WO2026000074A1

WO2026000074A1 - Use of cd38 inhibitors for reducing th2 inflammation

Info

Publication number: WO2026000074A1
Application number: PCT/CA2025/050888
Authority: WO
Inventors: Guy Fernand André TREMBLAY
Original assignee: Welnx Co Inc
Current assignee: Welnx Co Inc
Priority date: 2024-06-25
Filing date: 2025-06-25
Publication date: 2026-01-02
Anticipated expiration: 2026-12-25

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 INFLAMMATION

CROSS REFERENCE TO RELATED APPLICATIONS

The 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 genetic background and is characterized by a disturbed skin barrier and excessive TH2I. AD is considered as a biphasic T cell-mediated disease where not only the chronic phase but also the acute phase entails TH2 signaling.

[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 profile producing cytokines such as IL-4, IL-5 and IL-13. Mucosal TH2 I may be initiated by the release of alarmin-type molecules from injured epithelial cells. TH2-induced fibrogenesis may underlie the mucosal and transmural fibrotic process found in Crohn’s disease and UC. TH2 cells contribute to intestinal mucosa inflammation by secreting IL-4 in UC. Despite a TH2 response in UC, neutralization of IL-13 via monoclonal antibodies was ineffective as a therapeutic strategy in patients with UC. Chronic IBD increases the risk of developing colon polyps and colon cancer.

[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 need for 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 smooth muscle 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 the

CD38 inhibitor is: a 6- thiazoloquinolin-2-one of formula (I), including those of formula (II); an indole-7-carboxamide of formula (III); a cyclohexyl-5-(thiazol-5-yl)-1 h-indole-7-carboxamide of formula (IV); a heterobicyclic amide of formula (V); a quinoline or azaquinoline of formula (VI); a pyridazine or pyrimidine of formula (VII); a pyrazine or pyrimidine carboxamide of formula (VIII); a tricyclic fused imidazole of formula (IXa) or (IXb), a N-(4-aminocyclohexyl)pyrimidine-4-carboxamide of formula (X), a 1,3-thiazoles and 1 ,2,4-thiadiazole of formula (XI), a 3-carbonyl imidazo[1 ,5-a]pyridine of formula (XII), a pyrazole of formula (Xllla), (Xlllb), or (Xlllc),

a heterobicyclic amide of formula (XIV), a heteroaryl amide of formula (XV) or (XV*), or a 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 the CD38 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 Model

Figure 2. (A) Murine TGF-beta 1 and (B) TGF-beta 3 in Nasal Lavage Fluid of CRS Mouse Model

Figure 3. (A) Murine IL-33 and (B) IL-31 in Nasal Lavage Fluid of CRS Mouse Model

Figure 4. (A) Murine RANTES (B) IP-10 (C) M I P-3 alpha and (D) Fractalkine in Nasal Lavage Fluid of CRS

Mouse Model

Figure 5. (A) Murine IL-12p40, (B) IL-12p70, (C) IL-23 and (D) IL-27 in Nasal Lavage Fluid of CRS Mouse

Model

Figure 6. Murine IL-2 in Nasal Lavage Fluid of CRS Mouse Model

Figure 7. (A) Murine Interferon gamma and (B) Interferon beta in Nasal Lavage Fluid of CRS Mouse Model

Figure 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 Control

Figure 9. Goblet Cell Count and Size in and in Nasal Septum Detail of CRS Mouse Model (A) Healthy Animal, (B) CRS- Untreated, (C) CRS - WX-001 , and (D) CRS - Positive Control

Figure 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 Polypectomy

Figure 11. Nasoendoscopy of a Human Subject with CRSwNP 13 Months Following In-Clinic Polypectomy

DETAILED DESCRIPTION OF THE INVENTION

[0026] Turning now to the invention in more details, there is provided a method for reducing TH2 inflammation or for treating or preventing a TH2 inflammation-associated condition in a subject comprising administering to the subject a therapeutically effective amount of CD38 inhibitor to said subject.

[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 a compound of the invention means that amount of therapeutic agent alone, or in combination with other therapies, that provides a therapeutic benefit in the treatment or prevention of a disease. 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 envisioned administered 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 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 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. In embodiments, 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, 9418-9446

Doyle 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*), or

15. 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,

• 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,

• 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,

• 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-(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 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-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,

[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:

R¹ represents H, alkyl (preferably methyl), O-alkyl (preferably O-methyl), or haloalkyl (preferably CF₃),

R² represents H or alkyl (preferably methyl or ethyl),

R³ represents:

H; alkyl (preferably C1-4 alkyl), unsubstituted or substituted with one or more OR¹², wherein R¹² is H or alkyl (preferably methyl); cycloalkyl (preferably C_3-6 cycloalkyl), unsubstituted or substituted with one or more alkyl (preferably methyl), heterocycloalkyl (preferably y-lactam), -OR¹⁴, wherein R¹⁴ is H or alkyl (preferably methyl), -OR¹⁵-OR¹⁶, wherein R¹⁵ alkyl (preferably ethyl), and wherein R¹⁶ is H or alkyl (preferably methyl), -CO-NHR¹¹, wherein R¹¹ is 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; and

R⁴ represents 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:

R² represents H or alkyl (preferably methyl or ethyl), and

R³ represents:

H; alkyl (preferably C1-4 alkyl), unsubstituted or substituted with one or more OR¹², wherein R¹² is H or alkyl (preferably methyl); cycloalkyl (preferably C_3-6 cycloalkyl), unsubstituted or substituted with one or more alkyl (preferably methyl), heterocycloalkyl (preferably y-lactam), -OR¹⁴, wherein R¹⁴ is H or alkyl (preferably methyl), -OR¹⁵-OR¹⁶, wherein R¹⁵ alkyl (preferably ethyl), and wherein R¹⁶ is H or alkyl (preferably methyl), -CO-NHR¹¹, wherein R¹¹ is 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:

R¹ represents H or alkyl (preferably methyl),

R² represents H or alkyl (preferably methyl or ethyl), and

R³ represents cycloalkyl (preferably C_3-6 cycloalkyl), unsubstituted or substituted with one or more -OR¹⁴, wherein R¹⁴ is H or alkyl (preferably methyl), -OR¹⁵-OR¹⁶, wherein R¹⁵ alkyl (preferably ethyl), and wherein R¹⁶ is H or alkyl (preferably methyl), -CO-NHR¹¹, wherein R¹¹ is H or alkyl (preferably methyl or ethyl); or heterocycloalkyl (preferably pyranyl), preferably unsubstituted, or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[0074] In more preferred embodiments, the CD38 inhibitor is of formula (II), wherein:

R¹ represents H,

R² represents alkyl (preferably methyl or ethyl), and

R³ represents cycloalkyl substituted with -OR¹⁵-OR¹⁶, wherein R¹⁵ represents alkyl (preferably ethyl), and wherein R¹⁶ represents 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), or

19) 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);

R¹ is Ci.5alkylS(O)₂CH₃, or C_1-6alkyl, wherein said alkyl can comprise straight-chain portions, branched chain portions, cycloalkyl portions, and wherein said C_1-6alkyl is optionally substituted by one OH or OCH₃ and wherein said C_1-6alkyl is optionally further substituted by 1 to 3 fluorine atoms; and

R² is H, C_1-3alkyl, or halogen, or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[0080] Preferably, R² is H or Cl. Most preferably, R² is 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; or

35) 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;

X¹ is CR^1A and X² is NR^5A , when bond a is a double bond and bond b is a single bond; or X¹ is NR^1B and X² is CR^5B , when bond a is a single bond and bond b is a double bond;

R^1A is H, C_1-4 alkyl, NO₂ , CN, CONR^aR^b , CH₂NR^aR^b, (CHR^c)_mOH, C_1-4haloalkyl, CHO, COO-R^a, or halo;

R^a, R^b, and R^c are each independently H or C_1-4 alkyl;

R^1B is H or C_1-4 alkyl optionally substituted with 3-5 membered monocyclic heterocyclyl or hydroxy;

R^5A is H or C_1-4 alkyl;

R^5B is H, halo, CN, C_1-4alkyl, C_1-4haloalkyl, NHR^b or CONHR^c ;

R² is 5-membered heteroaryl;

R³ is C_1-4 alkyl, C_3-6 cycloalkyl, bridged C_7-12 cycloalkyl, 5-6 membered monocyclic heterocyclyl optionally substituted with one or two oxo groups, or phenyl, wherein said alkyl, cycloalkyl, bridged cycloalkyl, heterocyclyl or phenyl is optionally substituted with one or two R^x groups, wherein R^x is halo, 3 to 6- membered heterocyclyl, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 hydroxyalkyl, SO₂Me or OR^d;

R^d is H or C_1-4 alkyl optionally substituted with C_1-4 alkoxy; R⁴ is H, halo, CN, C_1-4 alkyl, C_1-4 haloalkyl, NHR^e or CONHR^f ;

R^e and R^f are each independently H or C_1-4alkyl;

R⁶ is H or C_1-4 alkyl; n is O or 1 ; and m is 1, 2 or 3, provided that, when R^1A is H or C_1-4 alkyl; and R² is , then n is 1; and provided that when A1 is N, X¹ is N and R^1B is C_1-4 alkyl, then n is 1 ; and, in an alternative, when A1 is N; X¹ is N; R^1B is C_1-4 alkyl; and R³ is 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, R² is

[0088] In preferred embodiments, n is 0.

[0089] In preferred embodiments, R³ is , wherein Y is O, NH, SO₂ , CH₂ or CHR^X, and p is 0 or 1.

[0090] In preferred embodiments, R³ is

[0091] In preferred embodiments, Rx is C_1-4 hydroxy alkyl or OR^d, preferably wherein Rd is H or C_1-4 alkyl substituted with C_1-4 alkoxy.

[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; or

94) 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 CR^V , wherein R^v is H, halo, or C_1-4 alkyl;

W is N or CR^W , wherein R^w is H, halo, or C_1-4 alkyl; Ring A is a 5-membered heteroaryl group having 1 , 2 or 3 ring-forming heteroatoms selected from N, 0, and S, wherein the 5-membered heteroaryl group of Ring A is optionally substituted by 1 , 2, or 3 substituents independently selected from halo and C_1-4 alkyl; each R^N is independently selected from H, C_1-4 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_6-10 aryl, C^3-7 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, wherein said C_1-4 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_6-10 aryl, C³'⁷ cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of R^N are each optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from Cy, Cy-C_1-4 alkyl, halo, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d , C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, C(=NR^e)NR^cR^d, NR^cC(=NR^e)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)Rb, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d; each R^A, R^B, and R^c is independently selected from H, halo, C_1-4 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_2-6 aryl, C_3-7 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, wherein said alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_6-10 aryl, C_3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of R^A, R^B, and R^c are each optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from Cy, Cy-C_1-4 alkyl, halo, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d , C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, C(=NR^e)NR^cR^d, NR^cC(=NR^e)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d;

L is a C_1-4 alkylene linker; n is O or 1 ;

Q is H, C_1-10 alkyl, C_2-10 alkenyl, C_2-10 alkynyl, C_1-10 haloalkyl, C_6-10 aryl, C_3-14 cycloalkyl, 5-14 membered heteroaryl, or 4-14 membered heterocycloalkyl, wherein said C_1-10 alkyl, C_2-10 alkenyl, C_2-10 alkynyl, C_1-10 haloalkyl, C_6-10 aryl, C_3-14 cycloalkyl, 5-14 membered heteroaryl, or 4-14 membered heterocycloalkyl of Q are each optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from Cy¹, Cy¹- C_1-4 alkyl, halo, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, CN, NO₂, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, C(=NR^e1)NR^c1R^d1, NR^c1C(=NR^e1)NR^c1R^d1, NR^c1 R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1C(O)NR^c1 R^d1, NR^c1S(O)R^b1, NR^c1S(O)₂R^b1, NR^c1S(O)₂NR^c1 R^d1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, and S(O)₂NR^c1 R^d1; wherein Q is other than H when n is 0; each Cy is independently selected from C_6-10 aryl, C_3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted by 1 , 2, 3, or 4 substituents independently selected from halo, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_6-10 aryl-C_1-4 alkyl, C_3-7 cycloalkyl-C_1-4 alkyl, 5- 10 membered heteroaryl- C_1-4 alkyl, 4-10 membered heterocycloalkyl-C_1-4 alkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d , C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, C(=NR^e)NR^cR^d, NR^cC(=NR^e)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d; each Cy¹ is independently selected from C_6-10 aryl, C_3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted by 1 , 2, 3, or 4 substituents independently selected from halo, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_6-10 aryl, C_3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl, C_3-7 cycloalkyl-C_1-4 alkyl, 5-10 membered heteroaryl-C_1-4 alkyl, 4-10 membered heterocycloalkyl-C_1-4 alkyl, CN, NO₂, OR^a2, SR^a2, C(O)R^b2, C(O)NR^c2R^d2 , C(O)OR^a2, OC(O)R^b2, OC(O)NR^c2R^d2, C(=NR^e2)NR^c2R^d2, NR^c2C(=NR^e2)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2C(O)NR^c2R^d2, NR^c2S(O)R^b2, NR^c2S(O)₂R^b2, NR^c2S(O)₂NR^c2R^d2, S(O)R^b2, S(O)NR^c2R^d2, S(O)₂R^b2, and S(O)₂NR^c2R^d2; each R^a, R^b, R^c, R^d, R^a1, R^b1, R^c1, R^d1, R^a2, R^b2, R^c2, and R^d2 is independently selected from H, C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C_3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl, C_3-7 cycloalkyl-C_1-4 alkyl, 5-10 membered heteroaryl-C_1-4 alkyl, 4-10 membered heterocycloalkyl-C_1-4 alkyl, wherein said C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C_3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C-1-4 alkyl, C_3-7 cycloalkyl-C_1-4 alkyl, 5-10 membered heteroaryl-C_1-4 alkyl, 4-10 membered heterocycloalkyl-C-1-4 alkyl of R^a, R^b, R^c, R^d, R^a1, R^b1, R^c1, R^d1, R^a2, R^b2, R^c2, and R^d2 is optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from Cy², Cy²-C_1-4 alkyl, halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C₂ .6 alkynyl, CN, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)NR^c3R^d3, NR^c3C(O)OR^a3, C(=NR^e3)NR^c3R^d3, NR^c3C(=NR^e3)NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, NR^c3S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, and S(O)₂NR^c3R^d3; or R^c and R^d 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, C_1-4 alkyl, C_1-4 haloalkyl, CN, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)NR^c3R^d3, NR^c3C(O)OR^a3, C(=NR^e3)NR^c3R^d3, NR^c3C(=NR^e3)NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, NR^c3S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, and S(O)₂NR^c3R^d3; or R^c1 and R^d1 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, C_1-4 alkyl, C_1-4 haloalkyl, CN, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)NR^c3R^d3, NR^c3C(O)OR^a3, C(=NR^e3)NR^c3R^d3, NR^c3C(=NR^e3)NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, NR^c3S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, and S(O)₂NR^c3R^d3; or R^c2 and R^d2 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, C_1-4 alkyl, C_1-4 haloalkyl, CN, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)NR^c3R^d3, NR^c3C(O)OR^a3, C(=NR^e3)NR^c3R^d3, NR^c3C(=NR^e3)NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, NR^c3S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, and S(O)₂NR^c3R^d3; each Cy² is C_6-10 aryl, C_3-7 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, each optionally substituted by 1 , 2, 3, or 4 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-6 haloalkyl, C_2.6 alkenyl, C_2.6 alkynyl, CN, 0R^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, 0C(O)R^b3, OC(O)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)NR^c3R^d3, NR^c3C(O)OR^a3, C(=NR^e3)NR^c3R^d3, NR^c3C(=NR^e3)NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, NR^c3S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, and S(O)₂NR^c3R^d3; each R^a3, R^b3, R^c3, and R^d3 is independently selected from H, C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C_3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C-i- 4 alkyl, C_3-7 cycloalkyl-C_1-4 alkyl, 5-10 membered heteroaryl-C_1-4 alkyl, and 4-10 membered heterocycloalkyl- C_1-4 alkyl, wherein said C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C_3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl, C_3-7 cycloalkyl-C_1-4 alkyl, 5-10 membered heteroaryl-C_1-4 alkyl, and 4-10 membered heterocycloalkyl-C_1-4 alkyl of R^a3, R^b3, R^c3, and R^d3 are each optionally substituted with 1 , 2, or 3 substituents independently selected from OH, CN, amino, halo, C1- ₆ alkyl, C_1-6 alkylamino, di(C_1-6 alkyl)amino, C_1-6 alkoxy, C_1-6 haloalkyl, and C_1-6 haloalkoxy; each R^e, R^e1, R^e2, and R^e3 is independently selected from H, C_1-4 alkyl, 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 by n is O; and

Q is cyclohexyl optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from Cy¹, Cy¹- C_1-4 alkyl, halo, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, CN, NO₂, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, C(=NR^e1)NR^c1R^d1, NR^c1C(=NR^e1)NR^c1R^d1, NR^c1 R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1C(O)NR^c1 R^d1, NR^c1S(O)R^b1, NR^c1S(O)₂R^b1, NR^c1S(O)₂NR^c1R^d1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; 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.

