 78c of Haffner 2015 and Bosslet 2019,• 1 -Methyl-4-((tetrahydro-2Hpyran-4-yl)amino)-6-(thiazol-5-yl)quinolin-2(1 H)-one, corresponding to compound 78b of Haffner 2015,• 4-(((1 r,4r)-4-(2-Methoxyethoxy)cyclohexyl)amino)-1 , 8-d i methy l-6-(thiazol-5-y l)quinol i n2( 1 H)-one, corresponding to compound 79c of Haffner 2015,• 4-(((1 r,4r)-4-Methoxycyclohexyl)amino)-1 , 8-d i methy l-6-(th i azol-5-yl)qui nolin-2( 1 H)-one, corresponding to compounds 79d of Haffner 2015,• 5-(1 H-imidazol-1-yl)-N-(4-(2-methoxyethoxy)cyclohexyl)-1H-indole-7-carboxamide (corresponding to Example 5 of WO 2016 / 087975),• 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,• 2-(1 H-lmidazol-1-yl)-N-(4-(2-methoxyethoxy)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide, corresponding to compound RBN013209 of WO 2021 / 021986,• 5-(1 H -i m id azol-1 -yl)-N-((1 r, 4r)-4-((2, 2, 2-trifl uoroethy l)am i no)cyclohexy I)- 1 H-py razolo[3, 4-c]py rid i ne-7- carboxamide, corresponding to Example 115 of WO 2021 / 021986,• N-((1 r,4r)-4-(2-hydroxypropan-2-yl)cyclohexyl)-5-(1H-midazol-1 -yI)-1H-pyrazolo[4,3-d]pyrimidine-7- carboxamide, corresponding to Example 182 of WO 2021 / 021986.• 5-(1 H-imidazol-1-yl)-N-((1 r,4r)-4-((3,3,3-trifluoropropyl)amino)cyclohexyl)-1H-pyrazolo[3,4-c]pyridine-7- carboxamide, corresponding to Example 189 of WO 2021 / 021986,• 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, corresponding to Example 191 of WO 2021 / 021986,• N-((1 r,4r)-4-((2,2-difluoropropyl)amino)cyclohexyl)-5-(1H-midazol-1 -yI)-1H-pyrazolo[3,4-c]pyridine-7- carboxamide, corresponding to Example 193 of WO 2021 / 021986,• N-((1 r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-5-(1H-midazol-1 -yI)-1H-pyrazolo [3,4-c] pyridine-7- carboxamide, corresponding to Example 195 of WO 2021 / 021986,• 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 WO 2022 / 165114,• 2-(1 H-imidazol-1-yl)-N-(2-(2-methoxyethoxy)pyrimidin-5-yl)-6-(trifluoromethyl) pyrimidine-4-carboxamide, corresponding to Compound 1 of WO / 2022 / 228496,1722-(1 H-imidazol-1-yl)-N-(4-(2-methoxyethoxy)cyclohexyl)-6-methylpyrimidine-4-carboxamide, corresponding to Example 35 of W0 2021 / 207186,• 6-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(1-methyl-1 H-pyrazol-4-yl)picolinamide, corresponding to Example 12 of 2021 / 207186,• 4-amino-6-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide, corresponding to Example 15 of 2021 / 207186,• 4, 6-di(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide, corresponding to Example 16 of 2021 / 207186,• 6-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(thiazol-5-yl)picolinamide, corresponding to Example 17 of 2021 / 207186,• 4-chloro-6-(1 H-imidazol-1-yl)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-picolinamide, corresponding to Example 18 of 2021 / 207186,• 2-(1 H-imidazol-1-yl)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1 -methyl-1 H-pyrazol-4-yl)pyrimidine-4- carboxamide, corresponding to Example 27 of 2021 / 207186,• N-((1 