[00100] In preferred embodiments, the moiety represented by

[00102] In preferred embodiments, Ring A is a 5-membered heteroaryl group having 2 ring-forming N heteroatoms, , preferably

[00103] In preferred embodiments, each R^N is H.

[00104] In preferred embodiments, each R^A, and R^B is H.

[00105] In preferred embodiments, n is 0.

[00106] In preferred embodiments, Q is a C_3-14 cycloalkyl (preferably cyclohexyl) substituted with OR^a1, NR^c1R^d1, or - C(CH₃)₂-OH.

[00107] In preferred embodiments, each R^a1 is C_1-6 alkyl (preferably ethyl) substituted with OR^a3.

[00108] In preferred embodiments, each R^c1 is H. In preferred embodiments, each R^d1 is C_1-6 alkyl (preferably ethyl or propyl) substituted with halogen. In preferred embodiments, each R^a3 is independently C_1-6 alkyl, preferably methyl.

[00109] In embodiments, the CD38 inhibitor is:

[00110] 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, Example 229;

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; or 383) 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.

[00111] 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.

[00112] 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)

[00113] In embodiments, the CD38 inhibitor is a quinoline or azaquinoline as described in WO 2022/165114, incorporated by reference herein.

[00114] In embodiments, the CD38 inhibitor is of formula (VI):

(VI), wherein:

X³ is CR³ or N;

X⁴ is CR⁴ or N;

A is a 5-membered heteroaryl group having 1 , 2 or 3 ring-forming heteroatoms selected from N, 0, and S, wherein the 5-membered heteroaryl group of A is optionally substituted by 1 , 2, or 3 substituents independently selected from halo and C_1-4 alkyl;

L is a C_1-4 alkylene linker; n is O or 1 ;

Q is H, C_1-10 alkyl, C_2-10 alkenyl, C_2-10 alkynyl, C_1-10 haloalkyl, C_6-10 aryl, C_3-14 cycloalkyl, 5-14 membered heteroaryl, or 4-14 membered heterocycloalkyl, wherein said C_1-10 alkyl, C_2-10 alkenyl, C_2-10 alkynyl, C_1-10 haloalkyl, C_6-10 aryl, C_3-14 cycloalkyl, 5-14 membered heteroaryl, or 4-14 membered heterocycloalkyl of Q are each optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from Cy¹, Cy¹-C_1-4 alkyl, halo, C_1-6 alkyl, C_2.6 alkenyl, C_2.6 alkynyl, C_1-6 haloalkyl, CN, N0₂, 0R^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, C(=NR^e)NR^cR^d, NR^cC(=NR^e)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d, wherein said C_1-6 alkyl, C_2-6 alkenyl, and C_2-6 alkynyl are optionally substituted by 1 , 2, or 3 substituents independently selected from Cy¹, CN, N0₂, 0R^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, C(=NR^e)NR^cR^d, NR^cC(=NR^e)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d; each Cy¹ is independently selected from C_6-10 aryl, C_3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted by 1 , 2, 3, or 4 substituents independently selected from halo, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_6-10 aryl-C_1-4 alkyl, C_3-7 cycloalkyl-C_1-4 alkyl, 5- 10 membered heteroaryl-C_1-4 alkyl, 4-10 membered heterocycloalkyl-C_1-4 alkyl, CN, NO₂, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1 R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, C(=NR^e1)NR^c1R^d1, NR^c1C(=NR^e1)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1C(O)NR^c1R^d1, NR^c1S(O)R^b1, NR^c1S(O)₂R^b1, NR^c1S(O)₂NR^c1R^d1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, and S(O)₂NR^c1 R^d1;

R¹ is C_1-6 alkyl; R², R³, and R⁴ are each independently selected from H, halo, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_6-10 aryl, C_3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl- C_1-4 alkyl, C_3-7 cycloalkyl-C_1-4 alkyl, 5-10 membered heteroaryl-C_1-4 alkyl, 4-10 membered heterocycloalkyl- C_1-4 alkyl, CN, NO₂, OR^a2, SR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, OC(O)R^b2, OC(O)NR^c2R^d2, C(=NR^e2)NR^c2R^d2, NR^c2C(=NR^e2)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2C(O)NR^c2R^d2, NR^c2S(O)R^b2, NR^c2S(O)₂R^b2, NR^c2S(O)₂NR^c2R^d2, S(O)R^b2, S(O)NR^c2R^d2, S(O)₂R^b2, and S(O)₂NR^C2R^d2, wherein said C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_6-10 aryl, C_3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl, C_3-7 cycloalkyl-C_1-4 alkyl, 5-10 membered heteroaryl-C_1-4 alkyl, and 4-10 membered heterocycloalkyl-C_1-4 alkyl of R², R³, and R⁴ are each optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from halo, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, CN, NO₂, OR^a2, SR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, OC(O)R^b2, OC(O)NR^c2R^d2, C(=NR^e2)NR^c2R^d2, NR^c2C(=NR^e2)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2C(O)NR^c2R^d2, NR^c2S(O)R^b2, NR^c2S(O)₂R^b2, NR^c2S(O)₂NR^c2R^d2, S(O)R^b2, S(O)NR^c2R^d2, S(O)₂R^b2, and S(O)₂NR^C2R^d2; each R^a, R^b, R^c, R^d, R^a1, R^b1, R^c1, R^d1, R^a2, R^b2, R^c2, and R^d2 is independently selected from H, C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C_3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl, C_3-7 cycloalkyl-C_1-4 alkyl, 5-10 membered heteroaryl-C_1-4 alkyl, and 4- 10 membered heterocycloalkyl-C_1-4 alkyl, wherein said C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, Ce- io aryl, C_3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl, C_3-7 cycloalkyl-C_1-4 alkyl, 5-10 membered heteroaryl-C_1-4 alkyl, and 4-10 membered heterocycloalkyl-C_1-4 alkyl of R^a, R^b, R^c, R^d, R^a1, R^b1, R^c1, R^d1, R^a2, R^b2, R^c2, and R^d2 is optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, CN, NO₂, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, C(=NR^e3)NR^c3R^d3, NR^c3C(=NR^e3)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, NR^c3S(O)R^b3, NR^c3S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^C3R^d3; 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, C_1-4 alkyl, C_1-4 haloalkyl, CN, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, C(=NR^e3)NR^c3R^d3, NR^c3C(=NR^e3)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, NR^c3S(O)R^b3, NR^c3S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^C3R^d3; or R^c1 and R^d1 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, C_1-4 alkyl, C_1-4 haloalkyl, CN, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, C(=NR^e3)NR^c3R^d3, NR^c3C(=NR^e3)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, NR^c3S(O)R^b3, NR^c3S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^C3R^d3;

[00115] or R^c2 and R^d2 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, C_1-4 alkyl, C_1-4 haloalkyl, CN, 0R^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, C(=NR^e3)NR^c3R^d3, NR^c3C(=NR^e3)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, NR^c3S(O)R^b3, NR^c3S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^C3R^d3; each R^a3, R^b3, R^c3, and R^d3 is independently selected from H, C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C_3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein said C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C_3-7 cycloalkyl, 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, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, and C_1-6 haloalkoxy; and each R^e, R^e1, R^e2, and R^e3 is independently selected from H, C_1-4 alkyl, and CN; wherein when X³ is CR³ and X⁴ is CR⁴, then Ring A is not or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[00116] In embodiments, X³ is N.

[00117] In embodiments, X⁴ is N.

[00118] In embodiments, R¹ is C_1-6 alkyl, preferably methyl.

[00119] In embodiments, R² is H.

[00120] In embodiments, A is a 5-membered heteroaryl group having 2 ring-forming N heteroatoms, preferably

[00121] In embodiments, n is O.

[00122] In embodiments, Q is C_3-14 cycloalkyl (preferably cyclohexyl) substituted with OR^a.

[00123] In embodiments, R^a is C_1-6 alkyl substituted with OR^a3.

[00124] In embodiments, R^a3 is C_1-6 alkyl, preferably methyl.

[00125] 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; or

412) 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.

[00126] 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)

[00127] In embodiments, the CD38 inhibitor is a pyridazine or pyrimidine compound as described in WO 2022/228496, incorporated by reference herein.

[00128] In embodiment, the CD38 inhibitor is of formula (VII): wherein

Ai is halogen; or 5 or 6 membered unsaturated monocyclic heterocycle containing 1 to 3 heteroatoms selected from the group consisting of N, 0 and S, and optionally substituted with one or two C_1-6 alkyl optionally substituted with 1 , 2 or 3 halogen;

A2 is optionally having one or two carbon atoms replaced with nitrogen; wherein A2 is optionally substituted with 0 or 1 -OH; -CN; halogen; C_1-6 alkyl optionally substituted with 1 , 2 or 3 halogen; C_2-6 alkynyl; C_1-6 alkoxy; C_3-6 cycloalkoxy, in which the cycloalkyl optionally has one carbon atom replaced with 0 or S; -NR₁R₂ , in which each of R1 and R2 independently is H, C_1-6 alkyl, -C(O)C_1-6 is a 5 or 6 membered saturated or unsaturated heterocycle containing 1 to

3 heteroatoms selected from the group consisting of N, 0 and S, and optionally substituted with 1-2 C_1-6 alkyl;

A3 is selected from the group consisting of C_1-6 alkyl; -(CHR₃)n-C_3-8 cycloalkyl, in which the C_3-8 cycloalkyl optionally has one or two carbon atoms replaced with N, 0 or S, n is 0, 1 or 2, and R3 is H or C_1-6 alkyl; or in which the phenyl optionally has one or two carbon atoms replaced with

N, and k is O, 1 or 2; wherein A3 is optionally substituted with 0, 1 or 2 substituents independently selected from the group consisting of -OH; -CN; -OCH₂CH₂OCH₃; -CO-C_1-6 alkyl; halogen; C_1-6 alkyl optionally substituted with 1-3 halogen, methoxy or hydroxy; C_1-6 alkoxy optionally substituted with NH₂, dimethylamino, hydroxy or carboxy; C_3-6 cycloalkoxy; or C_3-8 cycloalkyl, in which the C_3-8 cycloalkyl optionally has one or two carbon atoms replaced with N, 0 or S and is optionally substituted with 1-3 halogen, C_1-6 alkyl, C_1-6 alkyl or hydroxy; and

R is H or C_1-6 alkyl; or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[00129] In embodiments, A1 is a 5 membered unsaturated monocyclic heterocycle containing two N heteroatoms

(preferably Preferably A1 is unsubstituted.

[00130] In embodiments, A2 is having two carbon atoms replaced with nitrogen, preferably Preferably, A2 is substituted C_1-6 alkyl optionally substituted with 1 , 2 or 3 halogen (preferably -CF₃).

[00131] In embodiments, A3 in which the phenyl has one or two carbon atoms replaced with N

(preferably ), and k is 0. Preferably, A3 is optionally substituted with -OCH₂CH₂OCH₃.

[00132] In embodiments, R is H.

[00133] 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; or

595) 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. [00134] 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)

[00135] In embodiments, the CD38 inhibitor is a pyrazine or pyrimidine carboxamide as described in WO 2021/207186, which is incorporated herein by reference.

[00136] In embodiments, the CD38 inhibitor is of formula (VIII): wherein:

X₁ and X₂ are independently CH or N, provided that X₁ and X₂ are not both CH;

Cy is C_3-7cycloal kyl optionally substituted with an oxo group or with one or two R^x groups, wherein R^x is halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 hydroxyalkyl, -NHSO₂C1-C4 alkyl, or -SO₂C_1-C4 alkyl;

R¹ is -H, -NR^aR^b , halo, -CN, -C(=O)NH₂, -COOH, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 hydroxyalkyl, C_2-4 alkenyl, C_1-4 alkoxy, C_1-4 alkoxyalkyl, C_1-4 alkylthio, C_1-4 alkylsulfone, C_1-4 alkoxyalkylthio, C_1-4 haloalkylthio, C_1-4 haloalkoxy, C_3-4 cycloalkyl, or a 5-membered heteroaryl, wherein the 5-membered heteroaryl is optionally substituted with one, two or three C_1-4 alkyl groups;

R² is a 5-membered heteroaryl optionally substituted with one, two or three deuterium or C_1-4 alkyl groups; R^d is H, C_1-4 haloalkyl, C_1-4 hydroxyalkyl, or C_1-4 alkyl optionally substituted with C_1-4 alkoxy;

R^a and R^b independently are -H or C_1-4 alkyl; and n is 0 or 1 , or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[00137] In embodiments, X₁ and X₂ are N. In embodiments, Xi is CH and X2 is N. In embodiments, R¹ is C_1-4 alkyl (preferably methyl), halo (preferably Cl), C_1-4 haloalkyl (preferably -CH₂F), a 5-membered heteroaryl (preferably ), or -NR^aR^b, wherein R^a and R^b are -H. In embodiments, R² is a 5-membered heteroaryl

(preferably In embodiments, Cy is cyclohexyl. In embodiments, R^d is C_1-4 alkyl (preferably ethyl) substituted with C_1-4 alkoxy (preferably methoxy); or C_1-4 haloalkyl (preferably -CHF2). In embodiments, n is 1.