r,4r)-4-(difluoromethoxy)cyclohexyl)-2-(1 H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide, corresponding to Example 42 of 2021 / 207186,• 6-(fluoromethyl)-2-(1H-midazol-1 -yI)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide, corresponding to Example 51 of 2021 / 207186,• 2-(1 H-imidazol-1-yl)-N-((1s,4s)-4-(2-methoxyethoxy)cyclohexyl)-6-methylpyrimidine-4-carboxamide, corresponding to Example 60 of 2021 / 207186,• (R)-N-(Tetrahydro-2H-pyran-3-yl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1,4]oxazepine-10-carboxamide, corresponding to Compound 1A of WO 2024 / 226685,• (R)-N-(1 , 1 -Dioxidotetrahyd rothiophen-3-y l)-5,6-d i hyd robenzo[f]i mid azo[1 , 5-d][ 1 ,4]oxazepine-10- carboxamide, corresponding to Compound 2A of WO 2024 / 226685,• N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10- carboxamide, corresponding to Compound 3A of WO 2024 / 226685,• N-(1-(Methylsulfonyl)piperidin-4-yl)-5,6-dihydrobenzo[f]imidazo[1,5-d][1 ,4]oxazepine-10-carboxamide, corresponding to Compound 4A of WO 2024 / 226685,• (R)-N-(1,1-Dioxidotetrahydrothiophen-3-yl)-4-oxo-4,5-dihydroimidazo[1 ,5-a]quinoxaline-8-carboxamide, corresponding to compound 12A of WO 2024 / 226685,• 2-(1H-midazol-1 -yI)-6-methyl-N-((1 r,4r)-4-((2, 2, 2- trifluoroethyl)amino)cyclohexyl)pyrimidine-4-carboxamide, corresponding to Example 1 of WO 2023 / 084206,173• N-((1r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-2-(1 H- imidazol-1-yl)-6-methyl-pyrimidine-4-carboxamide, corresponding to Example 2 of W0 2023 / 084206,• 6-cyclopropyl-N-((1 r,4r)-4-((2,2- difluoroethyl)amino)cyclohexyl)-2-(1 H-imidazol-1 -yl)pyrimidine-4- carboxamide, corresponding to Example 3 of WO 2023 / 084206,• N-((1 r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-2-(1 H- imidazol-1-yl)-6-methyl-pyrimidine-4-carboxamide, corresponding to Example 10 of WO 2023 / 084206,• 2-(1H-midazol-1 -yI)-6-methy l-N-(( 1 r, 4r)-4-(( 1 , 1 , 1 -trifluoro-2- methylpropan-2- yl)amino)cyclohexyl)pyrimidine-4-carboxamide, corresponding to Example 21 of WO 2023 / 084206,• 4-(1-methyl-1H-imidazol-5-yl)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)thiazole-2-carboxamide, corresponding to Example 1 of WO 2024 / 236315,• 3-(1-methyl-1 H-imidazol-5-yl)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)-1,2,4-thiadiazole-5- carboxamide, corresponding to Example 2 of WO 2024 / 236315,• 2-(1-methyl-1 H-imidazol-5-yl)-N-((1r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)thiazole-4-carboxamide, corresponding to Example 4 of WO 2024 / 236315,• N-((1 r,4r)-4-(3,3-difluoropyrrolidin-1 -yl)cyclohexyl)-4-(1 -methyl-1H-imidazol-5-yl)thiazole-2-carboxamide, corresponding to Example 9 of WO 2024 / 236315,• 1-(1 H-imidazol-1-yl)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)imidazo[1,5-a]pyridine-3- carboxamide, corresponding to Example 1 of WO 2024 / 236316,• N-((1 r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-1-(1 H-imidazol-1-yl)imidazo[1 ,5-a]pyridine-3- carboxamide, corresponding to Example 2 of