[00138] In embodiments, the CD38 inhibitor is:

[00139] 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; or

659) 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.

[00140] 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.

[00141] 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 WO 2021/207186, 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

[00142] In embodiments, the CD38 inhibitor is a tricyclic fused imidazole as described in WO 2024/226685, incorporated herein by reference.

[00143] 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;

R⁴ is selected from hydrogen, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 cyanoalkyl, C_1- ₆ alkoxyalkyl, C_1-6 alkyl-N(R₂₀)₂, C₃-₅ cycloalkyl, and 3- to 6-membered heterocycle;

R⁵ is selected from hydrogen and C_1-6 alkyl;

R⁶ is selected from hydrogen, C_1-6 alkyl, halogen, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 cyanoalkyl, C_1-6 alkoxyalkyl, C_1-6 alkyl-N(R20 )₂ , C_4-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl; R⁷ is selected from C3-C12 carbocycle and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more R⁸; each R⁸ is 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, C_1-6 alkyl-N(R²⁰)₂, C_1-6 aminoalkyl, C_1-6 hydroxyalkyl, C_1-6 cyanoalkyl, C_1-6 haloalkyl, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, 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, C_1-10 alkyl, -C_1-10 haloalkyl, -O-C_1-10 alkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 cyanoalkyl, and C_1-6 alkoxyalkyl;

R⁹ is selected from hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ aminoalkyl, C₁-C₆ cyanoalkyl, C₁-C₆ alkoxyalkyl, C₁-C₆ alkyl-N(R²⁰)₂, C_3-6 carbocycle and 4- to 6-membered heterocycle, wherein the C_3-6 carbocycle and 4- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO₂, -NH₂, oxo, C_1-10 alkyl, -C_1-10 haloalkyl, -O-C_1-10 alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ aminoalkyl, C₁-C₆ cyanoalkyl, C₁-C₆ alkoxyalkyl, C₁-C₆ alkyl-N(R²⁰)₂, C_2-10 alkenyl, and C_2-10 alkynyl; each R¹⁰ is independently selected from hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ aminoalkyl, C₁-C₆ cyanoalkyl, C₁-C₆ alkoxyalkyl, and C₁-C₆ alkyl- N(R²⁰)₂;

R¹⁷ is 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, C_1-6 alkyl-N(R²⁹)₂, C_1-6 aminoalkyl, C_1-6 hydroxyalkyl, C_1-6 cyanoalkyl, C_1-6 haloalkyl, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocycle and 5- to 12-membered heterocycle;

R¹⁸ is selected from hydrogen, halogen, -OH, -CN, -NO₂, -NH₂, -NHC_1-10 alkyl, -N(C_1-10 alkyl)₂, -O-C_1-10 alkyl, C₁-C₆ alkyl, and C₁-C₆ haloalkyl; R¹⁹ is selected from hydrogen, halogen, -OH, -CN, -NO₂, -NH₂, -N HC_1-10 alkyl, -N(C_1-10 alkyl)₂, -O-C_1-10 alkyl, C₁-C₆ alkyl, and C₁-C₆ haloalkyl; and

R²⁹ is independently selected at each occurrence from hydrogen; C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocycle, 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, C_1-10 alkyl, - C_1-10 haloalkyl, -0- C_1-10 alkyl, C_2-10 alkenyl, C_2-10 alkynyl, C_3-12 carbocycle, and 3- to 12-membered heterocycle, or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[00144] Preferably, Z is Preferably, X is 0. Preferably, R⁹ is hydrogen. Preferably, R¹⁷ is hydrogen.

Preferably, A is CR¹⁸ . Preferably, R¹⁸ is hydrogen. Preferably, D is CR¹⁹. Preferably, R¹⁹ is hydrogen. Preferably, R⁴ is hydrogen. Preferably, R⁵ is selected from hydrogen. Preferably, R⁶ hydrogen. Preferably, R⁷ is a 5- to 15- membered heterocycle (preferably «

[00145] 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 and is selected from -0-, -NR⁹ -, -S-, and -SO₂-; each R⁵⁰ is independently selected from hydrogen, halogen, C₁-

C₆ alkyl; or come together to form ; each R⁵¹ is independently selected from hydrogen, halogen, and C₁-C₆ alkyl; 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; R⁵ is selected from hydrogen and C_1-6 alkyl;

R⁷ is selected from hydrogen; and C_1-10 alkyl, C_2-10 alkenyl, C_2-10 alkynyl, C₃-C₁₄ carbocycle and 5- to 15- membered heterocycle, each of which are optionally substituted with one or more R⁸; each R⁸ is 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, C_1-6 alkyl-N(R²⁰)₂, C_1-6 aminoalkyl, C_1-6 hydroxyalkyl, C_1-6 cyanoalkyl, C_1-6 haloalkyl, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C₃-C₁₂ carbocycle, and 4- to 12-membered heterocycle, wherein the C_1-6 alkyl is optionally substituted with one or more R8* , and wherein the C₃-C₁₂ carbocycle and 4- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -CN, -N0₂, -NH₂, oxo, C_1-10 alkyl, -C_1-10 haloalkyl, -O-C_1-10 alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ aminoalkyl, C₁-C₆ cyanoalkyl, and C₁-C₆ alkoxyalkyl; 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, C_1-10 alkyl, -C_1-10 haloalkyl, -O-C_1-10 alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ aminoalkyl, C₁-C₆ cyanoalkyl, and C₁-C₆ alkoxyalkyl;

R⁹ is selected from hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ aminoalkyl, C₁-C₆ cyanoalkyl, C₁-C₆ alkoxyalkyl, C₁-C₆ alkyl-N(R²⁰)₂ , C_3-6 carbocycle and 4- to 6-membered heterocycle, wherein the C_3-6 carbocycle and 4- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO₂ , -NH₂ , oxo, C_1-10 alkyl, -C_1-10 haloalkyl, -O-C_1-10 alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ aminoalkyl, C₁-C₆ cyanoalkyl, C₁-C₆ alkoxyalkyl, C₁-C₆ alkyl-N(R²⁰)₂, C_2-10 alkenyl, C_2-10 alkynyl; each R¹⁴ is independently selected from halogen, -OH, -CN, -NO₂, -NH₂, -NHC_1-10 alkyl, -N(C_1-10 alkyl)₂, C_1-10 alkyl, -C_1-10 haloalkyl, -O-C_1-10 alkyl, C_2-10 alkenyl, C_2-10 alkynyl, C_3-12 carbocycle, and 3- to 12-membered heterocycle;

R¹⁷ is 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), -NR²⁰ S(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, C_1-6 alkyl-N(R²⁰)₂, C_1-6 aminoalkyl, C_1-6 hydroxyalkyl, C_1-6 cyanoalkyl, C_1-6 haloalkyl, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocycle, and 5- to 12-membered heterocycle;

R¹⁸ is selected from hydrogen, halogen, -OH, -CN, -NO₂, -NH₂, -NHC_1-10 alkyl, -N(C_1-10 alkyl)₂, -O-C_1-10 alkyl, C₁-C₆ alkyl, and C₁-C₆ haloalkyl;

R¹⁹ is selected from hydrogen, halogen, -OH, -CN, -NO₂, -NH₂, -NHC_1-10 alkyl, -N(C_1-10 alkyl)₂, -O-C_1-10 alkyl, C₁-C₆ alkyl, and C₁-C₆ haloalkyl; and

R²⁰ is independently selected at each occurrence from hydrogen; C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocycle, 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(C_1-6 alkyl), C_1-10 alkyl, - C₁- 1₀ haloalkyl, -O-C_1-10 alkyl, C_2-10 alkenyl, C_2-10 alkynyl, C_3-12 carbocycle, and 3- to 12-membered heterocycle, or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[00146] Preferably, Y is -O-. Preferably, each R⁵⁰ is hydrogen. Preferably, each R⁵¹ is hydrogen. Preferably, k is 2.

Preferably, A is selected from N and CRis. Preferably, is imidazole. Preferably, D is selected CR¹⁹.

Preferably, R¹⁹ is hydrogen. Preferably, R⁵ is hydrogen Preferably, R¹⁷ is hydrogen. . Preferably, R⁷ is

• C3-C14 carbocycle (preferably cyclohexyl) substituted with -OR²⁰, wherein R²⁰ is preferably C_1-6 alkyl (preferably ethyl) substituted with -O-C_1-10 alkyl, preferably methoxy, or

• a 5- to 15-membered heterocycle, preferably piperidinyl substituted with -S(O)₂(R²⁰), wherein R²⁰ is preferably C_1-6 alkyl (preferably methyl); or tetrahydropyranyl, or tetrahydrothiophenyl.

[00147] 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 36A

697) N-((1r,4r)-4-(Propylsulfonamido)cyclohexyl)-5,6-dihydrobenzo[f]imidazo[1 ,5-d][1 ,4]oxazepine-10-carboxamide, compound 37A

698) (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; or

851) 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.

[00148] 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), including

Examples 1 , 2, 3, 10, and 21 of WO 2023/084206

[00149] In embodiments, the CD38 inhibitor is a N-(4-aminocyclohexyl)pyrimidine-4-carboxamide as described in WO 2023/084206, incorporated herein by reference.

[00150] 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-C₃ alkyl, C₁-C₃ fluoroalkyl and C₁-C₃ hydroxyalkyl;

X¹ is CH or N, and X² is CH or N, wherein at least one of X¹ and X² is N;

L is a bond, CH₂, CHMe, CMe2 or CO;

R¹ is C₁-C4 alkyl, C₃-C₆ cycloalkyl, hydroxyl, -O-(C_1-C4 alkyl), or -O-( C₃-C₆ cycloalkyl), each of which may optionally be fluoro-substituted;

R² is hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, -CHO, -CO-(C₁-C₃ alkyl) or -CO-(C₁-C₃ fluoroalkyl);

R³ is hydrogen or methyl; or

R² and 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.

[00151] Preferably, Het is a 5-membered heteroaryl group comprising two N heteroatoms, preferably

[00152] Preferably, X¹ is N.

[00153] Preferably, X² is N.

[00154] Preferably, R¹ is C₁-C₄ alkyl or C₃-C₆ cycloalkyl, preferably methyl, or cyclopropyl.

[00155] Preferably, L is a bond. [00156] Preferably, R² is C1-C4 fluoroalkyl, preferably -CH₂-CF₃, -CH₂-CHF2, or -CfCHa -CF₃

[00157] Preferably, R³ is hydrogen.

[00158] Preferably, R² and 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, R² and R³, together with the nitrogen to which they are attached, form

[00159] In embodiments, the CD38 inhibitor is:

[00160] 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; or

876) 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.

[00161] 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

[00162] 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.

[00163] In preferred embodiments, the CD38 inhibitor is of formula (XI): wherein

Het 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-C₃ alkyl, C₁-C₃ fluoroalkyl, C₁-C₃ hydroxyalkyl, and 3- to 6-membered saturated heterocyclyl; one of X¹ and X² is S and the other of X¹ and X² is CR⁴ or N, wherein R⁴ is hydrogen, halo, CH₃, CF₃, or cyclopropyl; Cy is a C₃-C₉ cycloalkyl, 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-C₃ alkyl;

L is a bond, CH₂ , CHMe, CMe2 or CO;

R¹ is -NR²R³ , halo or C1-C4 fluoroalkyl;

R³ is hydrogen or methyl; or

R² and 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.

[00164] Preferably, Het is a 5-membered heteroaryl group comprising two N heteroatoms (preferably

), substituted with C₁-C₃ alkyl (preferably methyl). Preferably, X² is S and X¹ is CR⁴, wherein R⁴ is hydrogen.

Alternatively, X² is S and X¹ is N. Alternatively, X² is CR⁴, wherein R⁴ is hydrogen, and X¹ is S. Preferably, Cy is a C₃- C₉ cycloalkyl (preferably cyclohexyl). Preferably, L is a bond. Preferably, R¹ is -NR²R³. Preferably, R² is C₁-C₄ fluoroalkyl (preferably -CH₂CF₃). Preferably, R³ is hydrogen. Alternatively, R² and R³, together with the nitrogen to which they are attached, form a fluoro-substituted pyrrolidin-1 -yl group (preferably

[00165] In embodiments, the CD38 inhibitor is:

[00166] 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; or

901) 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.

[00167] 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;

(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;

[00168] 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-carboxamide

Example 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

[00169] In embodiments, the CD38 inhibitor is a 3-carbonyl imidazo[1 ,5-a]pyridine as described in WO 2024/236316, incorporated herein by reference.

[00170] 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-C₃ alkyl, C₁-C₃ haloalkyl, C₁-C₃ hydroxyalkyl, and 3- to 6-membered saturated heterocyclyl;

Cy is a C₃-C₉ cycloalkyl, 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-C₃ alkyl, C₁-C₃ haloalkyl, C₁-C₃ hydroxyalkyl, -O(C₁-C₃ alkyl), and -O(C₁-C₃ haloalkyl);

L is a bond, CH₂, CHMe, CMe2 or CO;

R¹ is hydrogen, halo, -NR²R³, C₁-C₃ alkyl, C₁-C₃ haloalkyl, -O(C₁-C₃ alkyl), or -O(C₁-C₃ haloalkyl);

R² is hydrogen or C₁-C₃ alkyl;

R³ is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 hydroxyalkyl; or

R² and R³ together 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-C₃ alkyl, C₁-C₃ haloalkyl, C₁-C₃ hydroxyalkyl, -O(C₁-C₃ alkyl), -O(C₁-C₃ haloalkyl), and oxo (=O); each of A¹, A², A³ and A⁴ is independently selected from N and CR⁴, provided that at least two of A¹, A², A³ and A⁴ are CR⁴, wherein R⁴ is hydrogen, halo, C₁-C₃ alkyl, or C₁-C₃ haloalkyl; 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. [00171] Preferably, Het is a 5-membered heteroaryl group comprising two N heteroatoms (preferably Preferably, Cy is a C3-C9 cycloalkyl, preferably cyclohexyl. Preferably, L is a bond. Preferably, R¹ is -NR²R³.

[00172] Preferably, R² is hydrogen. Preferably, R³ is C1-C4 haloalkyl (preferably -CH₂CF₃). Alternatively, R² and R³ together 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, A³ and A⁴ is CR⁴. Preferably, each R⁴ is hydrogen.

[00173] In embodiments, the CD38 inhibitor is:

[00174] 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); or

919) 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.

[00175] 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.

[00176] 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

[00177] 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.

[00178] In preferred embodiments, the CD38 inhibitor is of formula (Xllla), (Xlllb), or (Xlllc):

(Xlllc).

[00179] 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 to Compound 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

[00180] In embodiments, the CD38 inhibitor is a heterobicyclic amide as described in WO 2023/227867, incorporated herein by reference.

[00181] In preferred embodiments, the CD38 inhibitor is of formula (XIV): wherein: one of R¹ and R² is -C(O)NHR³ and the other one of R¹ and R² is 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-C₃ alkyl, wherein the C₁-C₃ alkyl is optionally substituted with one or more substituents independently selected from halo, hydroxyl and C₁-C₃ alkoxy;

R³ is a saturated 3- to 9-membered carbocyclic or heterocyclic group optionally substituted with one or more substituents independently selected from -NR⁴R⁵ and C₁-C₃ alkyl, wherein the C₁-C₃ alkyl is optionally substituted with one or more substituents independently selected from halo, hydroxyl and C₁-C₃ alkoxy;

R⁴ is hydrogen or C₁-C₃ alkyl;

R⁵ is C1-C4 alkyl (preferably C₁-C₃ alkyl) optionally substituted with one or more substituents independently selected from halo, hydroxyl and C₁-C₃ alkoxy; or

R⁴ and R⁵ together 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-C₃ alkyl, C₁-C₃ haloalkyl, C₁-C₃ alkoxy and oxo ( =O) [preferably independently selected from halo, hydroxyl, C₁-C₃ alkoxy and oxo (=O)]; each of A¹, A², A³ and A⁴ is 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.

[00182] Preferably, R1 is a 5-membered heteroaryl group containing two N heteroatoms (preferably or ) unsubstituted or substituted with C₁-C₃ alkyl (preferably ethyl) substituted with hydroxyl; and R² is - C(O)NHR³. Alternatively, R¹ is -C(O)NHR³ and R² is a 5-membered heteroaryl group containing two N heteroatoms independently (preferably

[00183] Preferably, R³ is a saturated 3- to 9-membered carbocyclic (preferably cyclohexyl), substituted with -NR⁴R⁵. Preferably, R⁴ is hydrogen. Preferably, R⁵ is C1-C4 alkyl (preferably ethyl) substituted with halo. Alternatively, R⁴ and R⁵ together 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.

[00184] Preferably, A¹ and A² are N, A³ and A⁴ are CH; and X and Y are C. Alternatively, A¹ is N, and A², A³ and A⁴ are CH, X is N, and Y is C. Alternatively, A¹, A², and A³ are CH, A⁴ is N, X is N, and Y is C. Alternatively, A¹ and A³ are CH, A² and A⁴ are N, X is N, and Y is C. Alternatively, A¹, A³, and A⁴ are CH, A² is N, X is N, and Y is C.

Alternatively, A¹ is N, A², A³, A⁴ are CH, X is N, and Y is C.

[00185] Preferably, n is 1.

[00186] 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.

[00187] 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;

[00188] 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

[00189] In embodiments, the CD38 inhibitor is a heteroaryl amides as described in WO 2022/077034, incorporated herein by reference.

[00190] In preferred embodiments, the CD38 inhibitor is of formula (XV) or (XV*):

[00191] 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*);

R¹ is 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, -OCH₃ and -OCF₃;

R² is H, halo, -CN, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, perfluoro(C_1-C6)alkyl, perfluoro(C_1-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)-, ((C_1-C₃)alkyl)₂N- -CF₃, -OCH₃ and -OCF₃;

R³ is H, halo, (C_1-C₃)alkyl, -CF₃, (C_1-C₃)alkoxy, -OCF₃ or (R⁷)₂N-; wherein R⁷ is H or (C_1-C₃)alkyl; each R⁴ is independently H or (C_1-C₃)alkyl; wherein (C_1-C₃)alkyl is optionally substituted with 1-3 substituents independently selected from the group consisting of H, halo, -CN, (C_1-C₃)alkyl, -NH², (C1- C₃)alkyl-(NH)-, ((C_1-C₃)alkyl)₂N-, -CF₃, -OCH₃ and -OCF₃;

R⁵ is selected from the group consisting of (C_1-C₃)alkyl, perfluoro(C_1-C₃)alkyl, HO-(C₂-C4)alkyl-, cycloalkyl, heterocycloalkyl, and aryl; wherein (C_1-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, (C_1-C₃)alkyl-(NH)-, ((C_1-C₃)alkyl)₂N-, -CF₃, -OCH³ and -OCF³; R6 is independently H or (C_1-C₃)alkyl; wherein (C_1-C₃)alkyl is optionally substituted with 1-3 substituents independently selected from the group consisting of H, halo, -CN, (C_1-C₃)alkyl, -NH², (C_1-C₃)alkyl-(NH)-, ((C_1-C₃)alkyl)₂N-, -CF₃, -OCH₃ and -OCF₃; n is an integer from one to three;

R⁸ is H, -CH₃ or-CF₃;

Het is a heterocycle of the formula:

each R⁹ is independently selected from H, halo, (C₁-C₆)alkyl, -CF₃, (C₁-C₆)alkoxy, -OCF₃, -CN, (R¹¹)₂N-, RI₂(O)(C=0)-, R¹²O((C_1-C₃)alkyl)-(NR¹¹)-, R¹³-(C=O)-(NR¹¹)- and (R¹¹)₂ N-(C=O)-; each R¹⁰ is independently selected from H, (C₁-C₃)alkyl, -CF₃, -OCH₃, -OCF₃, -CN, (R¹¹)₂N-, Ri2(O)(C=0)-,

RI₂O-(( C_1-C₃)alkyl)-(NR¹¹)-, R¹³-(C=O)-(NR¹¹)-, and (R¹¹)₂N-(C=O);

R¹¹ is independently H or (C₁-C₃)alkyl;

R¹² is H or (C_1-C₃)alkyl; and

R¹³ is (C_1-C₃)alkyl, or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[00192] Preferably, the CD38 inhibitor is of formula (XV). Preferably, — X— Y— Z— is =CR¹— CR²=CR³— or =N— CR²=CR³— . Preferably, R¹ is 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, R³ is H. . Preferably, each R⁹ is independently H or -CF₃, preferably one R⁹ is H and the other is -CF₃. Preferably, each R¹⁰ is H.

[00194] 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 61

1042) 6-(1 H-imidazol-1 -y l)-3-f I uoro-N-(pyrid in-3-y I) picol i namide, Compound 62

1043) 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 ; or

1062) 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.

[00195] 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)

[00196] In embodiments, the CD38 inhibitor is a picolinamide and pyrimidine carboxamides as described in WO 2023/235880, incorporated herein by reference.

[00197] In preferred embodiments, the CD38 inhibitor is of formula (XVI): R³

R^{1 <}^R² R⁵

(XVI), wherein:

R¹ is selected from N and CR¹¹;

R² is selected from N and CR¹²;

R³ is selected from hydrogen, halogen, -CN, -OR¹⁶ , -SO₂R¹⁶ , C₁-C₆ alkyl, C_3-12 carbocycle, and 3- to 12- membered heterocycle, wherein the C₁-C₆ alkyl, C_3-12 carbocycle, 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-C₆ alkyl, -N(C₁-C₆ alkyl)₂ , -C₁-C₆ haloalkyl, -O-C₁-C₆ alkyl, C₁-C₆ alkyl, C_2-10 alkenyl, C2- 10 alkynyl, C_3-12 carbocycle, and 3- to 12-membered heterocycle;

R⁴ is 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;

R⁵ is selected from hydrogen and C₁-C₆ alkyl;

R⁷ is selected from an optionally substituted saturated 4- to 8-membered heterocycle, optionally substituted C_3-5 cycloalkyl, optionally substituted C_7-10 cycloalkyl, and substituted C₆ cycloalkyl, wherein the 4- to 8- membered heterocycle, C_3-5 cycloalkyl, and C_7-10 cycloalkyl are each optionally substituted with one or more Rs, and the Ce cycloalkyl is substituted with one or more R^8A, and the Ce cycloalkyl is further optionally substituted with one or more R^8B;

R⁸ is independently selected at each occurrence from halogen, -OR²⁰, -S R²⁰, -N(R²¹)₂, -NO₂, =O, =S, =N(R²⁰), -CN, C_1-6 aminoalkyl, C_1-6 hydroxyalkyl, C_1-6 cyanoalkyl, C_1-6 haloalkyl, C_1-6 alkoxyalkyl, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, -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 R⁴ is imidazole, R³ is hydrogen, R⁷ is pyrrolidine substituted with oxo and haloalkyl, the haloalkyl is selected from C₁ haloalkyl and C_3-6 haloalkyl; and wherein when R¹ is N, R³ is imidazole, R⁷ is C4 cycloalkyl, and R⁸ is -OR²⁰, the C_1-6 alkyl of R²⁰ is selected from C₁ alkyl and C_3-6 alkyl;

R^8A is independently selected at each occurrence from halogen, C_1-6 haloalkyl, -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(NR² ₀₂), -S(O)(NR²¹)R²⁰, and -S(O)(NR²¹)N(R²¹)₂;

R^8B is independently selected each occurrence from -OR²⁰, -SR²⁰, -N(R²¹)², -NO₂, =O, =S, =N(R²⁰), -CN, C_1-6 aminoalkyl, C_1-6 hydroxyalkyl, C_1-6 cyanoalkyl, C_1-6 haloalkyl, C_1-6 alkyl, C_2-6 alkenyl, and C_2-6 alkynyl; each R⁹ is independently selected from halogen, -OH, -CN, -NO₂, -NH₂, -NHC_1-10 alkyl, -N(C_1-10 alkyl)₂, C_1-10 alkyl, - C_1-10 haloalkyl, -0- C_1-10 alkyl, C_2-10 alkenyl, C_2-10 alkynyl, C_3-12 carbocycle, and 3- to 12-membered heterocycle;

R¹¹ is selected from hydrogen, halogen, -OH, -CN, -NO₂, -NH₂, -NHC_1-10 alkyl, -N(C_1-10 alkyl)₂, -O-C_1-10 alkyl, C₁-C₆ alkyl, and C₁-C₆ haloalkyl;

R¹² is selected from hydrogen, halogen, -OH, -CN, -NO₂, -NH₂, -NHC_1-10 alkyl, -N(C_1-10 alkyl)₂, -O-C_1-10 alkyl, C₁-C₆ alkyl, and C₁-C₆ haloalkyl;

R¹⁶ is selected from hydrogen; C_1-6 alkyl, and C_3-12 carbocycle, wherein the C_1-6 alkyl, and C_3-12 carbocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, - CN, -NO₂, -NH₂, -NHC_1-10 alkyl, -N( C_1-10 alkyl)₂, -O-C_1-10 alkyl, C_2-10 alkenyl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C_2-10 alkynyl, C_3-12 carbocycle, and 3- to 12- membered heterocycle;

R²⁰ is independently selected at each occurrence from hydrogen; C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocycle, 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, C_1-10 alkyl, -C_1-10 haloalkyl, -O-C1- 10 alkyl, C_2-10 alkenyl, C_2-10 alkynyl, C_3-12 carbocycle, and 3- to 12-membered heterocycle; and

R²¹ is independently selected at each occurrence from hydrogen; C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocycle, 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, C_1-10 alkyl, -C_1-10 haloalkyl, -O-C1- 10 alkyl, C_2-10 alkenyl, C_2-10 alkynyl, C_3-12 carbocycle, and 3- to 12-membered heterocycle. or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

[00198] 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-6-yl)-6-(1H-midazol-1 -yI)-4-methylpicolinamide (31A);

1094) 6-(1 H-lmidazol-1 -yl)-4-methyl-N-(tetrahydro-2H-pyran-4-yl)picolinamide (32A);

1095) N-Cycloheptyl-6-(1H-midazol-1 -yI)-4-methylpicolinamide (34A);

1096) N-(3,3-Difluorocyclopentyl)-6-(1H-midazol-1 -yI)-4-methylpicolinamide (35A);

1097) N-(1 ,1-Dioxidotetrahydro-2H-thiopyran-3-yl)-6-(1H-midazol-1 -yI)-4-methylpicolinamide (36A);

1098) (S)-6-(1 H-lmidazol-1 -yl)-4-methyl-N-(tetrahydrofuran-3-yl)picolinamide (38A);

1099) (S)-6-(1 H-lmidazol-1 -yl)-4-methyl-N-(pyrrolidin-3-yl)picolinamide hydrochloride (41a);

1100) (R)-6-(1 H-lmidazol-1 -yl)-4-methyl-N-(tetrahydrofuran-3-yl)picolinamide (42A); 1101) tert-Butyl (R)-3-(6-(1H-midazol-1 -yI)-4-methylpicolinamido)pyrrolidine-1 -carboxylate (43a);

1102) (R)-6-(1 H-lmidazol-1 -yl)-4-methyl-N-(tetrahydro-2H-pyran-3-yl)picolinamide (44a);

1103) (S)-6-(1 H-lmidazol-1 -yl)-4-methyl-N-(tetrahydro-2H-pyran-3-yl)picolinamide (45a);

1104) (S)-6-(1H-midazol-1 -yI)-4-methyl-N-(1-(methylsulfonyl)pyrrolidin-3-yl)picolinamide (46a);

1105) tert-Butyl (S)-3-(6-( 1 H-imidazol-1 -y l)-4-methy I picoli n amido) piperidi ne- 1 -carboxylate (47A);

1106) (S)-6-(1 H-lmidazol-1 -yl)-4-methyl-N-(piperidin-3-yl)picolinamide dihydrochloride (48A);

1107) tert-Butyl ( R)-3-(6-( 1 H-imidazol-1 -yl)-4-methy I picoli n amido) piperidi ne- 1 -carboxylate (49A);

1108) (S)-6-(1 H-lmidazol-1 -yl)-4-methyl-N-(1-(methylsulfonyl)piperidin-3-yl)picolinamide (50A);

1109) (R)-6-(1 H-lmidazol-1 -yl)-4-methyl-N-(piperidin-3-yl)picolinamide dihydrochloride (51 A);

1110) (R)-6-(1 H-lmidazol-1 -yl)-4-methyl-N-(pyrrolidin-3-yl)picolinamide dihydrochloride (52A);

1111) (R)-6-(1 H-lmidazol-1 -yl)-4-methyl-N-(1-(methylsulfonyl)pyrrolidin-3-yl)picolinamide (53A);

1112) (R)-6-(1 H-lmidazol-1 -yl)-4-methyl-N-(1-(methylsulfonyl)piperidin-3-yl)picolinamide (54A);

1113) (S)-N-(1 ,1-Dioxidotetrahydrothiophen-3-yl)-6-(1H-midazol-1 -yI)-4-methylpicolinamide (55A);

1114) (R)-6-(1 H-lmidazol-1 -yl)-4-methyl-N-(1 -methyl-2-oxopiperidin-3-yl)picolinamide (56A);

1115) ( R)-N-( 1 , 1 -Dioxidotetrahyd ro-2H -th iopy ran-3-yl)-6-( 1 H-imidazol-1 -y l)-4-methy I picol i n am ide (57A);

1116) (R)-6-(1 H-lmidazol-1 -yl)-4-methyl-N-(2-oxopiperidin-3-yl)picolinamide (58A);

1117) (R)-6-(1 H-lmidazol-1 -yl)-4-methyl-N-(1 -methylpiperidin-3-yl)picolinamide (59A);

1118) (S)-6-(1 H-lmidazol-1 -yl)-4-methyl-N-(2-oxopiperidin-3-yl)picolinamide (60A);

1119) 2-(1 H-lmidazol-1 -yl)-6-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrimidine-4-carboxamide (61A);

1120) ( R)-6-Bromo-N -(tetrahyd ro-2H-pyran-3-y l)-4-(trifl uoromethyl) picol i namide;