WO 2024 / 236316,• 4-{[(1 r,4r)-4-(2-Methoxyethoxy)cyclohexyl]amino}-1-methyl-6-[1-(oxan-2-yl)-1 H-pyrazol-4-yl]quinolin-2(1 H)- one, corresponding to Compound 11 of Doyle 2023,• 4-{[(1 r,4r)-4-(2-Methoxyethoxy)cyclohexyl]amino}-1-methyl-6-(1 H-pyrazol-4yl)quinolin-2(1 H)-one, Compound corresponding to Compound 12 of Doyle 2023,• 8-{[(1 r,4r)-4-Hydroxy-4-methylcyclohexyl]amino}2-(1H-midazol-1 -yI)-5-methylpyrido[3,2-d]pyrimidin-6(5H)- one, corresponding to Compound 13 of Doyle 2023,• 2-(1 H-lmidazol-1 -yl)-5-methyl-8-[(oxan-4-yl)amino]pyrido[3,2-d]pyrimidin-6(5H)-one, corresponding to Compound 14 of Doyle 2023,• 2-(1H-midazol-1 -yI)-N-((1r,4r)-4-((2, 2, 2-trifluoroethyl)amino)cyclohexyl)pyrido[2,3-d]pyrimidine-4- carboxamide, corresponding to Example 4 of WO 2023 / 227867,N-((1 r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-2-(1H-midazol-1 -yI)pyrrolo[2,1-f][1, 2, 4]triazine-4- carboxamide, corresponding to Example 12 of WO 2023 / 227867,174N-((1s,4r)-4-((S)-3-fluoropyrrolidin-1-yl)cyclohexyl)-2-(1H-midazol-1 -yI)pyrrolo[2,1-f][1 ,2,4]triazine-4- carboxamide, corresponding to Example 13 of W0 2023 / 227867,• N-((1r,4r)-4-((R)-3-fluoropyrrolidin-1-yl)cyclohexyl)-2-(1 H-imidazol-1-yl)pyrrolo[2,1-f][1,2,4]triazine-4- carboxamide, corresponding to Example 14 of WO 2023 / 227867,• 8-(1H-midazol-1 -yI)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)imidazo[1 ,2-a]pyrazine-6- carboxamide, corresponding to Example 19 of WO 2023 / 227867,• 8-(1 H -i m id azol-1 -yl)-N-((1 r, 4r)-4-((2, 2, 2-trifl uoroethy l)am i no)cyclohexy l)-[ 1 , 2, 4]tri azolo[1 ,5-a]pyrazine-6- carboxamide, corresponding to Example 20 of WO 2023 / 227867,• 4-(1H-midazol-1 -yI)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)pyrazolo[1 ,5-a]pyrazine-6- carboxamide, corresponding to Example 21 of WO 2023 / 227867,• 2-(1 H-imidazol-1-yl)-N-((1 r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)pyrrolo[2, 1-f][1 ,2,4]triazine-4- carboxamide, corresponding to Example 29 of WO 2023 / 227867,• N-((1 r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-8-(1H-midazol-1 -yI)imidazo[1 ,2-a]pyrazine-6- carboxamide, corresponding to Example 41 of WO 2023 / 227867,• N-((1 r,4r)-4-(3,3-difluoroazetidin-1-yl)cyclohexyl)-8-(1H-midazol-1 -yI)-[1, 2, 4]triazolo[1,5-a]pyrazine-6- carboxamide, corresponding to Example 45 of WO 2023 / 227867,• N-((1 r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-8-(1H-midazol-1 -yI)-[1 ,2,4]triazolo[i,5-a]pyrazine-6- carboxamide, corresponding to Example 48 of WO 2023 / 227867,• 4-((cyclopropyl)oxy)-6-(1H-midazol-1 -yI)-N-(2-(trifluoromethyl)pyridin-4-yl)picolinamide, corresponding to Compound 32 of WO 2022 / 077034,• 6-(1H-midazol-1 -yI)-4-methoxy-N-(2-(trifluoromethyl)pyridin-4-yl)picolinamide, corresponding to Compound 35 of WO 2022 / 077034,• 2-(1H-midazol-1 -yI)-6-methoxyethoxy-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide, corresponding to Compound 39 of WO 2022 / 077034, or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