1121) (R)-6-(1H-midazol-1 -yI)-N-(tetrahydro-2H-pyran-3-yl)-4-(trifluoromethyl)picolinamide (62A);

1122) (R)-N-(2,6-Dioxopiperidin-3-yl)-6-(1 H-imidazol-1-yl)-4-methylpicolinamide (63A);

1123) (R)-N-(6,6-Dimethyltetrahydro-2H-pyran-3-yl)-6-(1 H-imidazol-1-yl)-4-methylpicolinamide (64A);

1124) (S)-N-(6,6-Dimethyltetrahydro-2H-pyran-3-yl)-6-(1H-midazol-1 -yI)-4-methylpicolinamide (65A);

1125) (R)-N-(5,5-Difluorotetrahydro-2H-pyran-3-yl)-6-(1H-midazol-1 -yI)-4-methylpicolinamide (66A);

1126) (R)-N-(5,5-Ddifluorotetrahydro-2H-pyran-3-yl)-6-(1 H-imidazol-1-yl)-4-methylpicolinamide (67 A);

1127) (R)-N-(1 ,1-Dioxidotetrahydrothiophen-3-yl)-2-(1H-midazol-1 -yI)-6-methylpyrimidine-4-carboxamide (68A); 1128) (R)-2-(1 H-lmidazol-1 -yl)-6-methyl-N-(tetrahydro-2H-pyran-3-yl)pyrimidine-4-carboxamide (69A);

1129) (S)-N-(4,4-Difluorotetrahydro-2H-pyran-3-yl)-6-(1 H-imidazol-1-yl)-4-methylpicolinamide (70A);

1130) (R)-N-(4,4-Difluorotetrahydro-2H-pyran-3-yl)-6-(1H-midazol-1 -yI)-4-methylpicolinamide (71A);

1131) 6-(1 H-lmidazol-1 -yl)-4-methyl-N-(1-((tetrahydrofuran-3-yl)sulfonyl)piperidin-4-yl)picolinamide (72A);

1132) 2-(1 H-lmidazol-1 -yl)-N-(1-(methylsulfonyl)piperidin-4-yl)pyrimidine-4-carboxamide (73A);

1133) 6-Bromo-N-(1-(methylsulfonyl)piperidin-4-yl)-4-(trifluoromethyl)picolinamide;

1134) (1 ,1 -Dioxidotetrahyd roth iophen-3-y l)-2-( 1 H-imidazol-1 -yl)pyrimidine-4-carboxamide (74A);

1135) 2-(1 H-lmidazol-1 -yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(trifluoromethyl)pyrimidine-4- carboxamide (75A);

1136) 6-Chloro-3-methyl-N-(1 -(methy Isu Ifony l)pi perid in-4-y l)picol i nam ide;

1137) (R)-2-(1 H-lmidazol-1 -yl)-N-(tetrahydro-2H-pyran-3-yl)-6-(trifluoromethyl)pyrimidine-4-carboxamide (76A);

1138) (R)-N-(1,1-Dioxidotetrahydrothiophen-3-yl)-2-(1 H-imidazol-1-yl)-6-(trifluoromethyl)pyrimidine-4- carboxamide (77A);

1139) (R)-6-Bromo-N-(1 , 1 -d ioxidotetrahydrothiophen-3-y l)-4-(trif I uoromethy l)picol i n am ide;

1140) (R)-N-(1,1-Dioxidotetrahydrothiophen-3-yl)-6-(1 H-imidazol-1-yl)-4-(trifluoromethyl)picolinamide (78A);

1141) 6-(1 H-lmidazol-1 -yl)-3-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)picolinamide (79A);

1142) (R)-2-(1 H-lmidazol-1 -yl)-N-(tetrahydro-2H-pyran-3-yl)pyrimidine-4-carboxamide (80A);

1143) (R)-6-(1 H-lmidazol-1 -yl)-3-methyl-N-(tetrahydro-2H-pyran-3-yl)picolinamide (81 A);

1144) 6-(1 H-lmidazol-1 -yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-4-(trifluoromethyl)picolinamide (82A);

1145) ( R)-6-C hloro-3-methy l-N-(tetrahyd ro-2 H-pyran-3-yl) picol in amide;

1146) (R)-6-(1 H-lmidazol-1 -yl)-4-methyl-N-(1-(oxetan-3-yl)piperidin-3-yl)picolinamide (83A);

1147) (S)-N-( 1 , 1 -Dioxidotetrahyd ro-2H -thiopyran-3-y l)-6-( 1 H-imidazol-1 -y l)-4-methy I picoli n amide (84A);

1148) tert-Butyl (S)-3-(6-(1H-midazol-1 -yI)-4-methylpicolinamido)pyrrolidine-1 -carboxylate;

1149) tert-Butyl (S)-3-(6-chloro-4-methylpicolinamido)piperidine-1 -carboxylate;

1150) (S)-6-(1 H-lmidazol-1 -yl)-4-methyl-N-(1-methyl-2-oxopiperidin-3-yl)picolinamide (85A);

1151) (R)-N-(1 , 1 -Dioxidotetrahydrothiophen-3-yl)-6-(1 H-imidazol-1-yl)-4-methylpicolinamide (86A); or

1152) 6-(1 H-lmidazol-1 -yl)-4-methyl-N-(1-(oxetan-3-ylsulfonyl)piperidin-4-yl)picolinamide (87A); or a pharmaceutically acceptable salt, ester, prodrug, solvate, stereoisomer, tautomer, or derivative thereof.

Administration and Dosage

[00199] The CD38 inhibitor may be administered by any route of administration useful for administering pharmaceutically active ingredients. In embodiments, the inhibitor is for oral administration (swallowed, absorbed in the Gl tract); buccal administration (placed between gum and cheek, absorbed through oral mucosa); sublingual administration (placed under the tongue, absorbed into bloodstream); inhalational administration (inhaled into respiratory tract); intranasal administration (applied to nasal mucosa); intrapulmonary administration (delivered directly to lungs, e.g., alveoli); parenteral administration (including intravenous, intramuscular, and subcutaneous administration); cutaneous administration (applied to skin); transdermal administration (applied to skin for systemic absorption); topical administration (applied to a surface— skin, eye, mucosa— for local effect); mucosal administration (applied to a mucosa such as rectal administration and vaginal administration); ophthalmic administration (topical to the eye surface); intraocular administration (inside the eyeball); intraorbital administration (into the orbital cavity around the eye); otic administration (into the ear canal); intra-articular administration (into a joint); intracapsular administration (into a capsule, e.g., joint or organ capsule); intraperitoneal administration (into the peritoneal cavity, abdomen); intradermal administration (into the dermis, skin layer); intraosseous administration (into the bone marrow); implantable administration (drug delivery via implanted device or depot).

[00200] In preferred embodiments, the CD38 inhibitor is for oral administration to the subject.

[00201] In alternative preferred embodiments, the CD38 inhibitor is for topical administration to the skin of the subject. In preferred embodiments, the CD38 inhibitor is for cutaneous administration to the skin of the subject. In preferred embodiments, the CD38 inhibitor is for transdermal administration to the skin of the subject.

[00202] In alternative preferred embodiments, the CD38 inhibitor is for local administration to the airway of the subject. In preferred embodiments, the CD38 inhibitor is for inhalational or intranasal administration.

[00203] In alternative preferred embodiments, the CD38 inhibitor is for inhalational administration. Inhalational administration is a non-invasive route of drug delivery in which the active agent is inhaled through the mouth or nose and transported to the respiratory tract. In preferred embodiments, the CD38 inhibitor is for inhalational administration to the lungs.

[00204] In most preferred embodiments, the CD38 inhibitor is for intranasal administration. Intranasal administration is a localized or systemic drug delivery method in which the active agent is applied directly to the nasal mucosa. It offers an absorption pathway that bypasses first-pass metabolism and enables direct access to the systemic circulation or central nervous system.

[00205] Any suitable amount of the CD38 inhibitor may be administered to the subject. The dosage will depend on many factors including the mode of administration. Typically, the amount of the CD38 inhibitor contained within a single dosage unit will be an amount that effectively prevent or treat a TH2 inflammation-associated condition without inducing significant toxicity i.e., a so-called “therapeutically effective amount”. [00206] For the prevention, treatment or reduction in the severity of a TH2 inflammation-associated condition, the appropriate dosage of the CD38 inhibitor will depend on the specific disease or condition to be treated, the severity and course of the disease or condition, whether the CD38 inhibitor is administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to the CD38 inhibitor, and the discretion of the attending physician.

[00207] The CD38 inhibitor is suitably administered to the patient at one time or over a series of treatments. Preferably, it is desirable to determine the dose-response curve in vitro, and then in useful animal models prior to testing in humans. The present disclosure provides exemplary dosages for the CD38 inhibitor. For example, depending on the type and severity of the disease, about 1 pg/kg to 1000 mg per kg (mg/kg) of body weight per day. Further, the effective dose may be 0.5 mg/kg, 1 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg/ 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 55 mg/kg, 60 mg/kg, 70 mg/kg, 75 mg/kg, 80 mg/kg, 90 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, 175 mg/kg, 200 mg/kg, and may increase by 25 mg/kg increments up to 1000 mg/kg, or may range between any two of the foregoing values. A typical daily dosage might range from about 1 pg/kg to 100 mg/kg or more, depending on the factors mentioned above.

[00208] For repeated administrations over several days or longer, depending on the condition, the treatment is sustained until a desired suppression of disease symptoms occurs. However, other dosage regimens may be useful. The progress of this therapy is easily monitored by conventional techniques and assays.

[00209] The above are simply guidelines since the actual dose must be carefully selected and titrated by the attending physician based upon clinical factors unique to each patient or by a nutritionist. The optimal daily dose will be determined by methods known in the art and will be influenced by factors such as the age of the patient and other clinically relevant factors. In addition, patients may be taking medications for other diseases or conditions. The other medications may be continued during the time that the CD38 inhibitor is given to the patient, but it is particularly advisable in such cases to begin with low doses to determine if adverse side effects are experienced.

Pharmaceutical Compositions

[00210] The pharmaceutical composition of the invention may be prepared in a manner well known in the pharmaceutical art by mixing the CD38 inhibitor having a suitable degree of purity with one or more optional pharmaceutically acceptable carriers or excipients (see Remington: The Science and Practice of Pharmacy, by Loyd V Allen, Jr, 2012, 22^ndedition, Pharmaceutical Press; Handbook of Pharmaceutical Excipients, by Rowe et al., 2012, 7th edition, Pharmaceutical Press).

[00211] An "excipient" as used herein has its normal meaning in the art and is any ingredient that is not an active ingredient (drug) itself. "Pharmaceutically acceptable excipient" as used herein refers to any excipient that does not interfere with effectiveness of the biological activity of the active ingredients and that is not toxic to the subject, i.e., is a type of excipient and/or is for use in an amount which is not toxic to the subject. Excipients are well known in the art, and the present compositions are not limited in these respects. [00212] In certain embodiments, the composition comprises one or more excipients, including for example and without limitation, one or more binders (binding agents), thickening agents, surfactants, diluents, release-delaying agents, colorants, flavoring agents, fillers, disintegrants/dissolution promoting agents, lubricants, plasticizers, silica flow conditioners, glidants, anti-caking agents, anti-tacking agents, stabilizing agents, anti-static agents, swelling agents, coatings, barrier layer formulations, and any combinations thereof.

[00213] As those of skill would recognize, a single excipient can fulfill more than two functions at once, e.g., can act as both a binding agent and a thickening agent. As those of skill will also recognize, these terms are not necessarily mutually exclusive.

[00214] Examples of commonly used excipient include water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, and the like, as well as combinations thereof. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols, such as mannitol, sorbitol, or sodium chloride in the composition. Additional examples of pharmaceutically acceptable substances are wetting agents or auxiliary substances, such as emulsifying agents, preservatives, or buffers, which increase the shelf life or effectiveness.

[00215] In embodiments, the CD38 inhibitor is formulated as a spray. Preferably, then, the pharmaceutical composition is for nasal administration or administration by inhalation / is administered nasally or by inhalation.

[00216] In embodiments in which the pharmaceutical composition is for nasal administration, the pharmaceutical composition can be formulated as:

• A nasal powder - a dry powder formulation inhaled through the nose. Nasal powders may be formulated using bulking agents to increase the volume of the powder and improve handling (e.g., lactose, mannitol, and microcrystalline cellulose), stabilizers to help maintain the stability of the active pharmaceutical ingredient (e.g., trehalose and sucrose), a mucoadhesive agents to enhance the residence time of the powder on the nasal mucosa (e.g., chitosan and carbomers), an absorption enhancers to improve the permeability of the nasal mucosa to the active pharmaceutical ingredient (e.g., bile salts and surfactants like polysorbates), and lubricants to improve the flow properties of the powder (e.g., magnesium stearate and talc). Nasal powders can be administered using spray devices: these devices are designed to disperse the powder into fine particles (aerosol) that can be inhaled through the nose. They often use a mechanical pump or pressurized aerosol to achieve this.

• A nasal liquid spray - a liquid formulation delivered into the nostrils using a pump or aerosol device. Nasal liquid sprays may be formulated using a liquid or an emulsion to suspend the carboxyalkyl starch microparticles (e.g., water, ethanol, and propylene glycol, glycerin and polyethylene glycol), emulsifying agents to stabilize the emulsion (e.g., polysorbates and lecithin), preservatives to prevent microbial growth (e.g., benzalkonium chloride and parabens), buffering agents to maintain the pH (e.g., sodium phosphate and citric acid), and viscosity enhancers to improve the residence time on the nasal mucosa (e.g., hydroxypropyl methylcellulose and carbomers). Nasal liquid sprays can be administered using spray devices: these devices are designed to deliver a fine mist of the liquid formulation into the nostrils. They also often use a mechanical pump or pressurized aerosol to achieve this.

• Nasal drops - a liquid formulation administered drop by drop into the nostrils. Nasal drops may be formulated using a liquid to suspend the carboxyalkyl starch microparticles (e.g., water, ethanol, propylene glycol, glycerin and polyethylene glycol), preservatives, buffering agents, and viscosity enhancers to improve the residence time on the nasal mucosa (e.g., hydroxypropyl methylcellulose and carbomers Nasal drops can be administered using dropper bottles: these bottles are designed to deliver the liquid formulation drop by drop into the nostrils. They often use a squeeze mechanism to achieve this.

• A nasal gel - a semi-solid formulation applied inside the nostrils. Nasal gels may be formulated using liquids to suspend the active pharmaceutical ingredient (e.g., water, ethanol, and propylene glycol), gelling agents to create the semi-solid consistency (e.g., carbomers and hydroxypropyl methylcellulose), preservatives, buffering agents, and humectants to keep the nasal mucosa moist (e.g., glycerin and sorbitol). Nasal gels can be administered using applicators: these devices are designed to deliver the gel formulation into the nostrils. They often use a squeeze mechanism or a pre-filled syringe to achieve this.