39. The method / use / inhibitor for use / composition for use of any one of claims 1 to 38, wherein 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, or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

40. The method / use / inhibitor for use / composition for use of any one of claims 37 to 39, wherein the prodrug is an ester, an amide, a guanidine, a carbamate, a carbonate, or a phosphate.17541 . The method / use / inhibitor for use / composition for use of any one of claims 1 to 40, wherein the CD38 inhibitor is for oral administration to the subject.

42. The method / use / inhibitor for use / composition for use of any one of claims 1 to 40, wherein the CD38 inhibitor is for topical administration to the skin of the subject.

43. The method / use / inhibitor for use / composition for use of any one of claims 1 to 40, wherein the CD38 inhibitor is for cutaneous administration to the skin of the subject.

44. The method / use / inhibitor for use / composition for use of any one of claims 1 to 40, wherein the CD38 inhibitor is for transdermal administration to the skin of the subject.

45. The method / use / inhibitor for use / composition for use of any one of claims 1 to 40, wherein the CD38 inhibitor is for local administration to the airway of the subject.

46. The method / use / inhibitor for use / composition for use of any one of claims 1 to 40, wherein the CD38 inhibitor is for inhalational or intranasal administration.

47. The method / use / inhibitor for use / composition for use of claim 46, wherein the CD38 inhibitor is for inhalational administration, and is preferably formulated as a suspension, a dry powder, or an aerosol.

48. The method / use / inhibitor for use / composition for use of claim 46, wherein the CD38 inhibitor is 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.

49. The method / use / inhibitor for use / composition for use of any one of claims 1 to 48, wherein the CD38 inhibitor is formulated as a spray.

50. The method / use / inhibitor for use / composition for use of claim 48, wherein the CD38 inhibitor is contained in an inhaler or a nasal spray comprising a canister containing the CD38 inhibitor, an atomizer for dispersing the CD38 inhibitor into an aerosol, and an outlet to disperse the aerosol into the nose or mouth of a patient.51 . The method / use / inhibitor for use / composition for use of any one of claims 1 to 50, wherein the CD38 inhibitor is used in combination with one or more other pharmaceutically active ingredient(s).

52. The method / use / inhibitor for use / composition for use of claim 51 , wherein the one or more other pharmaceutically active ingredient(s) is a prophylactic agent and / or a therapeutic agent.

53. The method / use / inhibitor for use / composition for use of claim 51 or 52, wherein the CD38 inhibitor and said one or more other pharmaceutically active ingredient(s) are administered in a single dosage form or in separate dosage forms.

54. The method / use / inhibitor for use / composition for use of any one of claims 51 to 53, wherein the CD38 inhibitor is administered to the subject before, concomitantly, before, or after said one or more other pharmaceutically active ingredient(s) is administered.17655. The method / use / inhibitor for use / composition for use of any one of claims 51 to 54, wherein the one or more other pharmaceutically active ingredient(s) is for preventing or treating the TH2 inflammation- associated condition.

56. The method / use / inhibitor for use / composition for use of any one of claims 51 to 55, wherein the CD38 inhibitor is used / administered in combination with said one or more other pharmaceutically active ingredient(s), which is already used by the subject to prevent or treat the TH2 inflammation-associated condition.

57. The method / use / inhibitor for use / composition for use of any one of claims 51 to 56, wherein the one or more other pharmaceutically active ingredient(s) is a one or more other CD38 inhibitor.

58. The method / use / inhibitor for use / composition for use of any one of claims 51 to 56, wherein the one or more other pharmaceutically active ingredients(s) is a glucocorticoid, a beta-2 agonist, a muscarinic antagonist, an antimicrobial, an antibiotic, an antihistamine, a leukotriene modifier, a probiotic, a TRP channel modulator, an anthelmintic, a fungicide, an antifibrotic agent, a PARP modulator, an immunotherapeutic agent, and / or hyaluronic acid., preferably a glucocorticoid.