• A nasal insert - a solid dosage form placed inside the nostrils to release the active pharmaceutical ingredient over time. Nasal inserts may be formulated using bioadhesive polymers to prolong the contact time with the nasal mucosa (e.g., polycarbophil and hydroxypropyl cellulose), stabilizers (e.g., trehalose and sucrose), absorption enhancers, and plasticizers to improve the flexibility and reduce the brittleness of the insert (e.g., glycerin and polyethylene glycol). Nasal inserts can be administered by being placed inside the nostrils: these inserts are designed to release the active pharmaceutical ingredient over time, providing controlled and sustained active pharmaceutical ingredient delivery.

• A nasal film - a thin film applied to the nasal mucosa and dissolve to release the active pharmaceutical ingredient. Nasal films may be formulated using bioadhesive polymers, plasticizers, stabilizers (e.g., trehalose and sucrose), and absorption enhancers. Nasal films can be administered by placing the thin film inside the nostrils: these films are designed to dissolve upon contact with the nasal mucosa, releasing the active pharmaceutical

• A nasal foam - a foam formulation that expand upon administration to cover a larger surface area of the nasal mucosa. Nasal foams may be formulated using liquids to suspend the carboxyalkyl starch microparticles (e.g., water, ethanol, and propylene glycol), foaming agents to create the foam structure (e.g., sodium lauryl sulfate and polysorbates), stabilizers (e.g., trehalose and sucrose), preservatives, and viscosity enhancers. Nasal foams can be administered using foam dispensers: these devices are designed to deliver the foam formulation into the nostrils. They often use a mechanical pump to achieve this.

[00217] In preferred embodiments, the pharmaceutical composition of the invention is formulated as a nasal powder, preferably formulated as a nasal spray.

[00218] In embodiments in which the pharmaceutical composition is for administration by inhalation, the pharmaceutical composition can be formulated as: • a suspension containing microparticles dispersed in a liquid medium. They are commonly used in metered- dose inhalers (MDIs). They are designed to be administered via inhalation, allowing the drug to be delivered directly to the lungs for local or systemic effects. Such a suspension may be formulated using suspending agents to maintain the uniform distribution of microparticles (e.g., hydroxypropyl methylcellulose and carboxymethyl cellulose), surfactants to reduce surface tension and improve particle dispersion (e.g., polysorbates and sorbitan esters), preservatives, and stabilizers (e.g., citric acid and sodium citrate). Suspensions for metered-dose inhalers (MDIs) can be manufactured by dispersing the active ingredient and excipients in a liquid medium, using high-shear mixing or ultrasonic energy to reduce particle size and ensure uniform distribution, and then filling the suspension into pressurized containers equipped with metering valves. This method ensures accurate dosing and effective drug delivery.

• a dry powder - a fine powder that is inhaled using a dry powder inhaler (DPIs). They are used for medications such as bronchodilators and anti-inflammatory drugs. They are designed to be inhaled using a dry powder inhaler (DPI), allowing the drug to be delivered directly to the lungs for local or systemic effects. They may be formulated using bulking agents to increase the volume of the powder and improve handling (e.g., lactose, mannitol, and microcrystalline cellulose), stabilizers (e.g., trehalose and sucrose), mucoadhesive agents to enhance the residence time of the powder on the respiratory mucosa (e.g., chitosan and carbomers), and lubricants.

• an aerosol - a formulation in which the drug is suspended in a propellant and delivered as a fine mist. MDIs are a common device for aerosol delivery. It may be formulated using propellants to create the pressure needed to deliver the drug as a fine mist (e.g., hydrofluoroalkanes (HFAs) and chlorofluorocarbons (CFOs)), surfactants to stabilize the suspension and ensure uniform distribution (e.g., lecithin and oleic acid), solvents to dissolve or suspend the active ingredient and excipients (e.g., ethanol and water), and preservatives. Aerosols for metered-dose inhalers (MDIs) can be manufactured using the cold filling method: this involves cooling the propellant and active ingredient mixture to a low temperature, filling the mixture into aerosol containers, and then sealing the containers with metering valves. This method ensures accurate dosing and effective drug delivery.

[00219] The CD38 inhibitor may be contained in an inhaler or a nasal spray comprising a canister containing the CD38 inhibitor or the pharmaceutical composition of the invention, an atomizer for dispersing the pharmaceutical composition into an aerosol, and an outlet to disperse the aerosol into the nose or mouth of a patient.

[00220] The CD38 inhibitor may be injected parenterally; this being intramuscularly, intravenously, or subcutaneously. For parenteral administration, the CD38 inhibitor may be used in the form of sterile solutions containing solutes for example, sufficient saline or glucose to make the solution isotonic. Fluid unit dosage forms may be prepared by utilizing the CD38 inhibitor and a sterile vehicle (i.e., sterile water alone or combined e.g., with a PEG, such as PEG400), and, depending on the concentration employed, the CD38 inhibitor may be either suspended or dissolved in the vehicle. Other suitable vehicles may include olive oil, ethyl oleate, and glycols. If needed, a suitable quantity of lidocaine hydrochloride may also be included. Once in solution, the CD38 inhibitor may be injected, and filter sterilized before filling a suitable vial or ampoule followed by subsequently sealing the carrier or storage package. Adjuvants, such as a local anesthetic, a preservative, or a buffering agent, may be dissolved in the vehicle prior to use. Stability of the pharmaceutical composition may be enhanced by freezing the composition after filling the vial and removing the water under vacuum (e.g., freeze drying). Parenteral suspensions may be prepared in substantially the same manner, except that the CD38 inhibitor should be suspended in the vehicle rather than being dissolved, and, further, sterilization is not achievable by filtration. The CD38 inhibitor may be sterilized, however, by exposing it to ethylene oxide before suspending it in the sterile vehicle. A surfactant or wetting solution may be advantageously included in the composition to facilitate uniform distribution of the CD38 inhibitor.

[00221] The CD38 inhibitor may also be administered via transdermal routes using dermal or skin patches.

[00222] The CD38 inhibitor may be administered orally in the form of tablets, coated tablets, capsules (including softgel capsules), or granules, containing suitable excipients non-limiting examples of which are starch, lactose, white sugar, and the like. The CD38 inhibitor may be administered orally in the form of solutions which may contain coloring and/or flavoring agents. The CD38 inhibitor may also be administered sublingually in the form of tracheas or lozenges in which the active ingredient(s) is/are mixed with sugar or corn syrups, flavoring agents, and dyes, and then dehydrated sufficiently to make the mixture suitable for pressing into solid form.

[00223] The solid oral compositions may be prepared by conventional methods of blending, granulation, compression, coating, filling, tabletting, or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art. The tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.

[00224] Oral liquid preparations may be in the form of emulsions, suspensions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water alone or combined e.g., with a PEG, such as PEG400; or other suitable vehicle before use. Such liquid preparations may or may not contain conventional additives. Non limiting examples of conventional additives include suspending agents such as sorbitol, syrup, natural gums, agar, methyl cellulose, gelatin, pectin, sodium alginate, hydroxyethyl cellulose, carboxymethylcellulose, aluminum stearate gel, or hydrogenated edible fats; emulsifying agents such as sorbitan monooleate or acacia; non-aqueous vehicles (which may include edible oils) such as almond oil, fractionated coconut oil, oily esters selected from the group consisting of glycerine, propylene glycol, ethylene glycol, and ethyl alcohol; preservatives such as for instance methyl para- hydroxybenzoate, ethyl para-hydroxybenzoate, n-propyl parahydroxybenzoate, n-butyl parahydroxybenzoate or sorbic acid; and, if desired conventional flavoring such as saccharose, glycerol, mannitol, sorbitol, or coloring agents.

[00225] The CD38 inhibitor may be administered in the form of suppositories. Suppositories may contain pharmaceutically acceptable vehicles such as cocoa butter, polyethylene glycol, sorbitan, esters of fatty acids, lecithin, and the like.

[00226] In an embodiment of the present disclosure, the pharmaceutical composition is in the form of a unit dose or dosage form, such as an oral dosage form. The unit dose presentation forms for oral administration may be tablets, coated tablets and capsules and may contain conventional excipients. Non-limiting examples of conventional excipients include binding agents such as acacia, gelatin, sorbitol, or polyvinylpyrrolidone; fillers such as lactose, dextrose, saccharose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants such as talc, stearic acid, calcium or magnesium stearate, polyethylene glycols (PEG), gums, gels; disintegrants such as starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulphate.

[00227] In an embodiment, the composition or unit dose comprises a saline solution. In another embodiment, the composition comprises PEG, preferably a low-molecular-weight grade PEG such as PEGw.ln an embodiment, the composition or unit dose comprises from about 10 or 20% to about 70 or 80% of PEG, for example from about 20% to about 60%, from about 30% to about 50%, or from about 35% to about 45% of PEG, preferably a low-molecular- weight grade PEG such as PEG^o.ln a further embodiment, the composition or unit dose comprises about 40% of PEG, preferably a low-molecular-weight grade PEG such as PEG400.

[00228] The above-noted composition or unit dose may be a sustained or delayed release composition or dosage form. Delayed release of the active ingredient (CD38 inhibitor described herein) can be effected by the use of one or more release-delaying and/or release-sustaining agents. Any combination of release-delaying and/or release- sustaining agents may be used in the composition described herein. A release-delaying agent acts to increase the period before release begins from a dosage form, and a release-sustaining agent acts increase the period of time during which the active ingredient is released from a dosage form. The length of the lag period before delayed release occurs and the rate of release can by controlled using methods known to those of skill in the art, for instance by varying the choice, combination, form, shape and/or amount of release-delaying agent(s) and/or release- sustaining agent(s).

[00229] The delayed or sustained release formulations can be prepared, for example, by coating active ingredient or an active ingredient-containing composition with one or more release-delaying agent(s)and/or release-sustaining agent(s). In other instances, the release-delaying agent(s) and/or release-sustaining agent(s) can be intermixed with or in co-solution with the active ingredient. For example, delayed release by osmotic rupture can be achieved by a dosage form comprising one or more swelling agents that are contained in combination with the active ingredient within a semipermeable coating. The increase in volume of the swelling agent upon exposure of the unit dosage form to bodily fluids causes the semipermeable coating to rupture. In such agents, both the swelling agent and the semipermeable coating can be considered to be release-delaying agents. Thus, delayed release can be achieved by a combination of release-delaying agents, where each release-delaying agent does not necessarily delay release by itself.

[00230] Delayed release and/or sustained can be achieved by various processes such as dissolution, diffusion, erosion (e.g., based on the inherent dissolution of the agent and incorporated excipients), and/or rupture (e.g., by swelling). Common mechanisms include bulk erosion of polymers which restrict diffusion of the drug, surface erosion, (e.g., of layered medicaments), or rupture. Rupture can be osmotically controlled, for instance by swelling that results from the osmotic infusion of moisture. Rupture can also result from the reaction of effervescent agents, e.g., citric acid/sodium bicarbonate, with water or other fluids that penetrate into the dosage form. Release, including delayed release, from a unit dosage form can be achieved by more than one mechanism. For example, release can occur for example by simultaneous swelling and diffusion, simultaneous diffusion and erosion, and simultaneous swelling, diffusion, and erosion.

[00231] Two common classes of release-delaying agents are "enteric" (allowing release within a specific milieu of the gastro-intestinal tract) and "fixed-time" (allowing release after a “predetermined” or “fixed” time period after administration, regardless of gastro-intestinal milieu), each of which is discussed in more detail below. Enteric release-delaying agents for instance allow release at certain pHs or in the presence of degradative enzymes that are characteristically present in specific locations of the Gl tract where release is desired. The formulation may comprise more than one release-delaying agent from any class, such as a combination of enteric and fixed-time release- delaying agents. In another embodiment, the release-delaying agent allows the release of drug after a predetermined period after the composition is brought into contact with body fluids ("fixed-time delayed release"). Unlike enteric release, fixed-time release is not particularly affected by environmental pH or enzymes.

[00232] A large number of fixed-time release-delaying agents are known to those of ordinary skill in the art. Exemplary materials which are useful for making the time-release coating of the invention include, by way of example and without limitation, water soluble polysaccharide gums such as carrageenan, fucoidan, gum ghatti, tragacanth, arabinogalactan, pectin, and xanthan; water-soluble salts of polysaccharide gums such as sodium alginate, sodium tragacanthin, and sodium gum ghattate; water-soluble hydroxyalkylcellulose wherein the alkyl member is straight or branched of 1 to 7 carbons such as hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose; synthetic water-soluble cellulose-based lamina formers such as methyl cellulose and its hydroxyalkyl methylcellulose cellulose derivatives such as a member selected from the group consisting of hydroxyethyl methylcellulose, hydroxypropyl methylcellulose, and hydroxybutyl methylcellulose; other cellulose polymers such as sodium carboxymethylcellulose, cellulose acetate, cellulose acetate butyrate and ethyl cellulose; and other materials known to those of ordinary skill in the art. Other film-forming materials that can be used for this purpose include poly(vinylpyrrolidone), polyvinylalcohol, polyethylene oxide, a blend of gelatin and polyvinylpyrrolidone, gelatin, glucose, saccharides, povidone, copovidone, poly(vinylpyrrolidone)-poly(vinyl acetate) copolymer. Other materials which can be used in the time-release coating include Acryl-EZE®, Eudragit® NE, RL and RS, hydroxypropylcellulose, microcrystalline cellulose (MCC, Avicel™ from FMC Corp.), poly(ethylene-vinyl acetate) (60:40) copolymer (EVAC from Aldrich Chemical Co.), 2-hydroxyethylmethacrylate (HEMA), MMA, and calcium pectinate can be included. Substances that are used as excipients within the pharmaceutical industry can also act as release-delaying agents.

[00233] Common types of fixed-time release dosage forms include erodible formulations, formulations that undergo osmotic rupture, or unit dosage form that use any combination of mechanisms for delayed release.

[00234] Fixed-time release-delaying agents can optionally achieve a delayed-burst release by osmotic rupture. Examples of such release-delaying agents include swelling agents, osmogens, binders, lubricants, film formers, pore formers, coating polymers and/or plasticizers. [00235] The release-delaying agent may comprise an "enteric" material that is designed to allow release upon exposure to a characteristic aspect of the gastrointestinal tract. In an embodiment, the enteric material is pH- sensitive and is affected by changes in pH encountered within the gastrointestinal tract (pH-sensitive release). The enteric material typically remains insoluble at gastric pH, then allows for release of the active ingredient in the higher pH environment of the downstream gastrointestinal tract (e.g., often the duodenum, or sometimes the colon). In another embodiment, the enteric material comprises enzymatically degradable polymers that are degraded by bacterial enzymes present in the lower gastrointestinal tract, particularly in the colon. Optionally, the unit dosage form is formulated with a pH-sensitive enteric material designed to result in a release within about 0-2 hours when at or above a specific pH. In various embodiments, the specific pH can for example be from about 4 to about 7, such as about 4.5, 5, 5.5, 6, 6.5 or 7.