59. The method / use / inhibitor for use / composition for use of claim 58, wherein the 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; fluclorolone acetonide; flucloronide; fludrocortisone; fludroxycortide; flugestone; flumetasone; flunisolide; fluocinolone; fluocinolone acetonide; fluocinonide; fluocortin; fluocortolone; fluoroformylone; fluoromethoIone (including fluoromethoIone acetate); fluperolone; fluprednidene; fluprednisolone; flurandrenolide; flurandrenolone; flurogestone; fluticasone; fluticasone furoate; fluticasone propionate; fluticonase; formocortal; halcinonide; halobetasol; halometasone; hydrocortisone (including hydrocortisone butyrate and hydrocortisone valerate); loteprednol; medrysone (hydroxymethylprogesterone); meprednisone; methylprednisolone (including methylprednisolone acetate); methylprednisone; mometasone; mometasone furoate; paramethasone; prebediolone; prebediolone acetate; prednicarbate; prednisolone (including prednisolone sodium phosphate and prednisone acetate); prednisone; prednylidene; pregnenolone; progesterone; rimexolone; tixocortol (including tixocortol pivalate); triamcinolone; triamcinolone acetonide; ulobetasol; vamorolone; or RU- 28362.

60. The method / use / inhibitor for use / composition for use of claim 59, wherein the glucocorticoid is triamcinolone; dexamethasone; momethasone; fluticasone; hydrocortisone; prednisolone; betamethasone; beclomethasone; ciclesonide; amcinonide; flunisolide; or budesonide.17761 . The method / use / inhibitor for use / composition for use of claim 58, wherein the 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.

62. The method / use / inhibitor for use / composition for use of claim 58, wherein the beta-2 agonist or muscarinic antagonist is formoterol; salmeterol; vilanterol; albuterol; umeclidinium; or salbutamol.

63. The method / use / inhibitor for use / composition for use of claim 58, wherein the the antimicrobial is cetylpyridinium chloride; chlorhexidine; clove; eucalyptol; hydrogen peroxide; mandelic acid; menthol; methyl salicylate; peppermint; povidone iodine; tea tree oil; thymol; triclosan; or xylitol.

64. The method / use / inhibitor for use / composition for use of claim 58, wherein 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; imipenem; tigecycline; fosfomycin; nitrofurantoin; metronidazole; trimethoprim-sulfamethoxazole; or vancomycin.

65. The method / use / inhibitor for use / composition for use of claim 58, wherein the 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; rupatadine; bilastine; ebastine; famotidine; nizatidine; or rynatan.

66. The method / use / inhibitor for use / composition for use of claim 58, wherein the leukotriene modifier is montelukast; zileuton; pranlukast; or zafirlukast.

67. The method / use / inhibitor for use / composition for use of claim 58, wherein the TRP channel modulator is camphor; capsaicin; clemizole; flufenamic acid; ginsenoside Rd; icilin; menthol; neomycin sulfate; parthenolide; peimine; peiminine; piperine; resin iferatoxin; riluzole; sumatriptan; or tranilast.

68. The method / use / inhibitor for use / composition for use of claim 58, wherein the anthelmintic is include albendazole; diethylcarbamazine; ivermectin; mebendazole; miltefosine; moxidectin; praziquantel; pyrantel pamoate; or triclabendazole.

69. The method / use / inhibitor for use / composition for use of claim 58, wherein the fungicide is azoxystrobin;178 benomyl; captan; carbendazim; chlorothalonil; copper oxychloride; cyproconazole; fludioxonil; mancozeb; metalaxyl; propiconazole; sulfur; tebuconazole; thiophanate-methyl; trifloxystrobin; or zineb.

70. The method / use / inhibitor for use / composition for use of claim 58, wherein 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; GSK2618960; MEDI9929 / AMG 157; or TQC2731.71 . The method / use / inhibitor for use / composition for use of claim 58, wherein the PARP modulators is niraparib; olaparib; rucaparib; or talazoparib.

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