[00236] Materials used for enteric release formulations, for example as coatings, are well known in the art and include, but are not limited to, cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, methylcellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate and carboxymethylcellulose sodium; acrylic acid polymers and copolymers, preferably formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate, and other methacrylic resins that are commercially available under the trade-name Acryl-EZE® (Colorcon, USA), Eudragit® (Rohm Pharma; Westerstadt, Germany), including Eudragit® L30D-55 and L100-55 (soluble at pH 5.5 and above), Eudragit® L-IOO (soluble at pH 6.0 and above), Eudragit® S (soluble at pH 7.0 and above, as a result of a higher degree of esterification), and Eudragits® NE, RL and RS (water-insoluble polymers having different degrees of permeability and expandability); vinyl polymers and copolymers such as polyvinyl pyrrolidone, vinyl acetate, vinylacetate phthalate, vinylacetatecrotonic acid copolymer, and ethylene-vinyl acetate copolymer; enzymatically degradable polymers such as azo polymers, pectin, chitosan, amylose and guar gum; zein and shellac. Combinations of different enteric materials may also be used. Multi-layer coatings using different polymers may also be applied. The properties, manufacture and design of enteric delivery systems are well known to those of ordinary skill in the art. See, e.g., Development of Biopharmaceutical Parenteral Dosage Forms (Drugs and the Pharmaceutical Sciences), by Bontempo (Publishers: Informa Healthcare (July 25, 1997).

[00237] The pharmaceutical composition of the invention may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the CD38 inhibitor. The pack or dispenser device may be accompanied by instructions for administration. Compositions comprising the CD38 inhibitor formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. Suitable conditions indicated on the label include the abovementioned TH2 inflammation-associated conditions.

Combination Therapy

[00238] In preferred embodiments, the CD38 inhibitor is used in combination with one or more other pharmaceutically active ingredient(s). Therefore, the method, use, treatment, and pharmaceutical composition of the invention comprises the use of the CD38 inhibitor with one or more other pharmaceutically active ingredient(s).

[00239] The one or more other pharmaceutically active ingredient(s) may be a prophylactic agent and/or a therapeutic agent.

[00240] The CD38 inhibitor and other pharmaceutically active ingredient(s) may be administered in a single dosage form or in separate dosage forms; these being conventional dosage forms as described above.

[00241] Herein, co-administration refers to the administration of the CD38 inhibitor with one or more other pharmaceutically active ingredient(s) in the course of a coordinated treatment to achieve an improved clinical outcome. Such co-administration may also be coextensive, that is, occurring during overlapping periods of time. For example, a CD38 inhibitor may be administered to a patient before, concomitantly, before and after, or after the one or more other pharmaceutically active ingredient(s) is(are) administered.

[00242] In preferred embodiments, the one or more other pharmaceutically active ingredient(s) is for preventing or treating the TH2 inflammation-associated condition. In an embodiment, the CD38 inhibitor is used/administered in combination with one or more other pharmaceutically active ingredient already used by the subject to prevent or treat the TH2 inflammation-associated condition.

[00243] In embodiments, the one or more other pharmaceutically active ingredients is a one or more other CD38 inhibitor, wherein these one or more other CD38 inhibitors are as described above.

[00244] In embodiments, the one or more other pharmaceutically active ingredients include glucocorticoids, beta-2 agonists, muscarinic antagonists, antimicrobials, antibiotics, antihistamines, leukotrienes modifiers, probiotics, TRP channel modulators, anthelmintics, fungicides, antifibrotic agents, PARP modulators, an immunotherapeutic agent, and/or hyaluronic acid.

[00245] In preferred embodiments, the one or more other pharmaceutically active ingredients is a glucocorticoid.

[00246] Herein, “glucocorticoids” (also called “glucocorticosteroids”) refers to a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor.

[00247] Non-limiting examples of glucocorticoids including 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; and RU-28362.

[00248] In most preferred embodiments, the glucocorticoid is triamcinolone; dexamethasone; momethasone; fluticasone; hydrocortisone; prednisolone; betamethasone; beclomethasone; ciclesonide; amcinonide; flunisolide; or budesonide.

[00249] Non-limiting examples of beta-2 agonists or muscarinic antagonists include 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; and zilpaterol.

[00250] In most preferred embodiments, the beta-2 agonist or muscarinic antagonist is formoterol; salmeterol; vilanterol; albuterol; umeclidinium; or salbutamol.

[00251] Non-limiting examples of antimicrobials include cetylpyridinium chloride; chlorhexidine; clove; eucalyptol; hydrogen peroxide; mandelic acid; menthol; methyl salicylate; peppermint; povidone iodine; tea tree oil; thymol; triclosan; and xylitol.

[00252] Non-limiting examples of antibiotics include 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; and vancomycin.

[00253] Non-limiting examples of antihistamines include 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; and rynatan.

[00254] Non-limiting examples of leukotriene modifiers include montelukast; zileuton; pranlukast; and zafirlukast.

[00255] Non-limiting examples of TRP channel modulators include camphor; capsaicin; clemizole; flufenamic acid; ginsenoside Rd; icilin; menthol; neomycin sulfate; parthenolide; peimine; peiminine; piperine; resiniferatoxin; riluzole; sumatriptan; and tranilast. [00256] Non-limiting examples of anthelmintics include albendazole; diethylcarbamazine; ivermectin; mebendazole; miltefosine; moxidectin; praziquantel; pyrantel pamoate; and triclabendazole.

[00257] Non-limiting examples of fungicides include azoxystrobin; benomyl; captan; carbendazim; chlorothalonil; copper oxychloride; cyproconazole; fludioxonil; mancozeb; metalaxyl; propiconazole; sulfur; tebuconazole; thiophanate-methyl; trifloxystrobin; and zineb.

[00258] Non-limiting examples of immunotherapeutic agents include 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; and TQC2731.

[00259] Non-limiting examples of PARP modulators include niraparib; olaparib; rucaparib; and talazoparib.

Other Definitions

[00260] The use of the terms "a" and "an" and "the" and similar referents in the context of describing the technology (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[00261] The terms "comprising", "having", "including", and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to") unless otherwise noted.

[00262] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context.

[00263] The use of any and all examples, or exemplary language (“e.g.”, "such as") provided herein, is intended merely to better illustrate embodiments of the claimed technology and does not pose a limitation on the scope unless otherwise claimed.

[00264] No language in the specification should be construed as indicating any non-claimed element as essential to the practice of embodiments of the claimed technology.

[00265] Herein, the term "about" has its ordinary meaning. The term “about” is used to indicate that a value includes an inherent variation of error for the device or the method being employed to determine the value, or encompass values close to the recited values, for example within 10% of the recited values (or range of values).

[00266] Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All subsets of values within the ranges are also incorporated into the specification as if they were individually recited herein.

[00267] Where features or aspects of the disclosure are described in terms of Markush groups or list of alternatives, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member, or subgroup of members, of the Markush group or list of alternatives.

[00268] Unless specifically defined otherwise, all technical and scientific terms used herein shall be taken to have the same meaning as commonly understood by one of ordinary skill in the art (e.g., in stem cell biology, cell culture, molecular genetics, immunology, immunohistochemistry, protein chemistry, and biochemistry).

[00269] Unless otherwise indicated, the preclinical work, and immunological techniques utilized in the present disclosure are standard procedures, well known to those skilled in the art. Such techniques are described and explained throughout the literature in sources such as, Ed Harlow and David Lane (editors) Antibodies: A Laboratory Manual, Cold Spring Harbour Laboratory, (1988), J. E. Coligan et al. (editors) Current Protocols in Immunology, John Wiley & Sons (including all updates until present), Ali S. Faqi (editor), A Comprehensive Guide to Toxicology in Nonclinical Drug Development, 3rd Edition, (2024), Academic Press, Magdalena M. Gorska (editor), Asthma: Methods and Protocols, Methods in Molecular Biology, Vol. 2506, (2022), Humana Press.

[00270] Other objects, advantages and features of the present invention will become more apparent upon reading of the following non-restrictive description of specific embodiments thereof, given by way of example only with reference to the accompanying drawings.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[00271] The present invention is illustrated in further details by the following non-limiting examples.

Example 1 ■ Efficacy of WX-001 on TH2 Inflammation and Barrier Dysfunction in a Murine Model of CRS

Experimental Procedures

Treatment

[00272] Herein, WX-001 is 4-((trans-4-(2-Methoxyethoxy)cyclohexyl)amino)-1-methyl-6-(thiazol-5-yl)quinolin- 2(1 H)one, supplied from Future Chemical Industry Col., Ltd., Jinan City, Snahndong Province, China, corresponding to compound 78c of 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.

Animal Model and Rationale

[00273] Male BALB/c mice (8-9 weeks old; 23 to 28 g) were selected for their documented susceptibility to TH2 - skewed inflammatory responses, mimicking human CRS pathophysiology. A minimum number of animals per group (3 to 6) was used to allow statistical analysis while minimizing animal use.

Sensitization and induction of Chronic Rhinosinusitis

[00274] Chronic Rhino Sinusitis (CRS) was experimentally induced using a combination of ovalbumin (OVA) and staphylococcal enterotoxin B (SEB), following a sensitization and challenge protocol that mimics TH2 -mediated upper airway inflammation. On Day 0, mice were sensitized via intraperitoneal (i.p.) injection with 0.9 mg of OVA and 77 μL of alum adjuvant suspended in 0.1 mL of phosphate-buffered saline (PBS). On Day 7, a second sensitization was performed using 0.45 mg of OVA with 77 μL of alum in 0.1 mL PBS. Control animals received PBS and alum only. Beginning on Day 14, mice were intranasally challenged with 1 mg of OVA dissolved in 20 μL PBS (10 μL per nostril) daily for 11 consecutive days. This repeated challenge promoted localized inflammation within the nasal passages. To induce epithelial dysfunction and further amplify the inflammatory response, SEB (25 ng) was administered intranasally on Days 1, 3, 7, 13, 15, 17, 19, 21 , 23 and 25. The SEB administration synergizes with the OVA-induced response by stimulating TNF-α expression and enhancing TH2 cytokine activity. This protocol is intended to produce a murine phenotype closely resembling human CRS with TH2 inflammation and nasal polyps, characterized by eosinophilic infiltration, goblet cell hyperplasia, and nasal epithelial remodeling.

Experimentai Groups and Treatment

[00275] Five experimental groups were studied:

1 . Vehicle only (no CRS) - 3 mice received PBS without OVA/SEB sensitization or drug treatment.

2. CRS + vehicle - 6 mice induced with CRS and administered PBS.

3. CRS + WX-001 low dose - 6 mice induced with CRS and treated with 10 mg/kg/day of WX-001 orally via gavage.

4. CRS + WX-001 high dose - 6 mice induced with CRS and treated with 20 mg/kg/day of WX-001.

5. CRS + vehicle + budesonide - 6 mice induced with CRS treated with intranasal budesonide (1 mg/kg).

[00276] WX-001 was administered once daily via oral gavage in phosphate-buffered saline (PBS) as vehicle. Budesonide was delivered intranasally in a total volume of 20 μL per administration.

Endpoints and Measurements

[00277] At sacrifice, the following evaluations were performed:

• Macroscopic and physiological assessments: Body weight changes and signs of infection were recorded.

• Cytokine profiling: Cytokines and chemokines were measured from the Nasal Lavage Fluid (NLF) supernatant using the Eve Technologies Mouse Cytokine/Chemokine 68-Plex Discovery Assay® (MD68), supplemented with IL-33 and TGF- . Figures are shown with one-way ANOVA, where a p-value less than 0.05 is marked with one star and a p-value is less than 0.01 with two.

Histopathology: Nasal tissues, including lateral sinuses and middle turbinates, were collected and processed for histological examination. Staining includes picrosirius red (PSR), periodic acid schiff (PAS), and hematoxylin & eosin.

[00278] Specific analyses include epithelial thickness, Goblet cell hyperplasia and hypersecretion (PAs) and Fibrosis (PSR).

Cytokine Results and Discussion

[00279] Cytokines tested showed that nasal lavage of murine sinuses in WX-001 test article groups have overall anti-inflammatory effects through reduction of cytokines in a CRS mouse model, including 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 Interferon beta (Figures 1 , 2, 3, 4, 5, 6, 7). Budenoside was used as an anti-inflammatory positive control in the preclinical murine CRS model.

[00280] IL-13 was diminished in a statistically significant manner in both treatment groups as well as the budesonide positive control group (Figure 1). IL-13 is a pleiotropic TH2 cytokine involved in TH2 I and TH2 inflammation- associated conditions. In those diseases and conditions, IL-13 favors the development of eosinophilic inflammation by promoting mucus production, tissue remodeling, airway hyperresponsiveness, and IgE class switching. Indeed, TH2 cells secrete IL-13, which together with IL-4 stimulate heavy-chain class switching to IgE. Allergen-activated mast cells contribute to the production of IL-4 and IL-13. As such, the diminishing of IL-13 supports usefulness of CD38 inhibitors for treating allergies.

[00281] IL-13 is predominantly produced by TH2 cells and ILC2 but also mast cells, eosinophils, NK cells, basophils, macrophages, dendritic cells and granulocytes. In CRS and asthma, IL-13 is responsible for initiating inflammatory responses and plays important roles in disrupting the nasal epithelial barrier integrity. IL-13 in AD leads to an increased susceptibility to skin infections, particularly from S. aureus. IL-13 triggers changes in epithelial and smooth muscle cells leading to tissue hypersensitivity reactions. The downregulation of IL-13 by WX-001 constitutes a clear indication that WX-001 counteracts TH2 inflammation.

[00282] TGF-beta 1 and TGF-beta 3 isoforms were strongly diminished in the treatment groups, along with the positive control budesonide, in statistically significant manners (Figure 2). The TGF-beta family has a critical signaling role in fibrosis, tumorigenesis and regulating immune responses. TGF-beta regulates tissue homeostasis at physiological conditions, inflammatory progression and wound healing in pathological conditions. TGF-beta is critical in the development and progression of TH2 inflammation-associated conditions, it is overexpressed in chronic inflammation, fibrosis, asthma, AD, CRS and COPD. In fact, fibrosis, which TGF-beta modulates, is a key feature in many TH2 inflammation-associated conditions.

[00283] Both IL-33 and IL-31 were shown to be downregulated by WX-001 treatment groups in a statistically significant manner (Figure 3). IL-33, an alarmin cytokine from the IL-1 family, protects from infections. As such, IL-33 acts as an initial innate signal of invasion shaping the adaptive immune response to TH2. IL-33 is mainly expressed in epithelial and endothelial cells and is also viewed as a first line of defense against microbes shaping adaptive immune responses. IL-33 is a strong inducer of TH2 immune responses and is involved in recruitment of inflammatory cells to the airways in allergic diseases. IL-33 contribution to asthma development has been clearly identified. IL-33 promotes lung fibrosis and bronchial remodeling in asthma. IL-33 can induce I L-5-producing TH2 cells and promote airway inflammation. IL-33 is involved in the development of eosinophilic airway inflammation in nonatopic COPD patients. Polarized TH2 cells, mast cells and basophils produce enhanced amounts of TH2 cytokines in response to IL-33 and eosinophils are amongst major responder cells. Tissues of CRSwNP are characterised by elevated expression of IL-33, and findings support the notion that IL-33 plays a crucial role in the pathogenesis of neutrophilic inflammation in patients with CRS. IL-33, which is up-regulated by IFN-gamma, contributes to the TH2 response and may enhance chronicity in CRSwNP. Elevated IL-33 levels were observed in recalcitrant CRS. The overexpression of IL-33 is associated with eosinophilia in CRS.

[00284] IL-31 and IL-33 secreted from epithelial cells are known to induce and boost the TH2 response by activating ILC2 cells and stimulating TH2 cell maturation. IL-31 and IL-33 were identified as having roles in the pathophysiology of chronic inflammation of the skin, including AD. In AD, IL-31 produced by TH2 cells and mast cells promotes pruritus and inflammation, whereas IL-33 from keratinocytes promotes TH2 cytokine response, induces expression of IL-5 and IL-13, and enhances eosinophils and immunoglobulins in keratinocytes. IL-31 works with other cytokines to upregulate mucin gene expression and mucus production in eosinophilic CRS and elevated levels of serum eosinophils correlate with IL-31 levels in patients with allergic CRS and asthma. The present results illustrate the impact IL-31 and IL-33 reduction can have on TH2 -associated inflammatory conditions.

[00285] Rantes, fractalkine, IP-10 and MIP-3 alpha and RANTES are chemokines shown here to be downregulated by WX-001 in Figure 4. IP-10, Rantes and fractalkine have functions as TH2 chemokines. CD38 is known to be implicated in chemotaxis and immune cell activation. Rantes is chemotactic for T cells, eosinophils, and basophils into inflammatory sites. Rantes has been implicated in eosinophilic disease driven by TH2 cells. T cells may produce Rantes to recruit eosinophils and other inflammatory cells in the airways. Fractalkine promotes TH2 cell survival in airway allergic reactions such as allergic rhinitis and asthma and was found to be linked with the development of allergic asthma in studies in mice. Studies have demonstrated elevated concentrations of IP-10 in nasal lavage fluid from allergic patients, suggesting a role in chronic TH2 inflammation. MIP-3 alpha is chemotactic for T cells and immature dendritic cells and can enhance the accumulation of intracellular calcium in these cells. MIP-3 alpha can recruit immature dendritic cells at sites of TH2 inflammation.

[00286] IL-12p40, IL-12p70, IL-23 and IL-27 cytokines were shown here to be lower with WX-001 treatment groups (Figure 5). IL-23 and IL-27 belong to the IL-12 superfamily of cytokines. IL-12 p40 exerts antimicrobial effects. IL-23 promotes expansion and maintenance of TH 17 cells. I L-12p40 and IL-23 are produced by antigen-presenting cells such as dendritic cells and macrophages in response to early innate signals. IL-23 was considered significant in the antigen-dependent activation of both TH2 and TH 17 cells and important in the active phase of allergic respiratory tract inflammation. Results in a mouse model of allergic rhinitis suggested that IL-17A and mostly IL-23 are significant in the pathology of allergic rhinitis. IL-23 signaling was shown to enhance TH2 polarization and regulate allergic airway inflammation. [00287] The benefits of blockade or deletion of IL-12 and IL-23 subunits in reducing intestinal inflammation have been demonstrated in models of UC. IL-12 expression is elevated in lamina propria mononuclear cells from patients with Crohn’s disease. The IL-23 receptor was found to be an IBD susceptibility locus. Different genes within the IL- 23-TH17 pathway have been associated with altered risk for both Crohn’s disease and UC. IL-12 family of cytokines in intestinal inflammation led to the development of biological agents that target IL-12 and/or IL-23. The local milieu of cytokines and other mediators affect T cell activation and differentiation which differs in different pathophysiological scenarios. TGF-(3 can inhibit the effect of IL-27 on TH1 differentiation. IL-27 has been shown to be expressed in the synovial tissue and fluids of RA joints. Studies revealed both anti- and pro-inflammatory activities of IL-27 on RA. As mentioned, IBDs and RA have been linked to TH2 responses.

[00288] IL-2 was reduced in the WX-001 treatment groups (Figure 6). IL-2 is involved in the initiation and amplification of T cells, including TH2 -type immune responses when induced by an antigen. IL-2 signalling in TH2 cells induces early expression of I L-4Ra. TH2 cell differentiation appears to require stimulation by IL-2. TH2 transcription factors GATA3 expression and STAT5 activation through IL-2 are essential for the initial stages of TH2 cell differentiation. T cells can produce IL-2 and lung ILC2 were shown to require IL-2 for co-stimulation of cytokine production in vitro. TH2 -derived IL-2 induces ILC2 proliferation and IL-13 secretion. In a direct cell to cell effect, ILC2 promotes TH2 polarization in in vitro co-culture of ILC2 with TH2 cells. A study demonstrated in patients with CRSwNP that, with concurrent IL-33 and IL-2 stimulation, ILC2 expressed significantly elevated levels of IL-13. Nevertheless, IL-2 may be more considered an early cytokine, which guides the fate of both TH1 and TH2 cells, and serves to demonstrate that the WX-001 therapeutic intervention could lower inflammation in patients with TH2 I.

[00289] Interferon gamma and Interferon beta were also decreased by treatment with WX-001 (Figure 7). These cytokines are generally associated with TH1 responses, showing that WX-001 not only has TH2 response modulating activities, but may be considered to generally anti-inflammatory, counteracting the TH1 response in addition to TH2. Interferon gamma provides pro-inflammatory responses responsible for killing intracellular parasites and perpetuating autoimmune responses. It is possible that the current CRS model displays some TH1 inflammation responses considering the use of the Staphylococcal enterotoxin B to stimulate epithelial dysfunction and exacerbated inflammation, which has been shown at higher doses to induce more TH1 cells and a lower TH2/TH1 ratio. Interferon gamma was shown to be involved in SLE which has been associated with TH2 responses. Interferon gamma is considered a major driver of excessive immune response, leading to massive leukocyte infiltration and mucosal damage in IBD.

Histology Results and Discussion

[00290] Photomicrographs with detail of level 2 sections of the nasal septum on Figure 8 show collagen distribution with picrosirius red staining (PSR) in the murine mouse model of CRS. Red (or opaquer on black and white) indicates collagen accumulation in the nasal septum, a marker for fibrosis. PSR is commonly used by those skilled in the art to determine fibrosis via distribution of collagen in healthy and fibrotic tissue sections using histological techniques.

[00291] After the 28 day-study, the untreated CRS animal has consistently more collagen deposition (Figure 8B) when compared to a healthy animal (Figure 8A). The therapeutic intervention with WX-001 (Figure 8C) demonstrates a clear reduction in the deposition of collagen when compared to the untreated CRS animal (Figure 8B). Deposition was also reduced in the budesonide positive control (Figure 8D), albeit the reduction in collagen was less evident than with WX-001 (Figure 8C). These results show that WX-001 clearly reduces fibrosis in a murine model of CRS, consistent with the observed reduction in TGF-beta.

[00292] The epithelial thickening was evident in the vehicle (untreated CRS) group in the murine mouse model of CRS (Figure 8B). The therapeutic intervention with WX-001 clearly reduces epithelial thickness (Figure 8C) to near normalcy (Figure 8A). So does the budesonide (Figure 8D), however the reduction in epithelial thickness seems less marked than in the treatment group (Figure 8C). Reduction in epithelial thickness highlights improvement in epithelial dysfunction seen in the vehicle group by the treatment with WX-001 , also which may be considered consistent with the observed reduction of IL-33.

[00293] Goblet cell hyperplasia was verified in Figure 9 by histology. The periodic acid schiff (PAS) staining reveals polysaccharides in the goblet cells, namely mucin secreted in the nasal epithelium of CRS mice. In Figure 9A healthy mice present no apparent mucin secreted from goblet cells. In Figure 9B, the CRS mouse model administered with vehicle displays evident goblet cell hyperplasia with hypersecretion of mucin. Figure 9C shows that WX-001 reduced goblet cell hyperplasia comparably in numbers to the budesonide positive control group (Figure 9D), as five goblet cells could be counted with WX-001 (Figure 9C, bottom), and six with budesonide in this detail of the nasal septum (Figure 9D, bottom), versus fourteen for the CRS group (Figure 9B, bottom). The strength of the PAS staining was fainter in the budesonide group, making counting difficult, also demonstrating a reduction in mucin hypersecretion in this group. Interestingly, if there were fewer goblet cells in the WX-001 group, the visible goblet cells were significantly larger than with other groups. The hypertrophy of the goblet cells is likely due to the blockade of secretion of mucin by WX-001 which lingers inside the goblet cells. Indeed, the secretion of mucin is calcium- dependent, and NAD consumption by CD38 leads to the synthesis of cADPR which regulates calcium release. Thus, the blockade of cADPR production is herein considered to lead to the abrogation of calcium release, and the inhibition of mucin secretion on Figure 90.

[00294] An elevated intracellular calcium concentration can activate downstream pathways involved in the regulation of TH2 I for calcium-dependent processes. cADPR is a mediator of intracellular calcium signaling contributing to various physiological processes by regulating calcium homeostasis. Fibroblasts, the primary cells involved in forming fibrotic tissue, rely heavily on calcium signaling to regulate their activity. In pulmonary fibrosis, enhanced Ca2+ signaling promotes fibroblast proliferation, differentiation, and extracellular matrix production, contributing to tissue scarring. Calcium-dependent processes include also histamine degranulation from mast cells. A calcium signal is essential for degranulation, generation of eicosanoids and optimal production of cytokines in mast cells in response to antigen and other stimulants. The signal is initiated by inositol 1,4,5-trisphosphate resulting in release of stored calcium from the endoplasmic reticulum and Golgi. Airway smooth muscle cells are dependent on ryanodine receptors and calcium release for contraction and IL-13 has been shown to regulate smooth muscle cell contraction via histamine-induced calcium transients which highlights the effect of IL-13 and calcium signaling on airway hyperresponsiveness in asthma. In immune cells, the serine/threonine phosphatase calcineurin dephosphorylates and activates nuclear factor of activated T cells (NFAT) which can then translocate to the nucleus where it binds to NFAT binding sites leading to the transcription of genes central to TH2I such as IL-4, IL-5, and IL-13. Therefore, enzymatic inhibition of CD38 is anticipated to reduce the TH2 response by modulating calcium signaling in immune cells. The effects of calcium signaling, and cADPR, are pleiotropic in TH2 inflammation, not only in immune cell signaling, but epithelial and subepithelial cell signaling. As such, it is noteworthy to mention the existence of paracrine signaling with CD38.

Example 2 - Case Report for CD38 Inhibition in a Human Subject with Chronic Rhinosinusitis with Nasal Polyps

[00295] A 50-year-old male subject with chronic sinusitis with nasal polyps (CRSwNP) had anosmia, nasal congestion, thick mucus rhinorrhea, posterior rhinorrhea and facial pressure commencing in 2013. The subject was formally diagnosed in the fall of 2013 by computed tomography (CT) (Figure 10A). The coronal shows prevalence of nasal polyps throughout the sinuses and intense sinus opacification consistent with CRSwNP. The subject reported a seasonality in overall CRSwNP symptoms with increased symptoms from August to October and was diagnosed with ragweed pollen allergy. The subject reported thick mucus secretions, anosmia, important nasal congestion, Aspirin- Exacerbated Respiratory Disease and Alcohol Hypersensitivity. The patient reported using budesonide in nasal rinse which reduces nasal congestion but that did not reduce thick mucus secretions nearly as well. The subject had had a functional endoscopic sinus surgery (FESS) under general anesthesia in 2015, with reoccurring symptoms and polyps within a year.

[00296] The subject had an exacerbation of CRS in 2023 involving an acute sinus infection with increased symptoms of nasal congestion and thick mucus secretions. The subject was treated with antibiotics and had a FESS in-clinic with a vacuum-powered microdebrider (Olympus single-use CELERIS) in October of 2023. The CT scan prior to in-clinical polypectomy (4 months prior to procedure) is shown on Figure 10B.

[00297] The sense of smell was restored a few days post surgery, however anosmia returned the week post polypectomy. The subject started using a CD38 inhibitor a few weeks after the in-clinic FESS. The subject had noticed some improvement in symptoms when using apigenin, a natural low potency inhibitor of CD38. The subject then started taking daily between 40 to 85 mg of 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 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.

[00298] The subject had a CT scan post polypectomy in 2024 7 months post FESS procedure, showing there was no recurrence of nasal polyps (Figure 10C). The submucosal edema across the osteomeatal complex and maxillary sinuses was largely reduced, when compared to the situation prior to FESS. The nasal polyps in the ethmoid and sphenoid sinuses are still present as they were not removed upon the in-clinic FESS. As such there did not seem to be reoccurrence, or growth of new nasal polyps. The subject reported that when taking the CD38 inhibitor the chronic nasal congestion disappeared. Difficulty in breathing through the nose was improved to the point of normalcy. There was very slight bleeding when blowing the nose during the first weeks of treatment which may have been caused by healing post polypectomy or reversal of the fibrotic phenotype. The maxillary ostia remained opened post in-clinic polypectomy, in the months that followed, as the nasal rinse filling the maxillary sinuses could be emptied by tilting the subject head forward and sideways. A nasal endoscopic examination performed 13 months following the in-clinic FESS (Figure 11), where we can see the inferior turbinate and nasal septum, shows no regrowth of nasal polyps.

[00299] When the subject kept using a corticosteroid nasal rinse BID as prescribed by the ENT physician, the nasal congestion was also reduced, the subject describing the effect as synergistic with the CD38 inhibitor. When taking only the budesonide corticosteroid nasal rinse, there was more mucus and postnasal drip. But with the CD38 inhibitor, the thick yellow discharges disappeared completely, and the appearance of nasal mucus was significantly clearer, with limited to no signs of over infection or inflammation, interestingly with enhanced cohesion of nasal mucus. The chronic nasal congestion gradually receded to mostly disappear. Nasal mucus became clear, with notably high surface tension in appearance. The subject also noticed return of olfaction. The effects observed on improvement of symptoms with CD38 inhibition were rapid for reduced mucus secretion, could be felt immediately for congestion, but also gradual to some extent as the chronicity in nasal congestion receded. Difficulty in breathing through the nose was significantly improved to normalcy. The subject was able to reduce and stop self-administration of CD38 inhibitor and budesonide over the longer run.

[00300] The scope of the claims should not be limited by the preferred embodiments set forth in the examples but should be given the broadest interpretation consistent with the description as a whole.

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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.

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

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

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 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.

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);

O 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 (XI I la), (XI I lb), or (XI lie),

a heterobicyclic amide of formula (XIV), a heteroaryl amide of formula (XV) or (XV*), or a 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 CD38 inhibitor is:

• 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-((2,2-difluoropropyl)amino)cyclohexyl)-5-(1H-midazol-1 -yI)-1H-pyrazolo[3,4-c]pyridine-7- carboxamide, corresponding to Example 193 of WO 2021/021986,

• 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, 172

2-(1 H-imidazol-1-yl)-N-(4-(2-methoxyethoxy)cyclohexyl)-6-methylpyrimidine-4-carboxamide, corresponding to Example 35 of W0 2021/207186,

• 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,

• 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,

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, 174

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,

• 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,

• 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,

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. 175

41 . 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. 176

55. 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. 177

61 . 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.